Guideline for Medication Management of Distressing Symptoms in Older Patients Receiving End‐of‐Life Palliative Care

ABSTRACT

Older patients receiving end‐of‐life palliative care often present with multiple geriatric syndromes, frailty, and comorbid symptom burden, resulting in a high risk of medication‐related harm. This guideline focuses on pharmacological management of distressing symptoms in older patients receiving end‐of‐life or hospice‐oriented palliative care, rather than disease‐modifying treatment of chronic conditions. The guideline was developed in accordance with the standards of the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system and the Reporting Items for Practice Guidelines in Healthcare (RIGHT). It addresses 15 common distressing symptoms and provides 65 recommendations. On the basis of the best available evidence, patient values, feasibility, and expert consensus, the panel formulated recommendations intended to support safe, rational, individualized, and goal‐concordant medication use in older patients at the end of life. This guideline aims to identify and recommend appropriate pharmacological treatments for common and refractory symptoms in older palliative care patients and to provide guidance for healthcare professionals on safe, rational, and standardized medication use.

1. Introduction

Rapid population aging has driven a continuous rise in the prevalence and mortality of chronic diseases, malignancies, and degenerative disorders among older adults. As these conditions progress, the volume of patients requiring palliative care has increased substantially [1, 2]. These patients frequently experience a constellation of distressing symptoms—including pain, dyspnea, anxiety, depression, nausea, and vomiting—which profoundly compromise their quality of life (QoL) and dignity at the end of life [3, 4]. Effective symptom control constitutes a cornerstone of palliative care and is fundamental to achieving patient‐centered outcomes, enhancing QoL, and preserving dignity in the terminal stage of illness [5]. Palliative care is a broad approach that can be integrated throughout the trajectory of serious chronic illness and is not synonymous with end‐of‐life care. As chronic diseases, malignancies, neurodegenerative disorders, and severe frailty progress, however, some older patients enter a stage in which the priority of care shifts from disease modification alone toward relief of distressing symptoms, minimization of treatment burden, and preservation of comfort. In this guideline, preservation of dignity refers to relief of avoidable suffering, respect for patient preferences, maintenance of autonomy where possible, and support for comfort and personhood during the final stage of life.

Because older patients receiving end‐of‐life palliative care often experience multiple concurrent symptoms and comorbidities, single‐agent therapy may be insufficient. However, combination pharmacotherapy should not be interpreted as routine polypharmacy. Medication use should be symptom‐driven, individualized, regularly reassessed, and deprescribed when the expected benefit no longer outweighs treatment burden or drug‐related harm. Pharmacological decision‐making in geriatric palliative care is inherently complex, rendering monotherapy often insufficient for adequate symptom control [6, 7]. Although existing guidelines address a range of end‐of‐life symptoms and provide general pharmacological recommendations [8], they often fail to adequately account for the distinct characteristics of older patients, such as age‐related physiological deterioration, multimorbidity, altered pharmacokinetics and pharmacodynamics, and heightened susceptibility to adverse drug events. Consequently, current protocols may not fully meet the clinical demand for precision and safety in this population. In real‐world practice, issues such as off‐label prescribing, polypharmacy, treatment fragmentation, and potentially inappropriate medication use are prevalent. These challenges contribute to suboptimal symptom control and significantly exacerbate medication‐related risks in older patients [9, 10, 11].

Grounded in the best available evidence and clinical experience within China, this guideline systematically synthesizes medication principles, recommended pharmacotherapies, and risk‐management strategies for geriatric palliative care. This guideline does not address disease‐modifying pharmacotherapy for chronic conditions, such as guideline‐directed treatment for heart failure, diabetes, chronic kidney disease, or other long‐term illnesses. Such treatments should follow disease‐specific clinical practice guidelines and should be individualized according to prognosis, goals of care, treatment burden, medication burden, and patient preferences. By establishing a service framework tailored to the Chinese context, this document aims to provide scientific and actionable decision‐making support for safe, rational, and goal‐concordant symptom management.

