Objective
The main purpose of this trial is to investigate whether a 1-week fire needle plus cupping treatment is different from that of famciclovir plus gabapentin or whether fire needles cupping need to be combined with famciclovir better effect. The secondary objective is to analyse the correlation between the concentration of substance P and β-endorphin (b-Ep) in peripheral plasma and changes in pain intensity.
Study design
As show in Figure 1, this study is a three-arm open randomized controlled trial consisting of the following: (a) fire needles plus cupping arm, (b) famciclovir plus gabapentin arm, and (c) fire needles plus cupping plus famciclovir arm (Figure 2). After randomization, arms a and c receive 1 to 7 treatment sessions of fire needles cupping therapy within 1 week. The administration of gabapentin depends on the needs of the patient of arm b. In addition, all patients can receive temporary analgesics, so that a sufficient pain therapy is guaranteed. Visual analogue scale (VAS) scores, symptoms, and physical scores are obtained before and after treatment. The concentrations of SP and β-Ep in peripheral plasma before and after treatment are detected by enzyme-linked immunosorbent assay, and demand for temporary analgesics and side effects of the patients are recorded daily. After 6 months, the participants will be followed up for postherpetic neuralgia.
Participants and recruitment
This study will recruit 96 patients by postering public posters in dermatology and acupuncture clinics and the website of the Sixth Affiliated Hospital of Kunming Medical University. When a potential participant sees the poster who can contact the dermatologists Zuohui Liang and Xiuhong Liu through the contact phone on the poster. Both dermatologists will enroll the participant in the study if all inclusion criteria and no exclusion criteria are met. After signing a consent form, they will contact Dr. Shihua Li by phone to unpack the envelopes and randomize the participants. The formal trial recruitment began in November 2018. The assistant researcher will assess and record the baseline status of the participants.
In order to achieve adequate participants enrollment to reach target sample size, we have developed two strategies to attract patients and published them on the recruitment poster: all participants are free of charge for using the treatment methods mentioned in the study plan; for participants with postherpetic neuralgia six months later, the Acupuncture Department provides 10 free acupuncture treatments.
Randomisation and allocation concealment
1) Block setting: 96 participants will be numbered 1-96 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 96 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 96 envelopes and sealed, and all envelopes are numbered in order. 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.
The above work was completed by Shihua Li, an otolaryngologist at the Sixth Affiliated Hospital of Kunming Medical University. Shihua Li was not involved in the treatment of this study and was not involved in data collection.
The envelope will be opened according to the patient’s serial number, and the dermatologists will obtain the patient’s random number and arm assignment by telephone.
Blinding
Since the acupuncturists and subjects could not be blinded to the fire needle and cupping treatment, in order to reduce the bias, we will conceal the randomized grouping method and the results of the grouping of subjects, and provide sensory tests (outcome evaluators), data inspectors and statistical analysts who are not aware of the grouping and treatment of subjects.
Participating physicians
Participating physicians in the trial are doctors in the Departments of Dermatology and Acupuncture and moxibustion at the Sixth Affiliated Hospital of Kunming Medical University. Acupuncturists are responsible for the treatment of fire needles and cupping. All acupuncturists have received a master’s degree in acupuncture and moxibustion and have undergone training in unified fire needle and cupping treatment.
Patient and public involvement
Patients and/or public were not involved in the design of this study.
Participants
Inclusion criteria
- 18 to 60 years old;
- 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, etc .;
- 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;
Exclusion criteria
- Insulin-dependent diabetes mellitus or other diseases that affect peripheral sensitivity (eg, polyneuropathy, chronic pain syndrome);
- Bleeding tendency(eg, taking anticoagulants, coagulation dysfunction, thrombocytopenia, etc.);
- Pregnancy or lactation;
- Surgery within the past 3 months;
- Diseases affecting quality of life (eg, cancer, paralysis);
- Mental illness (eg, 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.
Dropout
Case dropout
(1) Subjects experienced other comorbidities, complications, or special physiological changes during the trial. They were not suitable to continue the trial.
(2) During the trial, serious adverse events and important adverse events occurr 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 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 withdraws by himself.
(6) Lost follow-up.
