Naloxone plus enteral nutrition for gastrointestinal dysfunction in elderly cerebral infarction and peptic ulcer patients

Abstract

BACKGROUND

Cerebral infarction (CI) is a major subtype of ischemic stroke, with high incidence, recurrence rate, disability rate, and mortality rate in the elderly. Elderly CI patients are prone to peptic ulcer due to long-term use of antiplatelet drugs and stress factors, which further leads to gastrointestinal dysfunction, seriously affecting nutritional intake and rehabilitation. Naloxone, an opioid receptor antagonist, has neuroprotective potential, and enteral nutrition (EN) can improve gastrointestinal function. This study aims to explore the intervention effect of their combination.

AIM

To investigate the efficacy of naloxone combined with EN on gastrointestinal dysfunction in elderly patients with CI and peptic ulcer.

METHODS

In this randomized controlled trial, 110 elderly patients with CI and peptic ulcer were equally assigned to a control group (receiving standard therapy combined with EN) or a combination group (receiving standard therapy, EN, and naloxone). The National Institute of Health Stroke Scale (NIHSS) scores, Barthel Index (BI), Chinese version of the MOS 36-Item Short Form Health Survey (SF-36) scores, gastrointestinal function scores, and serum levels of motilin (MTL), gastrin (GAS), and somatostatin (SS) were compared. Adverse reactions were also recorded.

RESULTS

Compared with the control group, the combination group had lower NIHSS scores (5.88 ± 1.07 vs 8.73 ± 1.14, P < 0.001) and gastrointestinal dysfunction scores (5.14 ± 1.27 vs 8.62 ± 1.31, P < 0.001), higher BI (87.36 ± 4.42 vs 72.29 ± 3.23, P < 0.001) and SF-36 scores (76.26 ± 3.85 vs 70.21 ± 3.66, P < 0.001), increased serum MTL (201.31 ± 12.35 ng/L vs 186.81 ± 11.18 ng/L, P < 0.001) and GAS levels (94.46 ± 9.64 pg/mL vs 103.15 ± 10.52 pg/mL, P < 0.001), and decreased SS levels (5.69 ± 1.25 pg/mL vs 8.31 ± 1.19 pg/mL, P < 0.001). No significant difference in the incidence of adverse reactions was found between the two groups.

CONCLUSION

The combination of naloxone and EN is a safe and efficacious therapeutic approach for ameliorating gastrointestinal dysfunction and promoting overall recovery in elderly individuals with CI and peptic ulcer.

Key Words: Naloxone; Enteral nutrition support; Cerebral infarction; Peptic ulcer; Gastrointestinal dysfunction

Core Tip: This study investigates the combined effect of naloxone and enteral nutrition (EN) on alleviating gastrointestinal dysfunction in elderly patients with cerebral infarction (CI) and peptic ulcers. With CI being prevalent among the elderly and often accompanied by gastrointestinal complications, the research aims to provide evidence supporting the use of naloxone, an opioid receptor antagonist, alongside EN to improve gastrointestinal health and promote recovery.

INTRODUCTION

Cerebral infarction (CI), commonly referred to as ischemic stroke (IS), constitutes a primary subtype of stroke. This condition typically arises from multiple contributing factors that either reduce cerebral blood flow or cause vascular occlusion, leading to impaired function of the cerebrovascular system. It presents clinically with neurological deficits and symptoms corresponding to the region affected by ischemia, including sensory disturbances in the extremities, dysphasia, and altered levels of consciousness[1]. CI is particularly common in the elderly population and has high incidence, recurrence, disability and mortality rates. Especially in elderly patients with CI, due to long-term use of antiplatelet drugs and stress factors, peptic ulcer has become one of the common gastrointestinal complications in this group. Peptic ulcer often leads to gastrointestinal dysfunction, manifested as symptoms such as weakened intestinal motility, abdominal distension, loss of appetite, nausea and vomiting. These symptoms seriously affect the patient's nutritional intake and hinder their full recovery. For elderly patients with CI and peptic ulcers, how to effectively improve gastrointestinal function and promote gastrointestinal health recovery remains a major challenge in clinical medicine. Naloxone, as an opioid receptor antagonist, has high safety and efficacy. It is widely used to relieve respiratory depression caused by opioids and can effectively avoid causing pain[2]. Relevant literature has shown that naloxone can significantly improve neurological function in an IS model and help reduce brain tissue damage[3]. In addition, recent studies further revealed that naloxone has shown positive effects in the treatment of gastrointestinal dysfunction and helps to alleviate drug-induced intestinal damage and inflammation[4]. Enteral nutrition (EN) support, as an important clinical nutritional intervention, has been proven to provide patients with impaired gastrointestinal function with the necessary energy and nutrients, this promotes the healing and improvement of gastrointestinal function[5]. Based on this, this study's objective was to examine the efficacy of naloxone combined with EN on alleviating gastrointestinal dysfunction in elderly patients with CI and peptic ulcers using a randomized controlled trial, and to evaluate its impact on neurological function and quality of life, in order to give more evidence support for clinical treatment.