2. Methods

This guideline was prospectively registered in the International Practice Guideline Registry Platform in both Chinese and English (PREPARE 2025CN023). The corresponding protocol was published in the Chinese Journal of Evidence‐Based Medicine [12]. Detailed information regarding the guideline working groups and their roles, sponsoring institutions, patient involvement, target population, scope and objectives, identification and prioritization of clinical questions, evidence retrieval and selection, evidence appraisal, grading of evidence quality and recommendation strength, consensus development process, external review, dissemination and updating strategies, and the evaluation of implementation effectiveness is described in the published protocol.

Scope and target population: The target population of this guideline is adults aged 65 years or older receiving end‐of‐life or hospice‐oriented palliative care because of advanced cancer, end‐stage organ failure, advanced neurodegenerative disease, severe frailty, or other life‐limiting conditions. In this manuscript, “geriatric palliative care” refers to palliative care delivered to older patients with advanced life‐limiting illness while considering frailty, multimorbidity, cognitive impairment, altered pharmacokinetics and pharmacodynamics, polypharmacy, and increased vulnerability to adverse drug events. The guideline is not intended for all older adults living for years with stable chronic conditions.

During the guideline development process, additional experts were recruited and adjustments were made to the working group to address the large number of clinical questions. The final evidence evaluation group consisted of 30 members from geriatrics, palliative medicine, the national clinical research center for geriatrics, general practice, hospice and palliative care, geriatric neurology, emergency medicine, evidence‐based medicine, guideline methodology research, laboratory medicine, and nursing. The consensus panel comprised 34 multidisciplinary experts from palliative care centers, geriatric medicine centers, palliative medicine departments, evidence‐based medicine units, pharmacy departments, nursing, psychiatry, general practice, rehabilitation medicine, integrated traditional Chinese and Western medicine departments, and Good Clinical Practice (GCP) management offices.

To refine and prioritize clinical questions, the guideline working group conducted a Delphi survey among 70 researchers in relevant fields. Patient preferences and values were explicitly incorporated during the question‐confirmation phase, and seven patients receiving palliative care participated in structured questionnaire surveys. The final set of clinical questions was determined on the basis of aggregated and analyzed survey results.

The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the quality of evidence, which was categorized into four levels: high, moderate, low, and very low (Table 1) [13, 14, 15]. For clinical questions lacking direct supporting evidence, recommendations were developed on the basis of expert consensus and formulated as good practice statements (GPS) [16]. GPS recommendations were used for overarching clinical principles, assessment frameworks, or safety standards when the panel judged that the action was necessary for appropriate care and that formal evidence grading was not feasible or meaningful. In addition to evidence quality, the working group considered patient preferences and values in China, resource implications, feasibility, and the balance between benefits and harms when formulating recommendations.

TABLE 1.

Grading of evidence quality and strength of recommendations.

Category	Definition
Quality of evidence
High (A)	We are very confident that the estimated effect is close to the true effect
Moderate (B)	We are moderately confident in the estimated effect; the true effect is likely to be close to the estimate, but there is a possibility that it is substantially different
Low (C)	Our confidence in the estimated effect is limited; the true effect may be substantially different from the estimate
Very low (D)	We have very little confidence in the estimated effect; the true effect is likely to be substantially different from the estimate
Strength of recommendation
Strong (1)	The desirable effects of an intervention clearly outweigh the undesirable effects, or vice versa
Weak (2)	The balance between desirable and undesirable effects is uncertain, or evidence suggests that benefits and harms are closely balanced regardless of evidence quality

The consensus process was conducted using a structured Delphi methodology through an integrated intelligent platform for medical guideline and consensus development. Supporting materials—including draft recommendations, rationale statements, evidence summaries, search strategies, summary of findings tables, and evidence grading forms—were uploaded to the platform. Two rounds of Delphi surveys were conducted between October and December 2025 via the “Fangdian: Medical Guideline and Consensus Development Platform” (https://develop.guidelines‐registry.cn/my/guidelines).

