Impact of combined pregabalin and multimodal analgesia on cancer pain and quality of life in advanced colorectal cancer

Abstract

BACKGROUND

Colorectal cancer has high morbidity and mortality, with over 70% patients suffering from cancer pain. Advanced cases have complex pain mechanisms with neuropathic and nociceptive pain superposition. Conventional multimodal analgesia has limitations: Opioids cause adverse reactions, with poor pain control and frequent breakthrough pain in some patients, severely impairing quality of life. Pregabalin is effective for neuropathic pain, and its combined application value needs exploration.

AIM

To explore pregabalin plus multimodal analgesia's effects on advanced colorectal cancer pain and life quality.

METHODS

Total of 100 advanced colorectal cancer patients with moderate to severe pain in our hospital were selected and randomly divided into two groups (50 cases in each group): Guideline-based multimodal analgesia was used as the control, and the observation group was added with pregabalin. A 12-week intervention was conducted; numerical rating scale, cancer patient quality of life core scale, breakthrough pain, opioid dose, and adverse effects were recorded.

RESULTS

Both groups showed significant post-intervention declines in numerical rating scale scores, breakthrough pain frequency and daily opioid dosage (all P < 0.05); the observation group had lower levels [2.3 ± 0.8 points vs 3.7 ± 1.0 points, 0.4 ± 0.3 episodes per day vs 1.5 ± 0.6 episodes per day, 85.6 ± 20.3 mg oral morphine milligram equivalents vs 132.4 ± 25.6 mg oral morphine milligram equivalents, all P < 0.001]. Its cancer patient quality of life core scale overall score was markedly higher (68.5 ± 10.2 vs 52.4 ± 9.6, P < 0.001). Adverse reactions were relieved symptomatically, no severe events occurred.

CONCLUSION

Pregabalin plus multimodal analgesia relieves pain, cuts opioids and boosts life quality in advanced colorectal cancer safely.

Key Words: Pregabalin; Multimodal analgesia; Advanced colorectal cancer; Cancer pain; Quality of life; Opioid dosage; Adverse reaction

Core Tip: This study verifies that pregabalin combined with routine multimodal analgesia exerts a certain analgesic effect in advanced colorectal cancer patients with moderate-severe cancer pain, effectively reducing breakthrough pain and opioid dosage, significantly improving patients’ quality of life, with manageable adverse reactions, thus holding high clinical application value.

INTRODUCTION

Colorectal cancer is a highly prevalent malignant tumor worldwide, with its incidence and mortality rates ranking among the top of digestive system tumors, and it has shown a trend of affecting younger people in recent years[1]. According to clinical data, more than 70% of colorectal cancer patients experience pain of varying degrees, with the severity and duration varying depending on the stage of the disease[2,3]. Patients with advanced colorectal cancer still face multiple challenges from tumor progression, metastasis, and complications, among which pain caused by treatment and inflammation is one of the most common and serious symptoms affecting the quality of life of patients[4]. Advanced colon cancer not only brings physical pain to patients, but also easily triggers negative emotions such as anxiety and depression, which seriously weakens patients’ confidence in treatment[5]. Studies have shown that nearly 27.5% of patients with advanced CRC have anxiety symptoms, of which 28.3% have depressive symptoms[6].

At present, the core principle of clinical treatment of advanced cancer pain is multimodal analgesia, which combines opioids, nonsteroidal anti-inflammatory drugs, adjuvant analgesics and non-drug interventions, and formulates individualized plans according to the degree of pain of patients. The goal is to effectively control pain, reduce adverse reactions and maximize the improvement of patients’ quality of life. As the first-line drug for the treatment of moderate to severe cancer pain, opioids have a clear analgesic effect, but long-term high-dose use can easily lead to adverse reactions such as constipation, nausea and vomiting, tolerance and dependence. In addition, some patients still have problems such as poor pain control and frequent breakthrough pain, making it difficult to achieve ideal analgesic effect[7]. At the same time, the pain mechanism of patients with advanced colorectal cancer is complex, often involving the superposition of neuropathic pain and nociceptive pain. A single analgesic plan is often difficult to cover multiple pain types, which further increases the difficulty of clinical analgesia treatment.

