DOI: https://doi.org/10.21203/rs.3.rs-2236491/v1
Background: Postherpetic neuralgia (PHN) is pain that persists for 1 month or more after the shingles rash has healed, the incidence of which increases with age. Some patients with PHN will experience breakthrough pain (BTP), which is unpredictable and severe in intensity, and seriously affects patients' life quality and treatment compliance. The current clinical rescue programs are lagging behind and the effect is poor. Therefore, it has become an urgent clinical problem and research hotspot to explore timely and efficient treatment options for PHN patients with breakthrough pain. Oxycodone is widely used in the treatment of moderate to severe acute and chronic pain and cancer pain. In previous studies of cancer pain, oxycodone was found to have similar efficacy as morphine, with fewer adverse effects than morphine. The efficacy and adverse reactions of oxycodone in PHN with breakthrough pain have not been reported before. This trial intends to set up a study, using morphine as a reference, to explore the efficacy and safety of oxycodone in PHN patients with breakthrough pain, with the aim of exploring the best treatment option for patients with refractory PHN episodic pain.
Methods: This study is a prospective, double-blind, randomized controlled clinical trial involving 84 PHN patients with breakthrough pain (number of outbreaks ≥ 3 times/day, NRS score ≥ 7) hospitalized in the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. At the onset of painful outbreaks, rescue medication such as morphine patient controlled intravenous analgesia (PCIA) and equal amount of oxycodone PCIA will be given. The change in NRS score before and after the administration of the drugs and the effective rate of pain control will be evaluated to assess the efficacy and safety of the different regimens.
Discussion: We innovatively use oxycodone PCIA for the control of PHN episode pain, in order to shorten the duration of hospitalization and accelerate the recovery of patients. We hope to contribute our wisdom to the clinical problems that the current recue treatment of PHN breakthrough pain has significant lag and poor effect.
Trial registration number ChiCTR2200065358
As a common clinical neuropathic pain, postherpetic neuralgia (PHN) is often manifested as continuous or intermittent pain in the affected area after the healing of local skin herpes, which occurs in middle-aged and elderly people and those with low immunity. The clinical symptoms are varied and can be persistent burning pain, electric shock pain, intermittent stabbing pain, cutting pain, nociceptive hypersensitivity, sensory abnormalities and sensory dullness [1,2]. Existing data show that the annual incidence of herpes zoster is about 3 to 5‰, of which about 9% to 34% of patients will develop PHN. In addition, the incidence and prevalence of herpes zoster and PHN tend to increase gradually with age, about 65% of shingles patients aged 60 and above will develop PHN, and 75% of patients aged 70 and above will develop PHN, which seriously affects the quality of life of patients with shingles [3].
Breakthrough pain (BTP) refers to the malignant pain with transient and intense episodes that occur despite relatively stable background pain control and adequate application of analgesic drugs, generally occurring in the middle and late stages of oncology patients [4]. However, some PHN patients also suffer from breakthrough pain. The onset of pain is unpredictable and the pathological mechanism is complex, which not only seriously affects the daily activities of patients, leads to the decline of quality of life and treatment compliance, but also increases the expenditure of medical resources. Current clinical rescue analgesic regimens are lagging behind and have poor treatment outcomes [5]. Therefore, it has become an urgent clinical problem and research hotspot to explore timely and efficient treatment options for PHN patients with breakthrough pain.
The clinical characteristics of breakthrough pain in PHN are heterogeneous, with rapid onset (usually peaking at 5 minutes) and lasting only a few minutes or even tens of minutes, pose a challenge to the rapid effectiveness of rescue analgesic measures. The pain intensity is mostly moderate to severe. More than 40% of patients have sleep disorders, which seriously affect their quality of life. Up to 60% of patients have had suicidal thoughts. It is of great practical significance for exploring effective treatment options for BTP. The mechanism of BTP is complex, and studies have shown that varicella zoster virus (VZV) invades the host’s dorsal root ganglion, inflammatory demyelination changes occur in the damaged nerve fibers of the posterior roots of the spinal cord. And the involvement of the spinal ascending inhibitory conduction system leads to excessive excitatory signals afferents to the center, causing pathological changes in the peripheral and central nervous systems, resulting in persistent pain in the area of the affected nerve distribution, and central nervous system sensitization is the main cause of enlarged pain areas and recurrent transient pain in PHN patients [6,7]. In animal models of chronic pain, the release of presynaptic γ-aminobutyric acid (GABA) from the dorsal horn of the spinal cord is reduced after nerve injury, thereby failing to suppress nociceptive hyperalgesia and causing spontaneous or persistent pain attacks [8]. In a word, breakthrough pain in PHN is associated with enhanced pain signaling by central sensitization, manifested by an enlargement of the pain area (the actual pain area beyond the area of impaired nerve control), nociceptive sensory afferents beyond the usual pain, and repeated explosive episodes that reduce the patient's tolerance of the initiating pain sensation. At present, patients with PHN complicated with breakthrough pain are mainly treated with neurotrophic drugs, anti-neuropathic pain drugs and glucocorticoids as the basic treatment plan, and subcutaneous injection of morphine and other drugs for rescue analgesia during the BTP attack.
