Comprehensive Pain Management, Quality of Life, and Mental Health in Advanced Cancer: A Propensity Score-Matched Retrospective Study

Summary

This propensity score-matched study demonstrates that a multimodal pain management approach, combining standard analgesics with interventional, psychological, and palliative therapies, yields superior pain control, quality of life, and mental health outcomes, with reduced opioid escalation—suggesting potential benefits in mitigating opioid-related adverse events.

Abstract

For advanced cancer patients, unrelieved moderate-to-severe pain adversely affects quality of life and psychological well-being. While pain control is fundamental to palliative care, the benefits associated with a multimodal approach warrant investigation. This PSM-based retrospective study (2022–2025) evaluated the associations between comprehensive pain management and quality-of-life and mental health outcomes in advanced cancer. Participants received either comprehensive management (standard analgesics plus ≥1 adjunct modality: interventional oncology, thermotherapy, psychological counseling, or palliative support) or pharmacotherapy alone. One-to-one nearest-neighbor matching balanced demographics, disease status, and baseline pain severity. Primary endpoints (Numerical Rating Scale [NRS], Pain Management Index, European Organization for Research and Treatment of Cancer Quality of Life Core Scale, Hospital Anxiety and Depression Scale) were assessed at baseline and two weeks. Propensity matching yielded 60 balanced pairs from 150 patients (standardized mean differences < 0.1). At 2 weeks, multimodal therapy was associated with superior analgesia (NRS: 2.8 ± 1.1 vs 4.2 ± 1.3), higher response rates (58.3% vs 35.0%), and fewer undertreated cases (16.7% vs 41.7%) (all P < 0.05). Comprehensive care was associated with better functional capacity (68.5 ± 12.4 vs 55.3 ± 13.6), lower symptom burden (25.6 ± 8.9 vs 38.4 ± 11.2) (P < 0.001), and lower anxiety/depression scores (6.2 ± 2.8 vs 9.5 ± 3.1; 5.8 ± 2.5 vs 8.9 ± 3.0, P < 0.001). Opioid escalation was attenuated in the multimodal arm (47.26% vs 65.27%, P < 0.001), while adverse events were similar (P > 0.05). Regression identified comprehensive care as an independent correlate of better outcomes, and sensitivity analyses confirmed its robustness. In conclusion, comprehensive pain management was associated with superior pain control, better quality of life, and improved psychological outcomes in advanced cancer compared to standard analgesia, alongside reduced opioid escalation—a finding that may have clinical relevance for reducing opioid-related adverse events.

Introduction

In advanced malignancy, pain is a frequent and debilitating symptom that significantly impairs patients' quality of life, daily functioning, and mental health¹. According to epidemiological surveys, pain prevalence ranges from 54.6% to 69% among individuals with advanced-stage or metastatic malignancy², of which about 50% of patients with stage IV report moderate to severe pain, and a quarter of patients still experience severe pain that is difficult to control in the last week of life³. The pathophysiological mechanism of cancer pain is complex, often involving nociceptive, neuropathic, and mixed pain components, and breakthrough pain occurs frequently, which significantly interferes with the daily activities, sleep, social function, and emotional state of patients⁴.

Pain management is the core component of palliative care. The World Health Organization (WHO) three-step analgesia principle has long been used as the gold standard for cancer pain treatment, and strong opioids are the cornerstone for severe cancer pain treatment⁵. However, relying solely on drug analgesia has many limitations. First of all, ~30–40% of patients still cannot obtain satisfactory analgesia through standard drug treatment⁶. Secondly, prolonged opioid therapy commonly induces adverse effects, including constipation, nausea, and somnolence, while also posing risks of tolerance and potential misuse⁷. Moreover, the multidimensional nature of cancer pain determines that the simple biomedical model is difficult to comprehensively solve the pain of patients. Factors such as psychological pain, social isolation, and spiritual distress jointly affect the overall comfort of patients⁸.