MATERIALS AND METHODS

General information

A total of 110 individuals diagnosed with CI concurrent with peptic ulcer disease, who were admitted to our hospital from March 2023 to December 2024, were enrolled in this study. These participants were randomly allocated into two cohorts of 55 each: The control group, which received standard therapy along with EN, and the combination group, which was administered naloxone in addition to EN.

Inclusion criteria

The inclusion criteria are as follows: (1) Patients who, as verified by cranial computed tomography or magnetic resonance imaging, satisfy the CI diagnostic criteria in the "China stroke surveillance report 2021"[6]; (2) Patients with upper abdominal pain, nausea and vomiting, black stool or positive occult blood in stool, decreased appetite, slow weight gain, and painless gastroscopy showing ulcers, in line with the diagnosis of peptic ulcers in the "a comprehensive review on ulcer and their treatment"[7]; (3) Patients who meet the diagnosis of gastrointestinal dysfunction according to the terms, definitions and diagnosis of gastrointestinal function in critically ill patients recommended[8]; (4) Aged over 60 years; and (5) Patients who provide informed consent, willingly agree to participate in the study, and formally sign the consent documentation prior to enrollment.

Exclusion criteria

The exclusion criteria are as follows: (1) Patients with heart, liver, or kidney problems; (2) Patients who have cancerous growths; (3) Patients who have contraindications to the administration of the relevant medications; and (4) Patients who have a history of gastrointestinal disorders or malfunction.

Methods

Both groups received standard treatment, which included conventional thrombolysis (if applicable), oxygen inhalation, vasodilation, intracranial pressure reduction, and antiplatelet aggregation treatment. All patients also uniformly received proton pump inhibitors to prevent peptic ulcer complications. On this basis, the control group received standard therapy combined with EN support. The combination group received standard therapy combined with EN support plus naloxone treatment. Naloxone (specifically, 0.8 mg) was administered via intravenous drip in 250 mL of 10% glucose solution, twice daily for a duration of 14 days. EN intervention was performed using a nutrient solution (Milupa GmbH, National Medicine Standard HJ20170170, specification: 125 g/bag) via a silicone nasogastric tube. EN was delivered continuously and uniformly using a nutrition pump, with an initial rate set at 10-20 mL/hour and a total dose of 500 mL/day. The pump rate was subsequently adjusted based on the patient's vital signs and tolerance, with a maximum pump rate not exceeding 120 mL/hour and a total dose not exceeding 2000 mL/day. Strictly adhere to aseptic techniques during EN intervention to minimize infection caused by human factors. During nutritional intervention, elevate the patient's head of bed 35°-45° to reduce the risk of aspiration. Regularly aspirate gastric contents to assess whether gastric retention is occurring, allowing adjustments to the infusion rate or nutritional intervention plan. Closely monitor the patient. If a patient experiences severe adverse reactions, immediately administer symptomatic treatment, such as slowing or stopping the infusion.

Observation indicators

The extent of neurological impairment in patients was evaluated utilizing the National Institute of Health Stroke Scale (NIHSS)[9], which has a score range of 0 to 42. The more serious the neurological disability, the higher the score. The patient's capacity to do everyday tasks was evaluated using the Barthel Index (BI)[10]. Each of the ten items on the scale can receive a value of 0, 5, 10, or 15, for a total score of 100. The ability to take care of oneself is stronger when the score is higher. The assessment of quality of life was conducted using the Mos 36-Item Short Form Health Survey (SF-36) in Chinese[11]. The scale has 36 items and 8 dimensions. Each dimension has a total score of 100. The quality of life improves with a higher score. Gastrointestinal dysfunction score[12]: The severity of gastrointestinal dysfunction was assessed using a 4-point grading scale[13]. This evaluation system incorporates criteria such as dietary intake, presence of nausea and vomiting, physical examination findings, and duration of symptoms. The scores ranged from 0 to 15 points. Serum gastrointestinal hormone levels: A volume of 5 mL of venous blood was drawn, treated with an anticoagulant, and subsequently subjected to centrifugation to isolate the plasma. The serum levels of motilin (MTL), gastrin (GAS), and somatostatin (SS) in patients before and after treatment were measured by enzyme-linked immunosorbent assay. Occurrence of adverse events: The adverse reactions in both groups were documented and analyzed.