Pregabalin as a new type gamma-aminobutyric acid receptor agonists have the characteristics of rapid onset, long duration of action and good tolerability. By regulating the release of neurotransmitters, they can effectively inhibit the transmission of neuropathic pain signals and have been widely used as adjunctive analgesics in the fields of neuralgia and postoperative pain[8,9]. In recent years, studies have suggested that the combined use of pregabalin and opioids can produce a synergistic analgesic effect, which can enhance the analgesic effect while reducing the dosage of opioids, thereby reducing the incidence of related adverse reactions[10].

Given the current clinical needs and limitations of existing treatments for cancer pain in patients with advanced colorectal cancer, this study explores the application value of pregabalin combined with conventional multimodal analgesia. This research aims to provide evidence-based support for optimizing analgesia regimens, improving pain control, and enhancing quality of life in patients with advanced colorectal cancer, thus possessing significant clinical and practical value. Therefore, this study selected advanced colorectal cancer patients with moderate to severe cancer pain as research subjects for a controlled study to analyze the clinical efficacy and safety of this combined analgesic regimen.

MATERIALS AND METHODS

Research object

One hundred patients with advanced colorectal cancer and moderate to severe cancer pain admitted to our hospital between June 2023 and January 2025 were selected as the study subjects. Inclusion criteria: (1) The patient was diagnosed with colorectal cancer by pathological histology or imaging examination, and the clinical stage was IV[11]; (2) Pain intensity was assessed using the numerical rating scale (NRS)[12], with a score ≥ 4 and a duration of pain ≥ 1 week; (3) Expected survival ≥ 3 months; (4) Conscious and able to cooperate in completing the assessment questionnaire and throughout the intervention process; and (5) Patients and their families provided informed consent and signed an informed consent form. Exclusion criteria: (1) Those allergic to pregabalin, opioids, or other analgesics used in research; (2) Those with combined severe liver or kidney dysfunction, cardiovascular or cerebrovascular disease, mental illness, or cognitive impairment; (3) Those with factors affecting pain assessment, such as central nervous system metastasis or spinal canal compression; (4) Those who have recently received radiotherapy, chemotherapy, or other anti-tumor treatments that may affect pain status; and (5) Currently involved in other analgesia-related clinical research.

Methods

The intervention period for both groups of patients was 12 weeks. During the intervention, changes in pain and adverse drug reactions were closely monitored, and the treatment plan was adjusted in a timely manner.

Control group: Based on the study by Varrassi et al[13], the control group received routine multimodal analgesia. Opioids (such as oxycodone sustained-release tablets and morphine sustained-release tablets) were selected as the basic analgesic drugs according to the patient’s pain level. The initial dose was determined by titration and then the dosage was adjusted according to the NRS score. The target was an NRS score ≤ 3. Nonsteroidal anti-inflammatory drugs (such as celecoxib capsules) were used to assist analgesia, and antiemetics and laxatives were given to prevent adverse reactions. When necessary, non-pharmacological means such as psychological intervention and physical therapy were combined to optimize the analgesic effect.

Observation group: Based on the conventional multimodal analgesia regimen in the control group, pregabalin capsules (Chongqing Save Pharmaceutical Co., Ltd., 75 mg/capsule) were added for treatment. The initial dose of pregabalin was 75 mg twice daily, administered orally. After 3-7 days of initial medication, the dosage was adjusted according to the patient’s pain control and tolerance, with the maximum dose not exceeding 600 mg/day. The maintenance dose was determined within the first 4 weeks and kept stable for the subsequent 8 weeks to observe the long-term efficacy and tolerance of the fixed dose, with the maximum dose not exceeding 600 mg/day.