In recent years, the comprehensive pain management model has gradually attracted attention, which is, on the basis of standardized drug analgesia, integrating multidisciplinary treatment measures such as interventional therapy, psychological support, physical therapy, and palliative care⁹. Multidisciplinary approaches facilitate holistic evaluation of cancer pain's complex dimensions, ultimately improving patient functioning and well-being^10,11. Tumor interventional therapy can provide precise pain relief for pain caused by soft tissue masses¹². Psychological counseling, such as cognitive behavioral therapy and mindfulness training, can help relieve anxiety and depression and improve pain perception¹³. The multidisciplinary team (MDT) of palliative care focuses on the overall comfort and meaning of life of patients¹⁴. The hypothesized advantages of comprehensive pain management for advanced cancer patients' quality of life and psychological status await confirmation through rigorous clinical research^9,10.

Despite the growing adoption of multimodal pain management in many centers worldwide, evidence for its benefits in specific populations and real-world settings remains limited. Most existing studies have been conducted in Western populations or specialized palliative care units, and data from Chinese community-based hospital settings are sparse. Furthermore, the comparative effectiveness of this approach versus standard pharmacotherapy alone—particularly after controlling for selection bias using propensity score methods—has not been extensively evaluated in Chinese populations with advanced cancer. Multidimensional assessments covering pain control, quality of life, psychological outcomes, and opioid consumption in a single cohort are also scarce.

To address these gaps, this retrospective investigation employed propensity score-matched (PSM) cohorts to evaluate associations between multimodal pain therapy versus conventional pharmacologic management and clinical outcomes—including pain relief, quality of life, and psychological well-being—in a Chinese community hospital setting. The following hypotheses were proposed: (i) patients receiving comprehensive pain management may show lower pain intensity and higher pain relief rate than those receiving standardized drug analgesia alone; (ii) Comprehensive pain management may be associated with better quality of life and mental health, including improved functional status, reduced symptom burden, and improvements in anxiety and depression; (iii) The multimodal analgesia group showed attenuated opioid dose increases, while adverse reaction frequencies remained similar across cohorts. By evaluating the aforementioned hypotheses, we aim to generate preliminary evidence guiding improved analgesic approaches in advanced malignancy.

Protocol

Study design and patient selection
This retrospective cohort study was conducted at Lezhi County People's Hospital. The study protocol was approved by the institutional ethics committee (Approval No. LRYLL202602) on March 12, 2026. Data extraction was initiated only after formal ethics approval was obtained. Clinical data were obtained from the institutional electronic medical records retrospectively and a dedicated pain management database for patients treated between June 1, 2022, and June 30, 2025. The institutional ethics committee waived the requirement for informed consent because this retrospective study analyzed previously collected, anonymized clinical data and posed minimal risk to participants. The investigation was conducted in accordance with the principles of the Declaration of Helsinki. An overview of the study design and patient selection is presented in Figure 1.

Patients were included if they were aged ≥ 18 years, had pathologically or cytologically confirmed advanced malignancy (clinical stage III or IV), experienced cancer-related pain with a Numerical Rating Scale (NRS) score ≥ 4 (moderate to severe pain) at enrollment, had an expected survival of ≥3 months, and possessed complete clinical records containing all necessary evaluation indicators¹⁵. Exclusion criteria comprised severe cognitive impairment or psychiatric disease that precluded cooperation with pain assessment and quality-of-life investigation, severe non-cancer pain (e.g., acute surgical or traumatic pain) that could confound evaluation, emergency admission or hospital stay < 72 h that prevented treatment completion and efficacy assessment, allergy to opioids or a history of opioid abuse, and missing key baseline data (e.g., primary assessment scales).