Statistical analysis

Data analysis was conducted using SPSS statistical software, version 23.0. Continuous variables are presented as mean ± SD and were compared between groups using the independent samples t-test. Categorical variables are reported as n (%) and were analyzed using the χ² test for intergroup comparisons. Statistical significance was defined as a P value less than 0.05. Sample size calculation method for this study: Based on preliminary experiments and relevant literature, the effect size was set at 0.8, the significance level α = 0.05, and the power 1-β = 0.9. Using G*Power 3.1 software, the required sample size per group was calculated to be 52 cases. Considering a 10% attrition rate, 55 cases were finally included in each group, with a total sample size of 110 cases.

RESULTS

Comparison of general information

There were no statistically significant differences in gender (χ² = 0.144, P = 0.705), age (t = 0.351, P = 0.363), body mass index (t = 0.351, P = 0.363), and infarction location (χ² = 1.493, P = 0.684), as shown in Table 1.

Table 1 General information, n (%).

	Control group (n = 55)	Combination group (n = 55)	t/χ2	P value
Gender			0.147	0.702
Male	26 (47.27)	24 (43.64)
Female	29 (52.73)	31 (56.36)
Age (years)	68.23 ± 3.01	67.84 ± 3.24	0.574	0.567
BMI (kg/m2)	22.03 ± 2.42	21.72 ± 2.25	0.700	0.486
Infarction location			0.825	0.843
Brainstem	10 (18.18)	9 (16.36)
Cerebral lobe	14 (25.45)	15 (27.27)
Basal ganglia	29 (52.73)	27 (49.09)
Others	2 (3.64)	4 (7.27)

Comparison of NIHSS scores

After treatment, the NIHSS scores in the combination group being lower than that in the control group (P < 0.001; Table 2).

Table 2 Comparison of National Institute of Health Stroke Scale scores, mean ± SD.

Group	NIHSS score
	Before treatment	After treatment
Control group (n = 55)	12.09 ± 2.27	8.73 ± 1.14a
Combination group (n = 55)	12.14 ± 2.62	5.88 ± 1.07a
t value	0.039	12.270
P value	0.969	< 0.001

^aP < 0.05 vs the group before treatment.

NIHSS: National Institute of Health Stroke Scale.

Comparison of daily activities and quality of life

Following therapy, the combination group's BI and SF-36 ratings outperformed those of the control group (P < 0.001; Table 3).

Table 3 Comparison of daily activities and quality of life, mean ± SD.

Group	BI		SF-36 score
	Before treatment	After treatment	Before treatment	After treatment
Control group (n = 55)	51.23 ± 3.01	72.29 ± 3.23a	35.83 ± 9.04	70.21 ± 3.66a
Combination group (n = 55)	51.18 ± 3.74	87.36 ± 4.42a	36.01 ± 9.10	76.26 ± 3.85a
t value	0.056	20.480	0.074	8.508
P value	0.955	< 0.001	0.941	< 0.001

^aP < 0.05 vs the group before treatment.

BI: Barthel Index; SF-36: MOS 36-Item Short Form Health Survey.

Comparison of gastrointestinal dysfunction scores

Following the intervention, both groups exhibited a marked reduction in gastrointestinal dysfunction scores. Notably, the group receiving the combined therapy demonstrated a significantly greater improvement, with a lower score compared to the control group (P < 0.001; Table 4).

Table 4 Comparison of gastrointestinal dysfunction scores, mean ± SD.

Group	Gastrointestinal dysfunction score
	Before treatment	After treatment
Control group (n = 55)	12.26 ± 3.02	8.62 ± 1.31a
Combination group (n = 55)	12.41 ± 2.97	5.14 ± 1.27a
t value	0.479	13.660
P value	0.633	< 0.001

^aP < 0.05 vs the group before treatment.

Comparison of serum gastrointestinal hormone levels

Following the intervention, the combination group showed a significant increase in serum levels of MTL and GAS, along with a notable decrease in SS concentration, when compared to the control group (P < 0.001; Table 5).

