Study design
This single-center, single-blind randomized clinical trial was approved by the Ethics Committee of West China Hospital, Sichuan University, Chengdu, China (Version 2.0 of this protocol was approved on 30th December 2019, reference 2019[814]) and has been prospectively registered at Chictr.org.cn (ChiCTR1900025828) on 10th September 2019. It will be conducted in the Department of Pain Management, West China Hospital, from February 2020 to December 2020. The trial flowchart is shown in Figure 1. Additional file 1 shows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. The schedule of enrollment, interventions, and assessments follows the SPIRIT checklist (Figure 2).
A total of 98 participants will randomized into a control group or an experimental group. Assessors blinded to the randomization will collect data during the intervention period at baseline and study weeks 1, 4, and 12. The plasma levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 will be detected before and after ESWT to explore the biochemical mechanisms of ESWT for the treatment of PHN.
Selection of the participants
Patients diagnosed with PHN according to the European Consensus-Based (S2k) Guideline on the Management of Herpes Zoster will be informed of this trial (12). Potential participants will be identified according to their medical record at the time of hospital admission. After a brief introduction about the trial, patients may decide whether they will participate in this study. Then detailed information will be acquired to assess patient eligibility according to following criteria (Table 1). All participants must sign the informed consent form before treatment. In the consent form, participants will be asked if they agree to use of their data after withdrawing from the trial. Participants will also be asked for the permission to share relevant data with university researchers and regulatory authorities. Participants will be informed that this trial does not involve collecting biologic specimens for the storage. Two physicians in the Department of Pain Management will approach the patients about taking part in the trial, enroll participants, and obtain their informed consent.
Table 1. Eligibility criteria
Inclusion criteria
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Exclusion criteria
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▪ Diagnosed with PHN
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▪ Allergic to medical ultrasonic couplant
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▪ VAS ≥4 points
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▪ History of tumor
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▪ Age ≥18 years
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▪ Liver or kidney dysfunction
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▪ Describe symptoms clearly and have ability to self-evaluate
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▪ Schizophrenia or dementia
▪ Cannot be followed up on schedule
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▪ Did not previously receive ESWT
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▪ History of thrombosis
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▪ Did not participate in other clinical trials within past 3 months
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▪ Disturbance coagulation function using anticoagulants
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▪ Cardiac pacemaker use
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▪ Infection in the pain area
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▪ Pregnant or puerperal patients
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▪ Fracture or severe osteoporosis
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Abbreviations: ESWT, extracorporeal shockwave therapy; PHN, postherpetic neuralgia; VAS, visual analogue scale
Sample size
The sample size was estimated based on a previous study that used effective rates as the primary outcome (experimental group, 96%; control group, 77%) (13). Power analysis software (G*Power, version 3.1.9.4) was used with the superiority test (one-tailed test [α, 0.05; ß, 0.2) and estimated a sample size of 78 participants (39 participants per group). Considering potential dropout 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 patient and public involvement so we were unable to involve patients. We have invited patients to help us develop our dissemination strategy.
Randomization and blinding
Patients will be randomized into a control group or experimental group in a 1:1 ratio based on random numbers generated by Excel spreadsheet. Sealed opaque envelopes were used for allocation concealment. A researcher will generate the allocation sequence, and another researcher will assign participants to the control or experimental group. The assessors and statisticians were blinded to randomization and did not participate in the treatment.
Interventions
Control group
Patients in control group will receive conventional treatment including medication therapy and invasive interventional therapy.
Medication therapy
1.Anticonvulsion medicine
Gabapentin: Starting dose of 0.3 g on day 1, 0.6 g on day 2, and 0.9 g on day 3; then a maintenance dose of 0.9 g/day, adjusted based on the patient's reaction.
Pregabalin: Starting dose of 75 mg twice a day; then adjusted based on the patient's reaction.
2.Opioid analgesics
Oxycodone and acetaminophen: 1 tablet 3 times a day, adjusted based on the patient's pain intensity.
3.Neural nutrients
Mecobalamin: 0.5 mg three times a day.
Invasive interventional therapy.
Pulsed radiofrequency regulation guided by low-dose computed tomography will be administered based on the patient's condition.
