This single-center, randomized, single-blind clinical trial was approved by the ethics committee of West China Hospital of Sichuan University (Version 2.0 of this protocol was approved on 30th December 2019, reference 2019) and has been prospectively registered at Chictr.org.cn (ChiCTR1900025828) on 10th September 2019. It will be conducted in Department of Pain management, West China Hospital, Chengdu, China from February 2020 to December 2020. The trial flowchart is shown in Fig. 1. Additional file 1 is the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. The schedule of enrollment, interventions, and assessments follows the SPIRIT Figure (Fig. 2).
A total of 98 participants will be randomly divided into two groups: control group and experimental group. Assessors who are blinded to the randomization will collect data during the intervention period at baseline, 1 weeks, 4 weeks, and 12 weeks in this study. The plasma levels of TNF-α、IL-6 in patients will be detected before and after ESWT to explore part of the biochemical mechanism of ESWT for the treatment of PHN.
The sample size was estimated based on the effect from a previous study which used effective rates as primary outcome (experimental group= 96%; control group = 77%). we used power analysis software (G *power 188.8.131.52) with the superiority test (one-tailed test with alpha = 0.05 and beta = 0.2). It was estimated that a sample size of 78 participants (39 participants per group). Considering potential drop out rate of 20%, a total of 98 participants will be enrolled in this study.
Patient and Public Involvement
There were no funds or time allocated for PPI so we were unable to involve patients. We have invited patients to help us develop our dissemination strategy.
Randomization and blinding
Patients will be randomly divided into control group or experimental group in a 1:1 ratio according to random numbers generated by EXCEL table. Sealed opaque envelopes were used for allocation concealment. A researcher will generate the allocation sequence, and another researcher will assign participants to interventions. The assessors and statisticians were blinded to randomization and did not participate in the treatment.
Patients in control group will receive conventional treatment including medication therapy and invasive interventional therapy.
Gabapentin (A daily dosage of 0.3g on the first day, 0.6g on the second day and 0.9g on the third day. Then 0.9g/d was maintained and the dosage could be adjusted according to patient's reaction)
Pregabalin (Starting dose of 75mg twice a day and adjust the dosage according to the actual situation of the patients)
Oxycodone and acetaminophen tablets (One tablet three times a day and adjust the dosage according to pain intensity)
Mecobalamin (0.5mg three times a day).
Invasive interventional therapy
Low dose Computed Tomography (CT) guided pulsed radiofrequency regulation (according to the patient's condition) will be administered.
The experimental group will be treated with ESWT in addition to conventional therapy. The patients could be in prone, lateral, or seated position depending on the painful area. ESWT will be performed with radial extracorporeal shockwave generator (MASTERPULS MP100; Storz Medical AG, Tagerwilen, Switzerland) and all treatments should be performed by the same therapist who is formally trained. After applying the ultrasonographic coupling agent to the skin of treated area, the patients will receive 5000-7000 pulses every session by a R15 probe (radius of 15 mm) at a frequency of 10 Hz, with energy gradually increasing from 1 to 4 bar depending on patients’ reaction. The therapist will move the probe in transverse or longitudinal directions along the nerve. The procedure was performed every 3-5 days and 3-5 sessions constitute a therapeutic course.
Age, gender, Body Mass Index (BMI), previous history, duration of PHN, painful segment, medication use, previous treatment will be obtained at baseline.
The visual analogue scale (VAS) will be used to access pain intensity at baseline, 1 weeks, 4 weeks, and 12 weeks after treatment in this study. VAS comprises of a horizontal line which is 10 centimeters long with terminal descriptors of 0 = no pain and 10 cm = worst imaginable pain(13). The participants marked the position on the line according to their degree of pain and the VAS score was determined by measuring the distance from 0 to the marked point.
Secondary outcome as follows will be collected at baseline, 1 weeks, 4 weeks, and 12 weeks after treatment.
- The quality of life will be accessed by 36-Item Short-Form Health Survey (SF-36) which measures three aspects of health including functional ability, wellbeing and overall health(14).
- Anxiety and depression are common mental disorders in patients with chronic pain(15). The psychological state of patients will be measured by Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS).
- Pittsburgh sleep quality index (PSQI) will be used for accessing the sleep quality, which includes 19 questions and seven components (perceived sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, sleep medications and daytime dysfunction)(16).
- Mechanical withdrawal threshold will be tested using Von-Frey hairs (Aesthesiometer, Somedic, Sweden) according to the methods by Moharić M et al.(17), which presents level of peripheral sensitization.
- The plasma levels of TNF-α、IL-6 in patients will be detected before and after ESWT to explore part of the biochemical mechanism of ESWT for the treatment of PHN.
Adverse reactions will be recorded including petechiae and swelling of the skin, allergy, fever, paresthesia, pain aggravated, tissue edema and other adverse effect related to ESWT. At the same time, incidence of adverse reactions will be analyzed as a measurement of safety. Serious adverse events refer to events that prolong hospitalization time, cause disability, affect ability to work or endanger life in clinical trials. Once serious adverse events have occurred, treatment should be suspended immediately and remedy actions should be taken appropriately and freely in time. The serious adverse events will be reported to the ethical committees and relevant responsible units to determine whether to stop the research.
Data management and statistical analysis
All original data will be stored in case report form (CRF) and any personal information will be protected. The study supervisor has access to the trial dataset and make the final decision to terminate the trial. Audits of the trial will be performed bimonthly. Data analysis will be performed by SPSS software (version 22; SPSS Inc, Chicago, IL, USA). Continuous data will be presented as mean ± standard deviation while categorical variables will be reported as numbers or percentages. The basic characteristics of participants will be described and compared by student’s t-test to ensure comparability. All statistical analysis followed the principle of intent-to-treat analysis. The difference in treatment effect between the two groups will be evaluated by one-way ANOVA while using the repeated-measures analysis of variance (RM- ANOVA) to analyze the changes over time in the group. The duration of PHN and painful segment, as potential factors, will be assessed using the logistic regression. All tests were single-sided, and p＜0.05 was considered statistically significant.