Table 5 Serum gastrointestinal hormone levels in the two groups, mean ± SD.

Group	MTL (ng/L)		GAS (pg/mL)		SS (pg/mL)
	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Control group (n = 55)	117.95 ± 10.31	186.81 ± 11.18a	69.18 ± 12.38	103.15 ± 10.52a	9.21 ± 1.66	8.31 ± 1.19a
Combination group (n = 55)	118.02 ± 10.29	201.31 ± 12.35a	68.71 ± 12.44	94.46 ± 9.64a	9.17 ± 1.42	5.69 ± 1.25a
t value	0.033	6.453	0.198	4.514	0.140	11.270
P value	0.974	< 0.001	0.843	< 0.001	0.889	< 0.001

^aP < 0.05 vs the group before treatment.

MTL: Motilin; GAS: Gastrin; SS: Somatostatin.

Comparison of adverse reaction rates

No obvious adverse reactions were observed in both groups.

DISCUSSION

Stroke is typically categorized into two main types— ischemic and hemorrhagic—based on established neuropathological classification criteria. CI has emerged as the second leading cause of global mortality and is recognized as a major contributor to prolonged disability and persistent functional deficits worldwide. With the increasing trend of aging in the global population, the disease burden of IS continues to rise[14,15]. Epidemiological studies have shown that approximately 50% of stroke survivors will experience varying degrees of gastrointestinal dysfunction and related complications during the acute or recovery phase[16]. Recent years, the concept of the brain-gut axis has garnered growing interest and recognition within the field of neurogastroenterology. Research has demonstrated that following a stroke, the autonomic nervous system facilitates bidirectional information transfer between the central nervous system and the gastrointestinal tract. When brain damage leads to dysfunction of the autonomic nervous system, it may cause intestinal barrier dysfunction, leading to imbalance of the intestinal microbial community and increased intestinal permeability, thereby aggravating the occurrence of gastrointestinal dysfunction[17]. Naloxone is a powerful and highly selective opioid receptor antagonist that binds to the μ-opioid receptor with a far higher affinity than common opioids like heroin and fentanyl. Its mechanism of action is to competitively block the biological effects of endogenous or exogenous opioid peptides, thereby reversing the central nervous system inhibitory effects and other adverse reactions induced by opioids[18,19]. A growing body of research indicates that while naloxone is a critical intervention for opioid overdose, it also exhibits promising neuroprotective properties in experimental models of ischemic brain damage, including reducing cerebral edema, improving cerebral blood perfusion, inhibiting neuronal apoptosis, and modulating inflammatory responses[20-22]. In clinical nutritional support, nutritional interventions primarily include parenteral nutrition (PN) and EN. PN is a complex nutritional solution infused through a central or peripheral vein and includes trace elements, vitamins, carbohydrates, fat emulsion, amino acids, and electrolytes. It is suitable for critically ill patients with severely impaired gastrointestinal function, who cannot tolerate enteral feeding or have contraindications to EN. When the patient's digestive tract function is still good and there are no contraindications, the international consensus recommends giving priority to EN to maintain nutritional status. This method is consistent with the physiological pathway and aids in preserving the gut mucosa's integrity and immune system[23]. It should be noted that some patients with CI are at increased risk of developing iatrogenic peptic ulcers as a result of prolonged administration of nonsteroidal anti-inflammatory drugs used to prevent recurrent thrombosis, which in turn causes gastrointestinal motility disorders, mucosal barrier damage and reduced absorption function. In this case, early EN intervention not only helps to slow down the process of intestinal mucosal atrophy, but also can protect gastrointestinal function and reduce the risk of secondary infection and multi-organ dysfunction through multiple mechanisms such as maintaining intestinal microecological balance, controlling local immunological responses, decreasing intestinal permeability, and increasing the expression of tight junction proteins.

NIHSS scores significantly decreased in the combined treatment group, suggesting that naloxone and EN use together significantly promotes neurological recovery in CI patients. CI is often accompanied by varying degrees of neurological impairment, especially in motor, language, and cognitive impairments[24]. As an opioid receptor antagonist, naloxone may alleviate the neurological damage caused by CI by regulating the balance of neurotransmitters and helps to restore neurological function, potentially related to its neuroprotective mechanism[25]. At the same time, EN provides patients with essential nutrients, thereby accelerating the neural repair process. The synergistic effect of this combined treatment regimen led to a significant decrease in NIHSS scores, further verifying the efficacy of this therapy in CI recovery. Alternatively, the improvement in neurological function could be explained from the perspective of improving the overall condition (including gastrointestinal function) to indirectly assist in neurological rehabilitation.