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 analyze its efficacy and safety. For all dropout cases, the test conclusion form and reason for dropout shall be filled in the case report form.
Intervention
FC arm
This arm will be treated with Fire needle cupping, instead of famciclovir hydrochloride and gabapentin.
- 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- Medical cotton ball, alcohol lamp, lighter, iodophor, etc.
- Operational methods: Routine disinfection of skin with iodophor, lesions in accordance with the order of the head, middle, and tail of herpes, first prick the head, herpes cluster as a unit to prick in turn. The left handheld 95% alcohol lamp is close to the needle position (10-15cm). The needle in the right hand is burned to whitening by the external flame of the fire. Then prick into blisters or rashes. The needle goes straight out and penetrates into the skin of the herpes to reach its base (depending on the size of the blister). Prick early-onset herpes at first. For larger pustules or blood blisters (diameter ³5cm) with a large-scale fire, 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 is pricked three times. Then, sterilize skin with iodophor again. The treatment should be performed once a day for a total of 7 days. (Note: If there is no herpes and no pain, stop the fire needle and cupping treatment; forpain without herpes, continue the fire needle and cupping treatment until the pain disappears.)
- Skin care: After treatment, iodophor is used to clean and disinfect the skin. Ask patients to keep their skin dry and clean during treatment.
Mechanism of fire needle cupping
Based on the theory of traditional Chinese medicine, herpes zoster is dampness and heat that blocks the meridians and collaterals, causing blood stasis and Qi stagnation, so it is painful.After being burned, the pinhole of the fire needle pricking the herpes wall is bigger, and it is not easy to close quickly. With the negative pressure absorption of the cupping, the damp heat and blood stasis in the herpes area will be completely discharged with the pinhole of the fire needle, making the Qi and blood unobstructed without pain. Previous studies have shown that fire needle cupping can accelerate crusting and shedding of herpes[14]; on the basis of conventional western medicine, the method of fire needle cupping can adjust the concentration of SP in serum, so as to accelerate the relief of local neuralgia in AHZ[15].
FG arm
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/d.According to the manufacturer’s (Jiangsu Hengrui Pharmaceutical Co., Ltd.) recommendation (Table 1), the initial dose of 300 mg/d is gradually increased to 900 mg per day and then increased according to the patient’s needs (maximum dose: 3600 mg/d).
Table 1 demonstrates the gabapentin intake scheme used to reach the wanted therapeutic dosage.
FCF arm
This arm will be provided with therapy of fire needle cupping and famciclovir. The usage of fire needle cupping of this arm is the same as FC arms. Usage and dosage of famciclovir hydrochloride of this arm is the same as FG arm.
Temporary analgesics
If the patient's pain can not be controlled below 50mm (VAS score) during the treatment, we will temporarily give additional analgesics. According to the recommendations of the World Health Organisation, all three groups are likely to receive standardized analgesic treatment: 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
Adverse events (symptoms or diseases occurring during the trial) will be recorded and assessed at each session of intervention. The adverse events mainly include 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.
Fllow up
All participants will be followed up by telephone 6 months after the end of treatment to ask if there is postherpetic neuralgia.
Outcomes
Primary outcome
Changes in pain intensity before and after treatment (VAS 0-100 mm, where 0 = painless and 100 = maximum imaginable pain).
Secondary outcomes
Substance P and b-Epin in peripheral venous blood will be detected by enzyme-linked immunosorbent assay before and after treatment.
Quantitative scoring methods were used to evaluate the symptoms and physical signs before and after treatment, including Pain intensity local itching burning sensation rash colour No. of blisters blisters clusters ulcers fever local lymphadenopathy rash area. In addition, there are analgesics demands side effects and follow up results. For details, please see 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. 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.
Statistical methods
Samplesize estimation
We will compare the difference in efficacy of three therapies in arm a, b and c. Sample size estimation is based on the method of Health Statistics [16]. Type I error alpha = 0.05, 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:
[Please see the supplementary files section to access the formula.]
wherePmax =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. The rate of loss of follow-up should not exceed 10%.
Statistical analysis
For details of baseline characteristics, please see Table 3.
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 (LOCF) 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 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. 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.