Experimental group
The experimental group will be treated with ESWT in addition to conventional therapy. The patient may be placed in the prone, lateral, or seated position depending on the painful area. Treatment with ESWT will be performed with a radial extracorporeal shockwave generator (MASTERPULS MP100; Storz Medical AG, Tägerwilen, Switzerland), and all treatments will be performed by the same therapist who is formally trained in ESWT. After applying the ultrasonographic coupling agent to the skin of treated area, the patients will receive 5000 to 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 the patient’s reaction. The therapist will move the probe in transverse or longitudinal directions along the nerve. The procedure will be performed every 3 to 5 days, and a total of 3 to 5 sessions constitute a therapeutic course.
Adherence monitoring
Patients or their family members will be asked to report the actual drug intake to ensure treatment compliance. In addition, the therapist will gradually increase the energy of shockwave from 1 to 4 bar and adjust the energy according to the patient’s reaction to improve adherence to the intervention.
Outcome measure
General conditions
The patient’s age, gender, body mass index, previous medical history, duration of PHN, area of nerve pain, medication use, and previous treatments will be obtained at baseline.
Primary outcome
The visual analogue scale (VAS) will be used to evaluate pain intensity at baseline and at study weeks 1, 4, and 12. This scale is a 10-cm horizontal line with terminal descriptors of 0 (no pain) and 10 (worst imaginable pain) (14). The participants will mark the line position according to their degree of pain, and the VAS score is determined by measuring the distance from 0 to the marked point.
Secondary outcome
Secondary outcomes will be collected at baseline and at study weeks 1, 4, and 12.
- Quality of life will be accessed by 36-Item Short-Form Health Survey (SF-36) which measures three aspects of health: functional ability, well-being, and overall health (15).
- Anxiety and depression are common mental disorders in patients with chronic pain (16). The psychological state of patients will be measured by the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS).
- Sleep quality will be assessed by the Pittsburgh Sleep Quality Index (PSQI), which comprises 19 questions and 7 sleep components: perceived sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, sleep medications, and daytime dysfunction (17).
- Mechanical withdrawal threshold will be tested using Von-Frey hairs (Aesthesiometer, Somedic, Sweden) according to the methods used by Moharić et al. (18) to indicate the level of peripheral sensitization.
- Plasma levels of TNF-α and IL-6 will be detected before and after ESWT to explore the biochemical mechanisms of ESWT for the treatment of PHN.
The researchers will provide medical advice to participants who complete follow-up to promote participant retention. Participants who discontinue or deviate from intervention protocols will be recorded in the case report form, and their data, including outcome, adverse event, and the reason of dropping out, will be analyzed for further discussion.
Safety evaluation
Adverse effects will be recorded, including petechiae and swelling of the skin, allergy, fever, paresthesia, pain aggravation, tissue edema, and any other reported adverse reactions to ESWT. In addition, incidence of adverse effects will be analyzed as a measurement of safety. Serious adverse events are described as events that prolong hospitalization time, cause disability, affect ability to work, or endanger life in clinical trials. If a serious adverse event occurs, treatment will be suspended immediately and remedy actions taken appropriately and freely in time. All serious adverse events will be reported to the Ethics Committee and relevant responsible research units to determine whether to stop the clinical trial.
Monitoring
An Independent Data Monitoring Committee (IDMC), which is separate from the trial sponsor and competing interests, will supervise the trial including assessment of the progress, safety data, and efficacy endpoints. The trial sponsor may decide whether to continue, modify, or stop the trial according to the recommendations of the IDMC. The Project Management Group will review the trial conduct monthly. The Trial Steering Group and the IDMC will review trial conduct every 3 months, and the Ethics Committee will review trial conduct annually.
Data management and statistical analysis
All original data will be stored in a case report form and any personal information will be protected. The study supervisor will have 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, and categorical variables will be reported as numbers or percentages. The basic characteristics of participants will be described and compared by the student 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 analysis of variance (ANOVA) with a repeated measures ANOVA to analyze the changes over time in the intervention group. The duration of PHN and painful segment, as potential factors, will be assessed using the logistic regression. All tests will be single-sided, and p<0.05 will be considered statistically significant. All statistical analysis will follow the principle of intent-to-treat analysis. The patients randomized to the intervention group but who do not adhere to the intervention will be included in the final data analysis. Imputation method will be used to handle missing data if the assumption of missing at random is met.