The first round of Delphi consultation was conducted from October 22 to October 31, 2025, involving all 34 consensus experts, each of whom provided feedback on all draft recommendations. Seven recommendations did not reach consensus (agreement rate <80%) in the first round and proceeded to a second round of Delphi consultation conducted from December 12 to December 18, 2025. Again, all 34 experts participated and provided feedback. Three recommendations failed to achieve consensus in the second round (agreement rate <80%). Given the lack of consensus and insufficient supporting evidence, these recommendations were removed. Specifically, for Clinical Question 4, one recommendation was deleted, resulting in two final recommendations; for Clinical Question 13, two recommendations were deleted, resulting in two final recommendations.

After completion of the draft guideline, eight independent external experts who had not participated in the earlier development stages were invited to conduct an external review. Revisions were made on the basis of their feedback, and the final version of the guideline was subsequently completed.

3. Guideline Recommendations and Explanations

Clinical Question 1: Principles of Pharmacological Pain Management in Geriatric Palliative Care

Recommendation 1

The core principles of pain management in older adults receiving palliative care are comprehensive assessment, mechanism‐based analgesic selection, individualized titration, safety monitoring, and person‐centered care, as detailed below.

• (1) Comprehensive and mechanism‐based assessment

Pain assessment should include intensity, location, duration, temporal pattern, aggravating and relieving factors, etiology, and pain mechanism, including nociceptive/somatic pain, visceral pain, neuropathic pain, and mixed pain. Validated pain assessment tools should be used whenever possible, and observational tools should be considered for patients with cognitive impairment or limited communication.

• (2) Stepwise pharmacotherapy

Analgesic selection should be based on systematic pain assessment, with appropriate use of adjuvant analgesics and gradual dose titration according to response.

• Mild pain: Non‐opioid analgesics are recommended as first‐line therapy.

• Moderate pain: Weak opioids or low‐dose strong opioids may be used.

• Severe pain: Strong opioids are indicated.

At any pain intensity level, adjuvant analgesics and non‐pharmacological interventions may be combined based on clinical evaluation.

• (3) Safe and rational prescribing

When opioids are indicated, appropriate agents and formulations should be selected on the basis of individual characteristics. Dosing should follow titration principles, with close monitoring of analgesic efficacy and proactive management of adverse effects, particularly opioid‐induced constipation, sedation, delirium, falls, and respiratory depression.

• (4) Person‐centered and compassionate care

A rapid pain–response mechanism should be established. Treatment decisions should respect patients’ and families’ preferences, ensuring informed consent and shared decision‐making. Holistic care addressing physical, psychological, cultural, and spiritual dimensions should be provided to preserve dignity at the end of life.

Rationale and Evidence Summary

This recommendation is informed by six international guidelines, one Chinese guideline, and one expert consensus statement. Collectively, these sources emphasize comprehensive assessment, individualized treatment, multidisciplinary collaboration, and the balance between analgesic efficacy and safety. Pain management in palliative care should be grounded in thorough clinical assessment [17, 18]. Individualized treatment requires evaluation of functional status, cognitive capacity, comorbid conditions, and medication tolerance [19]. Validated assessment tools should be used to quantify pain intensity. For patients with impaired consciousness or cognitive decline, observational assessment instruments are recommended. For example, validated tools for advanced dementia can be used to guide individualized treatment planning [17, 20]. Analgesic selection should correspond to pain severity. For mild pain, nonsteroidal anti‐inflammatory drugs (NSAIDs) may be considered first‐line therapy, with careful attention to gastrointestinal and cardiovascular risks in older adults. For moderate‐to‐severe pain (≥4 on a numerical rating scale), weak opioids or strong opioids are recommended, with prompt titration to achieve adequate analgesia [21]. For breakthrough pain, immediate‐release opioid formulations should be administered at 10%–20% of the total opioid dose used in the previous 24 h [8]. Regular reassessment of efficacy and adverse effects is essential, and dose adjustments should be made according to disease progression and renal function [18]. In cases of refractory pain unresponsive to optimized conventional therapy, palliative sedation may be considered to relieve intolerable suffering, with careful attention to patient preferences and cultural or religious values. Excessive or non‐indicated sedation should be avoided [22, 23].