Oxycodone is a semi-synthetic opioid drug made from thebaine plant derivatives, which is a strong opioid analgesic and a pure opioid dual-receptor agonist, mainly acting on μ opioid receptors and κ opioid receptors in the central nervous system and smooth muscle to produce analgesia, and is widely used in the treatment of moderate and severe acute and chronic pain and cancer pain [9]. Previous studies [10] on cancer pain have found that oxycodone has similar efficacy as first-line drug morphine for moderate to severe cancer pain, but it has fewer adverse reactions than morphine: ① Gastrointestinal reactions such as nausea, vomiting and constipation are relieved; ② The risk of drug dependence and drug abuse is reduced, and it is less likely to cause side effects such as mental euphoria and respiratory depression; ③ Morphine is prone to drug resistance and needs to continuously increase the dose, and even significant hyperalgesia occurs in severe cases; ④ Strong opioids such as morphine and fentanyl reduce T cells and have immunosuppressive effects, but oxycodone has weaker immunosuppressive effects than morphine. This is due to the fact that oxycodone acts through dual opioid receptors and has a stronger binding force to κ receptors, and its analgesic effect is mainly achieved through κ receptors. The above-mentioned adverse reactions are mainly related to the action of μ receptors, which makes oxycodone comparable to morphine in terms of analgesic effects at equivalent doses with significantly fewer adverse effects. Studies comparing the efficacy of oxycodone and morphine have mainly focused on cancer pain in the past, while the mechanism of PHN breakthrough pain is similar to that of cancer pain to some extent. At present, morphine is mainly used for rescue analgesia. The efficacy and adverse reactions of oxycodone in PHN with breakthrough pain have not been reported before. In this project, we intend to set up a study, using morphine as a reference, to explore the efficacy and safety of oxycodone in PHN patients with breakthrough pain, with the aim of exploring the best treatment option for patients with refractory PHN episodic pain.
Oxycodone is available in a variety of dosage forms such as tablets, controlled-release tablets, injections, and suppositories, etc. There have been many studies at home and abroad on its application in PHN patients. Combined application with anti-neuropathic pain drugs (pregabalin, gabapentin) can effectively improve the clinical efficacy, shorten the course of disease recovery time, relieve pain symptoms more quickly, and improve patient satisfaction [11]. However, these studies mainly focused on the application of oxycodone controlled-release tablets in PHN, and did not evaluate the efficacy of PHN breakthrough pain. After all, breakthrough pain is a severe pain that has a rapid onset and short-lasting time. There is obviously a lag in the time-consuming to manage these pain flares even apart from the time consumption of medical staff issuing and executing medical orders. Then, the search for a dosing scheme that can indefinitely reduce the inevitable clinical time consumption between the onset of pain and the execution of analgesic medication, while allowing the drug to work as fast as possible, will hopefully significantly improve the clinical outcome of PHN breakthrough pain.
Patient controlled analgesia (PCA) is a treatment in which the physician pre-sets the dosage and administration of medication through an analgesic device according to the patient's physical condition and pain level, and then hands it over to the patient for self-administration [12]. When the patient is aware of pain or when the prodromal symptoms of pain appear, a single dosage analgesic drug is injected into the body through the controller, so as to achieve timely control of the breakthrough pain, which has the advantages of faster onset of action, no analgesic blindness, relatively stable blood concentration, individualized medication, and high patient satisfaction, and is currently mainly used for postoperative analgesia [13]. This technique has multiple routes of administration and can be classified according to different routes of administration: intravenous PCA (PCIA), epidural PCA (PCEA), subcutaneous PCA (PCSA) and peripheral nerve block PCA (PCNA), the most commonly used of which is PCIA, and oxycodone is one of the main analgesic opioids commonly used in PCIA. Based on the clinical characteristics of PHN breakthrough pain, the rapid onset of action of oxycodone intravenous application (2-3 min) and the advantages of PCIA in the control of BTP, it is reasonable to assume that oxycodone PCIA will be an excellent way for the treatment of PHN patient complicated with breakthrough pain.
