Study design
This study is a prospective, double-blind, randomized controlled clinical trial, carried out in the Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, and is expected to be conducted from 1 October 2022 to 31 December 2023. The design of this study protocol has referred to the Standard Protocol Items: Recommendations for Interventional Trials 2013 guideline [14], please see online supplemental material 1.
Study population
Inclusion criteria
1.Age between 18 and 90 years old.
2. PHN [15] patients with breakthrough pain (number of outbreaks ≥ 3 times/day, NRS score at the time of outbreak ≥ 7).
3. Patients ASA classification Ⅰ–Ⅲ.
4. Body mass index 18–27.9 kg/m2.
5. Able to give informed consent.
Exclusion criteria
1. Patients with allergic to morphine or oxycodone.
2. Patients with tumors causing immune deficiency and coexisting postherpetic neuralgia.
3. Patients with obvious decline in cognitive function.
4. Patients with serious physical diseases, including those with high-risk hypertension, respiratory failure, severe liver and kidney insufficiency, and severe cardiac insufficiency, etc.
5. Pregnant women or nursing mothers.
6. Patients who are unwilling to receive PCIA treatment.
7. Other circumstances that the investigator judges unsuitable to participate in the clinical trial.
Grouping and blind method
This study is a double-blind, randomized controlled study: the designated research coordinator, who does not participate in the follow-up study, will check the electronic medical record system and number patients with two-digit numbers according to the time of enrollment. Randomization of PM and PO groups will be generated by a statistician using SPSS 13.0 to generate block randomization details, with a random block size of 6. The random number and grouping details for each subject are placed in an opaque study envelope in a locked cabinet, handing over to the supervisor for storage and management. These envelopes are opened once the participant has signed a consent form. Once a random number is assigned, it will not be reused even if the subject originally assigned to it withdraws from the study.
PM group: morphine hydrochloride injection diluted with pump (50mg/100ml), PCIA parameters are set as follows: single injection dose 0.10mg/kg, lock time 4 hours, continuous infusion dose 0.1ml/h, loading dose set to 0.
PO group: oxycodone hydrochloride injection diluted with pump (50mg/100ml), PCIA parameters are set as follows: single injection dose 0.07mg/kg, lock time 4 hours, continuous infusion dose 0.1ml/h, loading dose set to 0.
Blinding the researchers: a designated study coordinator who is responsible for the preservation and preparation of drugs and information coordination among researchers. Assign a nurse to administer the drugs and record the participants’ basic information. Another researcher is follow-up person in charge of patient follow-up, as well as records data. Above-mentioned research workers will not know each other’s records during the whole study.
Blinding the patients: the intervention method for patients during the trial is intravenous electronic pump infusion, which will be performed strictly in a double-blind manner. We will use electronic micro-pumps of the same manufacturer, the same specification, and the consistent appearance, and there is no need to label the pump box with specific information such as the name of the drug. No masking of pump box is necessary as both Morphine Injection and Oxycodone Injection are clear, colorless liquids.
Interventions
Main instruments and drugs: patient-controlled intravenous analgesic pump, morphine hydrochloride injection, oxycodone hydrochloride injection.
Background pain management regimen for patients with PHN: All patients included in the clinical observation are routinely given pregabalin (Lot No. J20160021, Pfizer, USA), 75-225 mg PO BID; methylcobalamin tablets (Lot No. 150812, Eisai, Japan), 500 µg PO TID; and vitamin B1 (Lot No. H12020317, Jinshi, Tianjin), 10 mg PO TID. If the pain cannot be well controlled after 3 consecutive days of standard oral drug therapy, pulsed radiofrequency treatment (PRF) of the ganglion or peripheral nerve branches can be added on the basis of the drug regimen. According to the extent of the rash and pain area, the nerve segment invaded by the virus is determined and the corresponding puncture site is selected. Under the guidance of X-ray or ultrasound, we puncture the target location of the ganglion or peripheral nerve branch. After confirming that the needle tip is in a good position, connect the radio frequency instrument (RFG-1A radio frequency generator, COSMAN MEDICAL, USA), replicate the tingling sensation in the innervated area of the lesion with a current of 50 Hz and voltage of 0.3 V, and replicate the muscle tremor in the innervated area of the lesion with a current of 2 Hz and voltage of 0.5 V, followed by a PRF treatment at 42°C for 600 s.
Rescue analgesic regimen for PHN patients with breakthrough pain: The PM group used a patient-controlled intravenous pump configured after morphine hydrochloride injection dilution (50mg/100ml), with the following PCIA parameters setting: single injection dose of 0.10mg/kg, locking time of 4 hours, continuous infusion dose of 0.1ml/h and load Dose is set to 0. In the PO group, oxycodone hydrochloride injection is diluted with patient-controlled intravenous pump (50mg/100ml) and PCIA parameters are set as follows: single injection dose 0.07mg/kg, locking time 4 hours, continuous infusion dose 0.1ml/h and loading dose set to 0. If adverse reactions such as excessive sedation or respiratory depression occur in the two groups of patients after rescue analgesia, naloxone 2mg will be injected intravenously for resuscitation in a timely manner and repeated if necessary.
Recording of the rescue analgesia and numerical rating scale (NRS) scores: During hospitalization, the flare number and duration of BTP, the dosage of analgesic drugs and the number of presses and effective presses for PCA are recorded in PHN patients. The NRS scores are recorded before and 5 min, 10 min, 30 min, 2 h, and 4 h after rescue analgesia administration during hospitalization, and patients' NRS scores at rest and flare are recorded at 1 week, 2 weeks, 1 month, and 3 months after discharge. The proportion of achieving partial (reduction of NRS by 50% with respect to baseline) or total relief is calculated based on the recorded scores. (Figure 1)
Outcome measurements
The main observation indicators include the number and duration of breakthrough pain episodes, the dosage of analgesic drugs and the number of rescue analgesia, the NRS score and efficiency before and after medication, and the quality of sleep and life of patients (sleep quality is assessed by completion of the PSQI questionnaires and quality of life by completion of the SF-36 questionnaire). The secondary observation indicators include the occurrence of adverse reactions such as nausea, vomiting, constipation, urinary retention, respiratory depression and drug addiction, the length of hospital stay and satisfaction. (Figure 2)
Statistical analyses and sample size calculation
SPSS 13.0 software will be used for statistical analysis. All measurement data are expressed as mean ± SD. If the variances between groups are uniform, the measured values of each observation index among the groups are compared by ANOVA, otherwise, the rank sum test is used. The SNK-Q test is used for pairwise comparison within the group. The χ2 test is used to compare the count data, and P < 0.05 is considered statistically significant.
The primary variables for outcome measures are response rate and incidence of adverse events following rescue analgesia. Since there are no reports on the use of oxycodone PCA for breakthrough pain rescue analgesia in PHN, we referred to previous studies related to cancer breakthrough pain [16-18]. The adverse reaction rates after rescue analgesia with morphine and oxycodone were 58.9% and 48.8%, respectively. Taking the significance level α as 0.05, the test power 1-β as 0.8, the distribution of cases is expected to be 1:1, and 38 cases should be included in each group calculated by the software pass 15.0. Considering the dropout rate of 10% of enrolled personnel, 42 valid cases are finally included in each group. Therefore, a total of 84 patients are proposed to participate in the trial.
Patient and public involvement
Patients are not involved in the design, recruitment, or conduct of this study. Each patient will receive a "thank you letter" at the end of the final follow-up, and the findings will be disseminated to patients after they are published in a peer-reviewed journal.