In addition, the combined treatment group also showed significant improvements in BI and SF-36 scores, demonstrating that the patients' general quality of life and capacity for daily living have been successfully enhanced. CI patients are often accompanied by motor function and self-care ability disorders, which greatly affects their quality of life[26]. EN helps reduce functional decline caused by malnutrition by improving the nutritional status of patients. Naloxone improves neurological function, relieves motor disorders, and enhances patients' daily living ability. Combining the effects of the two, the combined treatment program significantly improves the patients' quality of life.

In terms of gastrointestinal function assessment, the combined treatment group showed a significant decrease in gastrointestinal dysfunction scores, while serum MTL and GAS levels increased significantly, indicating that EN support helps to enhance gastrointestinal motility and gastric acid secretion, thereby improving gastrointestinal function. MTL is a hormone secreted by the duodenum, which can promote gastrointestinal function by increasing lower esophageal sphincter pressure, strengthening gastric motility and regulating gastrointestinal activity. Its increased level has a positive effect on relieving symptoms such as abdominal distension and constipation caused by slow gastrointestinal motility[27]. The gastric antrum and duodenum's G cells are where GAS is primarily found. This peptide hormone plays a vital role in promoting gastric acid secretion, stimulating gastric motility, and supporting the proliferation of gastric mucosal tissue[28]. The increase in GAS levels indicates enhanced gastric acid secretion and improved gastric motility, which is crucial for promoting the recovery of gastrointestinal function. Studies have shown that the majority of patients with gastrointestinal vascular dysplasia can be safely and effectively treated with SS analogs[29]. The significant decrease in SS levels in the combined treatment group in this study indicates that by regulating the balance of gastrointestinal hormones, gastrointestinal discomfort symptoms are alleviated, thereby improving gastrointestinal dysfunction. These results further confirm the positive effect of naloxone combined with EN in improving gastrointestinal function.

During the observation period of this study, no obvious or serious drug-related adverse events or treatment-related complications were reported either the control group or the combined therapy group. This result indicates that the intervention strategy of naloxone combined with EN showed good safety and tolerability in clinical application. Elderly CI patients often have a variety of persistent underlying conditions. At the same time, immunosuppression, decreased organ reserve capacity, and polypharmacy are also common. Therefore, in the therapeutic management of such patients, it is very crucial to assess the safety of treatment regimens. The study results showed no serious adverse reactions, further confirming that this combined intervention model has good safety, offering a solid foundation for its clinical transformation and promotion in the elderly vulnerable population, thereby enhancing its feasibility and operability in clinical application.

While this investigation has yielded initial promising findings, it is subject to several limitations. First, this study is a single-center study with a relatively limited sample size, which may reduce statistical power and potentially limit the generalizability of the conclusions. To strengthen the validity and external applicability of these results, future research should employ multicenter designs with larger participant cohorts and utilize randomized controlled methodologies. Second, the follow-up time of this study is limited, which cannot fully assess the long-term impact of this combined treatment on patient prognosis, especially in terms of the persistence of neurological improvement, long-term improvement in quality of life, and the risk of delayed complications. Therefore, future studies need to extend the follow-up period and conduct longitudinal observations for several months or even longer to methodically assess the long-term safety and sustainability of therapy effects. Furthermore, this study focused primarily on macroscopic changes in clinical symptoms, functional scores, and routine biochemical indices. Although these findings demonstrate the overall efficacy of the treatment, additional studies are required to comprehensively elucidate the molecular mechanisms involved. Future research can delve deeper into the molecular and cellular levels, systematically elucidating the specific molecular pathways and regulatory mechanisms underlying the synergistic induction of CI and gastrointestinal dysfunction in patients with peptic ulcers by naloxone and EN, thereby providing a theoretical basis for developing more targeted treatments.

In summary, this study indicates that naloxone combined with EN has good safety in improving gastrointestinal dysfunction in elderly patients with CI and peptic ulcer, providing a potential new therapy for clinical practice.

CONCLUSION

In conclusion, the combination of naloxone and EN represents a safe and efficacious therapeutic approach for elderly patients with CI and peptic ulcer. This combined regimen not only significantly ameliorates gastrointestinal dysfunction, as evidenced by improved clinical scores and normalized gastrointestinal hormone levels, but also promotes neurological recovery and enhances overall quality of life.