Observation indicators and evaluation methods

The relevant indicators of the two groups of patients were assessed and recorded before the intervention (day 1 of treatment) and at the end of the 12-week intervention (day 84 of treatment).

Pain-related indicators: Pain intensity was assessed using the NRS score, with a score of 0-10 indicates no pain, 1-3 indicates mild pain, 4-6 indicates moderate pain, and 7-10 indicates severe pain. Higher scores indicate more severe pain. The number of daily breakthrough pain events was recorded for both groups (breakthrough pain is defined as a sudden increase in pain under basic analgesia, with an NRS score ≥ 5, requiring additional rescue medication for relief). The average daily dose of opioids was calculated and converted to daily oral morphine milligram equivalents (OME) for easy comparison between groups.

Quality of life assessment: The cancer patient quality of life core scale (QLQ-C30, version 3.0) was used to assess patients' quality of life. This scale includes six functional dimensions: Overall health status, physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning; and nine symptom dimensions, including fatigue, pain, insomnia, nausea, and vomiting. After standardization, higher scores in the functional dimensions and overall health status indicated a better quality of life; higher scores in the symptom dimensions indicated more severe symptoms.

Adverse reaction monitoring: Adverse reactions in both groups of patients were recorded throughout the intervention period, including dizziness, drowsiness, peripheral edema, constipation, nausea and vomiting, and skin itching. The incidence of various adverse reactions was statistically analyzed, and the severity and treatment outcomes of adverse reactions were analyzed.

Statistical analysis

SPSS 26.0 statistical software was used to analyze and process the research data. Quantitative data were expressed as mean ± SD. Paired t-tests were used for comparisons within groups before and after intervention, and independent samples t-tests were used for comparisons between groups. Categorical data were expressed as percentages (%), and χ² tests were used for comparisons between groups. A P value < 0.05 was considered statistically significant.

RESULTS

Comparison of general information between the two groups of patients

There was no significant difference between the two groups of patients in terms of general information such as gender, age, disease duration, tumor metastasis site, and baseline pain intensity, making them comparable (Table 1).

Table 1 Comparison of general information between the two groups of patients, n (%)/mean ± SD.

Index	Observation group (n = 50)	Control group (n = 50)	χ2/t	P value
Gender			0.16	0.689
Male	28 (56.00)	26 (52.00)
Female	22 (44.00)	24 (48.00)
Age (years)	12.35 ± 4.18	20.46 ± 4.52	2.23	0.028
Disease duration (months)	6.15 ± 2.38	12.58 ± 3.15	0.98	0.328
Sites of tumor metastasis	42.85 ± 5.63	33.67 ± 5.24	0.35	0.951
Liver	23 (46.00)	21 (42.00)
Lung	15 (30.00)	16 (32.00)
Abdominal cavity	8 (16.00)	9 (18.00)
Other	4 (8.00)	4 (8.00)
Baseline NRS score (scores)	26.34 ± 4.15	18.75 ± 3.86	0.38	0.705

NRS: Numerical rating scale.

Comparison of pain-related indicators before and after intervention in the two groups of patients

After the intervention, the pain-related indicators in both groups decreased significantly compared with those before the intervention (P < 0.05). The NRS score, number of daily breakthrough pains, and daily opioid dosage decreased more significantly in the observation group, and all indicators were lower than those in the control group. The differences between the groups were statistically significant (P < 0.05) (Table 2).

Table 2 Comparison of pain-related indicators between the two groups of patients before and after intervention, mean ± SD.

Index	Group	Before intervention	After intervention	t	P value
NRS score (points)	Observation group (n = 50)	6.8 ± 1.2	2.3 ± 0.8	6.92	< 0.001
	Control group (n = 50)	6.7 ± 1.3	3.7 ± 1.0
Number of pain attacks per day	Observation group (n = 50)	2.8 ± 0.9	0.4 ± 0.3	12.15	< 0.001
	Control group (n = 50)	2.7 ± 1.0	1.5 ± 0.6
Average daily dose of opioids (mg OME)	Observation group (n = 50)	185.3 ± 30.5	85.6 ± 20.3	10.38	< 0.001
	Control group (n = 50)	182.7 ± 29.8	132.4 ± 25.6

P < 0.05 for comparisons before and after intervention within the group; oral morphine milligram equivalents is the daily milligram equivalent of oral morphine. NRS: Numerical rating scale; OME: Oral morphine milligram equivalents.