PSM was performed to minimize selection bias. Propensity scores were estimated via multivariable logistic regression, with treatment assignment as the dependent variable. Covariates were selected a priori and included age, sex, tumor type, stage, bone metastasis, Eastern Cooperative Oncology Group (ECOG) score, baseline NRS, and pain type. One-to-one nearest-neighbor matching without replacement was applied with a caliper of 0.2 standard deviation (SD) of the logit-transformed propensity scores. The target estimand was the average treatment effect on the treated (ATT). Common support was confirmed by visual inspection of propensity score overlap; no patients were excluded for non-overlap. Of the 150 initially enrolled patients, 30 cases (18 study, 12 control) did not satisfy the caliper and were excluded. The remaining 60 matched pairs (120 patients) achieved standardized mean differences (SMDs) < 0.1 for all covariates, confirming adequate balance.

Prior to PSM, 150 patients met the eligibility criteria and were enrolled, comprising 82 cases in the study group (comprehensive management) and 68 in the control group. Among the 82 patients initially assigned to the study group, 44 (53.7%) received ablation/TACE, 18 (22.0%) received hyperthermia, 52 (63.4%) received psychological counseling, and 34 (41.5%) received palliative care support. Combination therapy (≥2 adjunctive modalities) was administered to 43 patients (52.4%), with interventional treatment plus psychological counseling being the most frequent combination (n = 22, 26.8%), followed by interventional treatment plus palliative support (n = 12, 14.6%) and psychological counseling plus palliative support (n = 9, 11.0%). The remaining 39 patients (47.6%) received a single adjunctive modality.

Sample size calculation
The primary outcome for sample size estimation was defined as the between-group difference in post-treatment pain intensity measured by the NRS. Based on previous pilot experiments and multimodal analgesia research¹⁶, the assumed mean NRS reduction was 3.5 points for the study group and 2.0 points for the control group, with a pooled standard deviation of 2.0. A two-sided significance level (α) of 0.05 and a statistical power of 80% were specified. Using a two-sample t-test, the minimum required sample size was calculated to be at least 52 cases per group. Accounting for expected data loss during propensity score matching (estimated at 20%) and the inherent limitations of retrospective studies, we selected 60 cases per group for analysis, totaling 120 matched patients. To ensure an adequate number of matched pairs, 150 patients were initially enrolled in the database.

Treatment groups
In routine clinical practice, the analgesic strategy was determined by the attending oncologist based on MDT recommendations. The decision to add a specific adjunctive modality was guided by the predominant pain mechanism and clinical presentation. Specifically, interventional oncology (ablation/TACE) was recommended for pain originating from soft tissue compression; local deep hyperthermia was considered for pain associated with pleural/peritoneal effusions or superficial metastatic lesions; psychological counseling was offered to patients with significant emotional distress, maladaptive coping, or anxiety/depression symptoms; and palliative care support was provided to those with complex existential concerns, family conflicts, or multifaceted symptom burdens requiring comprehensive team-based management. Patients who received standard pharmacotherapy alone (control group) did not receive any of the above adjunctive modalities, typically due to patient preference, good initial response to opioids, or absence of MDT referral during the study period¹⁷.

For patients in the study group, each adjunctive modality was delivered in accordance with standardized institutional protocols. Ablation/TACE was indicated for symptomatic soft-tissue masses, depending on lesion size, location, and patient performance status. Hyperthermia was indicated for pain refractory to opioids in the setting of effusion-related or superficial metastatic lesions, applied locally using a deep hyperthermia device at 40–43 °C for 30–60 min per session, two to three times weekly, for a total of six sessions over 2 weeks. Psychological counseling, indicated for patients with elevated anxiety or depression scores (HADS-A or HADS-D ≥ 8) or self-reported emotional distress, comprised individual 30 min sessions once weekly, incorporating cognitive-behavioral techniques (cognitive restructuring, behavioral activation), relaxation training (progressive muscle relaxation, guided imagery), and psychological support, delivered by a trained clinical psychologist or licensed psychotherapist, for a total of two sessions during the 2 week study period. Palliative care support, indicated for patients with complex physical symptoms, existential distress, or family communication needs, was provided by an MDT (oncologist, palliative care nurse, social worker, and chaplain when available), including comprehensive symptom review, life review, family meetings, and advance care planning discussions, with team meetings conducted weekly and individualized interventions delivered as needed throughout the two-week period. Adherence to scheduled interventions was defined as completion of at least 80% of planned sessions. Overall adherence rates were 92% for psychological counseling, 88% for hyperthermia, and 95% for palliative care support; interventional treatment adherence was 100% since it was delivered as inpatient procedures under direct supervision.

