1. The research background and principle of elderly cancer patients are often faced with moderately severe pain, the pain management is particularly complex in this group. The physiological functions of the elderly decline, often accompanied by a decrease in renal function, which significantly limits the safe use of many standard opioid analgesics, such as morphine. The active metabolites of morphine tend to accumulate in patients with renal insufficiency, increasing the risk of neurotoxicity. Another commonly used drug, oxycodone, may cause a relatively high incidence of gastrointestinal adverse reactions. Hydromorphinone is a potent opioid drug, and its pharmacological properties may offer a solution to this predicament. It is mainly metabolized through liver glucoaldehyde acidification, generating inactive metabolites, and does not rely on the complex cytochrome P450 enzyme system. Therefore, the risk of drug interactions is relatively low, and theoretically, it has a smaller impact on kidney function, especially suitable for elderly patients with reduced kidney function. However, although there have been some studies on imported hydromoradone preparations, domestic hydromoradone hydrochloride sustained-release tablets (such as Ruining ®) have lacked prospective and systematic clinical evidence in the cancer pain population characterized by dual risk factors of "old age" and "renal insufficiency" since their launch. This study aims to fill this crucial gap in evidence.
2. The research design and methodology described in this study using prospective, observational cohort design. Unlike randomized controlled trials, this study aims to observe the natural outcomes of standardized treatment regimens in elderly patients with different renal function statuses under real-world conditions. All eligible patients enrolled in the group will receive a unified analgesic treatment plan based on international authoritative guidelines: Firstly, subcutaneous injection titration of hydromorphinone injection will be performed to quickly determine the individualized dose required for pain control; After the pain stabilized, it was uniformly converted to the same dose of domestic hydromorphinone sustained-release tablets for oral maintenance treatment once daily. The total treatment observation period was 4 weeks.
The key to the research lies in "hierarchical comparison". Before treatment, the investigators will naturally divide the patients into two cohorts based on their estimated glomerular filtration rate (eGFR, a core indicator for evaluating renal function) : the "Elderly with renal insufficiency group" and the "Elderly with normal renal function Group". In this way, the investigators can directly compare the performance differences of the drug in these two types of people with different physiological states.
The sample size calculation (planned to include a total of 62 patients) was based on the primary safety endpoint - the change in eGFR values relative to baseline at week 4 of treatment. A clinically significant effect size was preset during the calculation, and sufficient statistical certainty was ensured to guarantee the reliability of the research results.
3. The core assessment and monitoring framework in addition to conventional pain intensity assessment (NRS) adopting digital grading method, quality of living survey and common adverse reactions, this research established dual core security monitoring system:
Dynamic monitoring of renal function: Serum creatinine will be systematically detected and eGFR calculated at five time points before and during treatment. This is not only used to compare the differences between groups, but more importantly, to monitor the dynamic trajectory of each patient's individual renal function and promptly detect any clinically significant signs of deterioration.
Active screening for neurotoxicity (OIN) : In response to neurotoxic symptoms such as delirium, drowsiness, and myoclonus that may be caused by opioids, the study will conduct active screening and assessment once a week using a series of standardized scales, for example, using the Confusion Assessment method (CAM) to screen for delirium. This systematic monitoring aims to capture the incidence and characteristics of OIN more precisely.
4. Data analysis, statistical analysis strategy will use advanced statistical models to cope with the complexity of clinical data. For the primary endpoint (eGFR change), covariance analysis will be used to correct for baseline eGFR differences during statistical analysis, thereby more purer assessing the impact of the treatment itself on renal function. For data such as pain scores that are repeatedly measured at different time points, generalized estimating equations will be used for analysis to effectively utilize all the information of the longitudinal data. Furthermore, if a sufficient number of neurotoxic events are observed in the study, the investigators will conduct an exploratory analysis and attempt to construct a clinical risk prediction tool (nomogram) using a multi-factor regression model to identify high-risk patients with OIN.
5. The risk control and clinical patient safety is the primary consideration. The research protocol is equipped with clear safety suspension rules: once a patient's eGFR drops by more than 30% from baseline or falls within the range of severe renal failure, the study medication will be immediately suspended and a multidisciplinary consultation will be initiated. For patients with moderate to severe neurotoxicity, there are already pre-established alternative analgesic regimens (such as switching to fentanyl transdermal patches). The entire research was carried out on the "Standardized Cancer Pain Treatment Demonstration Ward" platform of Tai 'an Cancer Hospital. This team has mature cancer pain management and emergency response procedures.
6. The value of the research and production in this study beyond the simple answer of "analgesia is effective", focus on "in the vulnerable groups is safe" more pressing clinical problem. Its achievements are expected to provide value on three levels:
Direct evidence: It provides the first prospective efficacy and safety data for the application of domestic hydromoradone sustained-release tablets in elderly patients with renal insufficiency.
Clinical guidance: Clarify the adverse reaction spectrum of this drug in this population, especially its specific effects on renal function and the nervous system, to provide a basis for clinical dose adjustment and risk early warning.
Methodological demonstration: Demonstrate how to answer practical questions about medication safety for specific high-risk populations through rigorous observational studies and advanced statistical methods.
Through this research, the investigators hope to provide decision support based on localized drugs and high-level evidence for clinicians when treating this complex and vulnerable patient group, ultimately promoting the precision and safety improvement of cancer pain management in the elderly.