Comparison of quality of life (QLQ-C30 scale) scores between the two groups of patients before and after intervention

After the intervention, the QLQ-C30 scale scores of both groups improved compared with those before the intervention (P < 0.05). The observation group showed more significant improvements in overall health status, emotional function, and cognitive function dimensions, and more significant reductions in fatigue, pain, and insomnia symptom dimensions. The differences between the groups were statistically significant (P < 0.05) (Table 3).

Table 3 Comparison of quality of life (cancer patient quality of life core scale) scores between the two groups of patients before and after intervention.

Dimensions	Group	Before intervention	After intervention	t	P value
Overall health	Observation group (n = 50)	42.3 ± 8.6	68.5 ± 10.2	7.85	< 0.001
	Control group (n = 50)	41.8 ± 8.9	52.4 ± 9.6
E-emotional function	Observation group (n = 50)	50.2 ± 9.3	72.3 ± 9.8	6.52	< 0.001
	Control group (n = 50)	49.7 ± 9.5	58.7 ± 10.1
Cognitive function	Observation group (n = 50)	48.5 ± 10.1	70.6 ± 10.5	6.98	< 0.001
	Control group (n = 50)	48.1 ± 9.8	56.3 ± 9.9
Tired	Observation group (n = 50)	58.6 ± 9.2	32.1 ± 8.4	7.23	< 0.001
	Control group (n = 50)	59.1 ± 9.4	45.6 ± 9.2
Pain	Observation group (n = 50)	65.3 ± 8.7	28.3 ± 7.6	8.65	< 0.001
	Control group (n = 50)	64.9 ± 8.9	42.8 ± 8.7
Insomnia	Observation group (n = 50)	57.8 ± 9.0	30.5 ± 8.2	7.51	< 0.001
	Control group (n = 50)	58.2 ± 9.3	44.3 ± 9.1

P < 0.05 for comparisons before and after intervention within the group; the higher the score of functional and overall health status dimensions and the lower the score of symptom dimension, the better the quality of life.

Comparison of adverse reaction rates between the two groups of patients

There was no statistically significant difference in the total incidence of adverse reactions between the two groups during the 12-week intervention (P > 0.05), and no serious adverse events occurred in either group throughout the study period. All adverse reactions were relieved after symptomatic treatment, indicating good safety. However, there were differences in the adverse reaction spectrum. The incidence of dizziness, drowsiness, and peripheral edema was slightly higher in the observation group, while the incidence of constipation, nausea, and vomiting was higher in the control group (P < 0.05) (Table 4).

Table 4 Comparison of the incidence of adverse reactions between the two groups of patients, n (%).

Type of adverse reaction	Observation group (n = 50)	Control group (n = 50)	χ2	P value
Dizziness	12 (24.00)	8 (16.00)	0.98	0.322
Lethargy	10 (20.00)	6 (12.00)	1.15	0.284
Peripheral edema	8 (16.00)	4 (8.00)	1.72	0.190
Constipate	6 (12.00)	18 (36.00)	8.57	< 0.001
Nausea and vomiting	4 (8.00)	14 (28.00)	7.81	0.005
Itchy skin	3 (6.00)	5 (10.00)	0.54	0.463
Overall incidence	23 (46.00)	21 (42.00)	0.16	0.689

DISCUSSION

The mechanism of cancer pain in patients with advanced colorectal cancer is complex, and it is characterized by the superposition of neuropathic pain and nociceptive pain in cancer[14]. Although conventional multimodal analgesia can relieve some pain, some patients still have problems such as poor pain control, frequent breakthrough pain and obvious adverse reactions of opioids, which seriously affect the quality of life of patients[15]. This study investigated the analgesic efficacy and quality of life improvement of pregabalin combined with conventional multimodal analgesia in advanced colorectal cancer patients with moderate to severe cancer pain. The results showed that the combined regimen had significant clinical efficacy and good safety, providing a new direction for the optimization of cancer pain management in advanced colorectal cancer.