Outcome measures
All outcomes were assessed at enrollment (baseline) and two weeks post-treatment by trained study staff who were not involved in clinical decision-making. Pain intensity was measured using the NRS (0–10)¹⁸, with pain response defined as a ≥50% reduction from baseline. Pain management quality was evaluated using the Pain Management Index (PMI)¹⁹, where a negative value indicated inadequate analgesia. The Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) was used to evaluate quality of life²⁰, with raw scores for functional and symptom domains linearly transformed to a 0–100 scale (higher scores indicated better function or worse symptoms, respectively). The Hospital Anxiety and Depression Scale (HADS)²¹ was administered to assess psychological well-being. It comprises separate anxiety (HADS-A) and depression (HADS-D) subscales, each scored from 0 to 21, with higher scores indicating more severe symptoms. Morphine equivalent daily dose (MEDD) was calculated at baseline and post-treatment to assess opioid requirement changes.

Adverse events associated with each treatment modality were assessed and graded in accordance with CTCAE version 5.0. Ablation-related grade 1-2 skin reactions (erythema, local warmth or superficial burns) occurred in 6 of 44 recipients (13.6%) with no grade ≥3 events. Hyperthermia-related local warmth sensation was reported by 12 of 18 recipients (66.7%), and mild superficial burns (grade 1) occurred in 2 patients (11.1%), both of which resolved with conservative management. No serious adverse events (grade ≥ 3) were attributed to hyperthermia. No specific adverse events were attributable to psychological counseling or palliative care support beyond those associated with standard pharmacotherapy. Importantly, the overall frequencies of common opioid-related adverse events (constipation, nausea/vomiting, somnolence, urinary retention, and respiratory depression) were compared between the two groups as secondary outcomes.

Statistical analysis
Data were analyzed using appropriate statistical software, with statistical significance defined as a two-sided P value < 0.05. The primary endpoint was defined as the between-group difference in posttreatment pain intensity (NRS). Secondary endpoints, analyzed in hierarchical order, included pain response rate, analgesic adequacy (PMI), quality-of-life (EORTC QLQ-C30), psychological distress (HADS), and opioid requirement changes. Sample size calculation, detailed in the preceding subsection, yielded 60 pairs after accounting for matching losses. For continuous variables, intergroup differences were assessed using paired t-tests for normally distributed variables (age, baseline NRS, hemoglobin, and post-treatment outcomes including NRS, EORTC QLQ-C30 domains, and HADS subscales) or Wilcoxon signed-rank tests for non-normally distributed variables (albumin, creatinine, and MEDD percentage increase). Distributional assumptions were evaluated with the Shapiro–Wilk test. Binary categorical variables were analyzed using McNemar's test, whereas variables with more than two categories were assessed using the McNemar–Bowker test. Change-score analysis (Δ values: post-treatment minus baseline) served as the primary approach for continuous outcomes. Multivariable linear regression models were constructed to identify independent correlates of improvements in outcomes (ΔEORTC functional domain, ΔHADS-A, and ΔHADS-D) using the full matched cohort in long-format data (n = 120). Covariates selected a priori included treatment group, age, sex, tumor type, cancer stage, bone metastasis, ECOG performance status, baseline NRS (for the quality-of-life model), and baseline HADS scores (for the psychological models). Multicollinearity was assessed using variance inflation factors (VIF > 10 excluded); model assumptions were verified via residual plots. No multiplicity adjustment was applied for primary and secondary endpoints, given their prespecified hierarchical order. Subgroup analyses stratified by tumor type and baseline pain intensity were performed on the matched pairs using paired t-tests. Sensitivity analyses—including kernel matching, inverse probability of treatment weighting (IPTW), and subgroup analyses—were conducted to test the robustness of the findings.