In summary, this project will utilize our existing clinical foundation and equipment to conduct the following studies: taking morphine PCIA as a reference, PCIA of equal amount of oxycodone will be used for comparative observation to evaluate the efficacy and safety of different regimens on breakthrough pain in patients with PHN. We expect that the above study will provide a strong theoretical basis for the treatment of clinical PHN patients with breakthrough pain.
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.
The incidence of PHN is high and the social patient base is large. When it is combined with breakthrough pain, the severe pain will not only seriously affect the daily activities of the patient, lead to a decline in the quality of life and sleep, but also increases the expenditure of medical resources, and even more easily leads to patients' depression and even suicidal thoughts.
Breakthrough pain is a pain flare of a rapidly increasing intensity, usually lasting from several to tens of minutes. Breakthrough pain is usually superimposed on persistent pain, usually in the same location as the continuous pain, is paroxysmal in nature (several to a dozen or so episodes per day), and is characterized by rapid onset (several minutes), short duration (approximately 30 minutes), and high intensity (at least 7 points on a 10- point NRS scale) [19]. In order to control this kind of pain, it is often necessary to select supplemental analgesia (rescue medication) with rapid onset drugs and routes of administration to meet the characteristics of the pain episode. Common remedies are the use of short-acting opioids, such as short-acting morphine, immediate-release fentanyl patches, etc. The time-to-effect curve of oral opioids do not match the temporal characteristics of most BTP episodes, with a slow onset (analgesia onset: 20–30 min; peak analgesia: approximately 60 min) leading to delayed or ineffective analgesia, while the effect of prolonged duration (3–6 hours) prone to persistent adverse effects [20, 21]. A short onset of effect is commonly obtainable only with parenteral or transmucosal administration of opioid analgesics. Thus, we opt for subcutaneous opioid injections to rescue analgesia. Subcutaneous injection of morphine is one of the most commonly used drugs for supplemental analgesia in PHN patients during the onset of breakthrough pain, but due to the slow onset of subcutaneous administration and the fact that morphine is a pure µ-opioid receptor agonist, it is likely to cause adverse effects such as nausea, vomiting, respiratory depression and constipation in patients. Finding new rescue drugs and remedial modalities may provide new approaches to the treatment of breakthrough pain in PHN.
Oxycodone is a semi-synthetic opioid analgesic with high oral bioavailability and is the only dual-opioid receptor agonist used in clinical practice, with similar analgesic effects to morphine, but with significantly fewer µ-receptor-related adverse effects. It has obvious advantages over morphine in the control of moderate to severe cancer pain. Moreover, controlled-release oxycodone is an effective analgesic drug in the treatment of neuropathic pain, which can treat stable pain, paroxysmal spontaneous pain and allodynia [22]. However, there is no research report on the treatment of PHN breakthrough pain.
Based on the above characteristics of breakthrough pain and the potential advantages of oxycodone, we use morphine as a conference to conduct the first comparison of the efficacy of oxycodone and morphine. At the same time, taking into account the unique advantages of PCIA in controlling breakthrough pain, we innovatively use oxycodone PCIA for the control of PHN episode pain, in order to shorten the duration of hospitalization and accelerate the recovery of patients. We hope to contribute our wisdom to the clinical problems that the current recue treatment of PHN breakthrough pain has significant lag and poor effect.
PHN: postherpetic neuralgia
BTP: breakthrough pain
NRS: numerical rating scale
VZV: varicella zoster virus
GABA: γ-aminobutyric acid
PCA: patient controlled analgesia
PCIA: intravenous PCA
PCEA: epidural PCA
PCSA: subcutaneous PCA
PCNA: peripheral nerve block PCA
PSQI: the Pittsburgh sleep quality index
SF-36: the short form 36 health survey questionnaire
Ethics approval and consent to participate This study protocol has been approved by the Medical Ethics Committee of Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology (UHCT22492). All of the experimental procedures will be in accordance with the Declaration of Helsinki and its later amendments. All participants included in the study will be fully informed about the study and written informed consent will be obtained from all participants and/or their legal guardians. All data will be recorded and restored in compliance with ethical and data protection guidelines.
Consent for publication Not applicable.
Availability of data and materials The datasets analysed during the current study will be available from the corresponding author on reasonable request。
Competing interests The authors declare that they have no competing interests.
Funding This study was supported by the Bethune Charitable Foundation (ezmr2022-044). The funding body will not be involved in study design; collection, management, analysis, or interpretation of data; writing of the report; or the decision to submit the report for publication.
Authors' contributions SS, DY, QY and TZ contributed substantially to the study design. QY and SS drafted the manuscript. SS, YD, QY and TZ revised and approved the final version before submission. All authors read and approved the final manuscript.
Acknowledgements Not applicable.