Pain control is one of the core goals of palliative care for patients with advanced cancer, and the NRS score, frequency of breakthrough pain, and opioid dosage are key indicators for assessing analgesic efficacy. The results of this study showed that pain-related indicators in both groups significantly improved after intervention compared to before intervention, but the improvement was more pronounced in the observation group. The NRS score decreased to 2.3 ± 0.8 points, the frequency of breakthrough pain decreased to 0.4 ± 0.3 times per day, and the average daily opioid dosage decreased to 85.6 ± 20.3 mg. OME was significantly lower than that of the control group. This result is closely related to the pharmacological properties of pregabalin. As a γ-aminobutyric acid receptor agonist, pregabalin can effectively block the transmission of neuropathic pain signals by regulating the release of neurotransmitters in the central nervous system and inhibiting the discharge of abnormally excited neurons[16,17]. Opioids mainly act on μ receptors and have a significant effect on nociceptive pain, but their effect on controlling neuropathic pain is limited[18,19]. Pregabalin makes up for this shortcoming and produces a synergistic analgesic effect with opioids. It not only enhances the overall analgesic effect, but also reduces the dosage of opioids. This is similar to the research conclusion of Gaber et al[20], which confirms that the combined use of pregabalin and opioids can enhance the analgesic efficacy through synergistic effect and reduce the required dose of opioids.

Frequent attacks of breakthrough pain are a major concern for patients with advanced cancer. Their occurrence is closely related to the complexity of pain mechanisms and the fact that basic analgesia regimens do not fully cover all types of pain[21]. The significant reduction in the number of breakthrough pains observed in this study further confirms the advantages of pregabalin in treating mixed pain. It can not only directly inhibit neuropathic pain, but also reduce the abnormal amplification of pain signals by reducing nerve sensitivity, thereby reducing the probability of triggering breakthrough pain. This finding has important clinical significance because effective control of breakthrough pain can significantly reduce patients' suffering experience, enhance their confidence in treatment, and lay the foundation for the smooth implementation of subsequent treatment.

Improving quality of life is an important goal in the treatment of patients with advanced cancer. The relief of symptoms such as pain, fatigue, and insomnia is closely related to the patient's overall health, emotional function, and cognitive function[22,23]. This study, using the QLQ-C30 scale, showed that the observation group had significantly better improvement in scores across the dimensions of overall health, emotional function, and cognitive function than the control group. Simultaneously, the scores for key symptoms such as fatigue, pain, and insomnia decreased more significantly. These results suggest that pregabalin combined with a multimodal analgesia regimen can not only effectively control pain but also improve sleep quality, reduce fatigue, and decrease pain-related anxiety and depression through pain relief, thereby comprehensively improving the patient's quality of life. Notably, the significant improvement in emotional and cognitive function in the observation group (emotional function increased from 50.2 to 72.3) within 4 weeks may not be solely attributed to pain relief. Pregabalin itself has a definite therapeutic effect on generalized anxiety disorder, and it can directly improve the anxiety symptoms common in advanced colorectal cancer patients, which in turn indirectly elevates the scores of emotional function and cognitive function dimensions. This direct psychological regulatory effect of pregabalin is an additional mechanism for the improvement of quality of life, supplementing the indirect benefits brought by pain relief.