Results

Initially, 150 patients with advanced cancer who met the eligibility criteria were enrolled, comprising 82 in the study group and 68 in the control group. Following 1:1 PSM, 60 well-matched pairs were successfully generated, yielding a final analytical cohort of 120 patients. After matching, we observed no significant between-group differences across all evaluated covariates: demographics (age, sex, marital status, education), oncological factors (tumor type/stage, bone metastasis), functional status (ECOG), pain profile...

Discussion

Employing PSM in a retrospective cohort, we examined associations in pain control, quality of life, and psychological well-being between advanced cancer patients managed with multimodal pain therapy and those receiving standard pharmacologic analgesia alone. After 2 weeks of intervention, the comprehensive pain management cohort was associated with more favorable outcomes compared to controls, including diminished pain intensity, elevated pain relief rates, superior quality of life, reduced anxiety and depression, a...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Analgesic Medications
Acetaminophen (Paracetamol) SR Tablets	Sino-American Tianjin Smith Kline & French Laboratories Ltd.	National Drug Approval No. H12021118	Non-opioid analgesic for mild cancer pain (Step 1 of WHO ladder)
Fentanyl Transdermal Patch	Henan Lingrui Pharmaceutical Co., Ltd.	National Drug Approval No. H20123327	Fentanyl transdermal patch, a strong opioid analgesic for severe cancer pain
Ibuprofen SR Capsules	Sino-American Tianjin Smith Kline & French Laboratories Ltd.	National Drug Approval No. H20123327	NSAID, non-opioid analgesic for mild cancer pain (Step 1 of WHO ladder)
Morphine (sustained-release)	Mundipharma (China) Pharmaceutical Co., Ltd.	National Drug Approval No. HJ20130900–HJ20130904	Sustained-release morphine sulfate, a strong opioid analgesic for severe cancer pain
Oxycodone (OxyContin)	Mundipharma (China) Pharmaceutical Co., Ltd.	National Drug Approval No. HJ20140312–HJ20140325	Sustained-release oxycodone hydrochloride, a strong opioid analgesic for severe cancer pain
Tramadol Hydrochloride SR Tablets (domestic)	North China Pharmaceutical Co., Ltd.	National Drug Approval No. H20020248	Tramadol hydrochloride, a weak opioid analgesic for moderate cancer pain
Assessment Tools
EORTC QLQ-C30 (Chinese Version)	European Organisation for Research and Treatment of Cancer	N/A	Chinese version of the core quality of life questionnaire for cancer patients, assessing functional and symptom domains
Hospital Anxiety and Depression Scale (HADS)	GL Assessment / Mapi Research Trust	N/A	Hospital Anxiety and Depression Scale, assessing anxiety and depression status.
Numerical Rating Scale (NRS)	N/A	N/A	Numeric Rating Scale (0-10), assessing pain intensity
Statistical Software
Sample Size Calculation Software	G*Power	Version 3.1.9.7	Used for a priori power analysis. Free software, available at https://www.psychologie.hhu.de/arbeitsgruppen/allgemeine-psychologie-und-arbeitspsychologie/gpower
Statistical Analysis Software	R Foundation for Statistical Computing	R (version 4.3.1)	Used for all data analysis. Open-source software (GPL license), available at https://www.r-project.org/
Statistical Analysis Software	IBM SPSS Statistics	Version 26.0	Used for all data analysis. Commercial license required; available at https://www.ibm.com/products/spss-statistics
Interventional Equipment
Deep Hyperthermia Unit (High-frequency)	Jilin Mida Medical Equipment Co., Ltd.	National Medical Device Registration No. 20163260187 (NRL-001)	Used for local deep hyperthermia to assist analgesia in patients with pleural/peritoneal effusions or superficial metastatic lesions
Medical Linear Accelerator (Vitalbeam)	Varian Medical Systems, Inc.	National Medical Device Registration No. 20163322474	Used for palliative radiotherapy of bone metastases and soft tissue masses