Safety is an important consideration in the selection of clinical analgesia regimens. Long-term use of opioids can easily lead to adverse reactions such as constipation, nausea and vomiting, which not only affect patients’ tolerance to treatment but also even seriously reduce the quality of life of advanced cancer patients, and constipation is even a more distressing symptom than pain for many patients[24]. In this study, there was no significant difference in the total incidence of adverse reactions between the two groups, and no serious adverse events occurred in either group, with all adverse reactions classified as mild to moderate in severity based on clinical grading criteria. This preliminary confirms the safety of pregabalin combined with multimodal analgesia regimens. More importantly, the significant differences in the adverse reaction spectrum between the two groups are the direct clinical manifestation of the opioid-sparing effect of pregabalin. The incidence of dizziness, drowsiness and peripheral edema in the observation group was slightly higher than that in the control group, while the incidence of moderate opioid-related constipation, nausea and vomiting in the control group was significantly higher (36% vs 12%, 28% vs 8%). This difference is not only related to the inherent adverse reaction characteristics of the two types of drugs, but also the direct result of the significant reduction in opioid dosage in the observation group due to the synergistic analgesic effect of pregabalin. The common adverse reactions of pregabalin are central nervous system depression-related symptoms, such as dizziness, drowsiness and mild peripheral edema, while the most common adverse reactions of opioids are gastrointestinal reactions, such as constipation, nausea and vomiting[25,26]. Notably, the reduced opioid dosage in the observation group due to the addition of pregabalin markedly reduced the incidence of moderate constipation and moderate nausea and vomiting - the most common and clinically troublesome moderate adverse reactions of opioids that severely impact the quality of life of advanced colorectal cancer patients. In contrast, the pregabalin-related adverse reactions such as dizziness, drowsiness and peripheral edema in the observation group were predominantly mild (only a small number were moderate), and all were relieved after symptomatic treatment without affecting the continuation of treatment, demonstrating good patient tolerance. This result fully confirms that the combination of pregabalin with conventional multimodal analgesia not only enhances the analgesic effect through synergistic action, but also achieves a substantial opioid-sparing effect, which in turn reduces the occurrence of moderate opioid-related adverse reactions that are difficult to alleviate and seriously affect the quality of life. This is far more than a simple “optimization of the adverse reaction spectrum”, but a clinical benefit that is more valuable for advanced cancer patients: It enables patients to obtain effective pain relief while avoiding the severe distress caused by moderate opioid-induced constipation and other symptoms, and significantly improves the overall tolerability and clinical experience of treatment.

This study has certain limitations: First, the sample size is relatively limited, and it is a single-center study with a relatively homogeneous patient population, which may lead to selection bias and limits the extrapolation of the results to a larger, more diverse clinical population. To address this, subsequent research can adopt a multi-center collaborative research design, enrolling patients from different regions, medical centers of different levels (tertiary, secondary), and with different baseline clinical characteristics (e.g., different tumor metastasis patterns, concurrent diseases, and prior analgesic regimens) to expand the sample size and improve the population representativeness. Meanwhile, stratified sampling can be used to ensure a balanced distribution of key variables such as pain subtypes and age groups, reducing selection bias and enhancing the external validity of the research results. The extrapolation of the current results needs to be further verified by multi-center, large-sample studies. Second, this study did not classify the patients’ pain subtypes in more detail. Whether there are differences in the response of patients with different pain subtypes to the combined regimen needs to be explored in depth by subsequent studies.

CONCLUSION

For patients with advanced colorectal cancer and moderate to severe cancer pain, combining pregabalin with a routine multimodal analgesia regimen can effectively enhance analgesia, reduce breakthrough pain, and decrease opioid dosage. It also significantly improves overall health and core functional dimensions, alleviates pain-related symptoms, and enhances quality of life, with manageable and well-tolerated adverse reactions. Considering the significant opioid-sparing effect and marked reduction in breakthrough pain, this regimen is recommended as a preferred option for advanced colorectal cancer patients with a predominant neuropathic pain component or those suffering from intolerable opioid-induced constipation. It provides a targeted and optimized analgesic approach for clinical cancer pain management, with important practical application value.