Opioid therapy should be considered when pain is moderate to severe, when pain remains inadequately controlled despite appropriate non‐opioid therapy, when severe pain is present at initial assessment, or when rapid symptom relief is required in end‐of‐life care. Initiation should be based on structured pain assessment, patient goals, prior opioid exposure, frailty, renal and hepatic function, and risk of adverse effects. In frail older patients, opioids should generally be started at a low dose, titrated cautiously, and reassessed frequently for analgesia, sedation, delirium, constipation, nausea, falls, and respiratory depression.

Effective pain management in older adults receiving palliative care requires a multidisciplinary team approach to optimize analgesic selection, monitor adverse effects, and improve overall QoL.

Clinical Question 2: Use, Dosing, and Safety Considerations of Opioid Analgesics in Geriatric Palliative Care

Recommendation 2

Opioid analgesics are effective for pain relief in older adults receiving palliative care (1B). However, older patients are at increased risk of opioid‐related adverse effects; therefore, the benefits and harms should be carefully weighed before initiation (1A).

Recommendation 3

In patients with cancer‐related pain, oral morphine, oral oxycodone, and transdermal fentanyl provide comparable analgesic efficacy. De‐emphasizing the traditional “second step” of the WHO analgesic ladder, initiation with low‐dose strong opioids (e.g., morphine 30 mg/24 h) combined with appropriate adjuvant analgesics is an effective strategy for moderate pain (2C).

Recommendation 4

In end‐of‐life patients whose pain is inadequately controlled with oral or transdermal regimens, conversion to continuous intravenous or subcutaneous infusion of short‐acting strong opioids is recommended. Patient‐controlled analgesia (PCA) can effectively reduce pain intensity. Treatment should be initiated at low doses, with careful titration and dynamic monitoring of analgesic response and adverse effects and prompt adjustment of infusion parameters as needed (1B).

Rationale and Evidence Summary

These recommendations are supported by two cohort studies [24, 25], three randomized controlled trials (RCTs) [26, 27, 28], two systematic reviews [29, 30], and one retrospective analysis [31]. Additional analyses examined opioid‐related medication errors [31], co‐prescription of opioids with laxatives and antiemetics [32], and implementation rates of evidence‐based pain management practices—including comprehensive pain assessment and bowel management orders [27]. However, the certainty of evidence for these outcomes was rated as very low, and therefore these findings were not incorporated into formal recommendations. Across the eight included studies, patients receiving palliative care services were more likely to be prescribed strong opioids (OR = 3.18, 95% CI: 2.05–4.94). Among these, 31.1% received morphine or hydromorphone. Direct initiation of strong opioids was associated with higher rates of anorexia (OR = 1.89, 95% CI: 1.49–2.39) and constipation (OR = 2.98, 95% CI: 2.35–3.80) [26]. Oral morphine (362/377) and transdermal fentanyl (461/479) were both effective in reducing cancer pain to mild intensity or complete relief within 14 days [29]. Comparative data indicate similar mean pain control intensity across morphine‐, oxycodone‐, and fentanyl‐based regimens [28]. A systematic review (n = 50) demonstrated that subcutaneous and intravenous opioid PCA effectively relieve cancer‐related pain, with serious adverse events being uncommon [30]. Overall, the evidence demonstrates the analgesic efficacy of strong opioids in geriatric palliative care, while highlighting the importance of careful dose selection, adverse‐effect monitoring, and individualized titration, particularly in frail older adults.

When selecting an opioid, clinicians should consider route feasibility, prior opioid exposure, renal function, hepatic function, frailty, drug–drug interactions, and expected prognosis. Morphine and hydromorphone have renally cleared metabolites and require caution in renal impairment; fentanyl may be useful when oral administration is not feasible but is not appropriate for opioid‐naïve patients at standard transdermal doses; oxycodone is affected by CYP3A and CYP2D6 interactions; methadone should generally be reserved for clinicians experienced in its use because of variable pharmacokinetics, QT prolongation risk, and interaction potential. During opioid rotation, an equianalgesic dose should be calculated and then reduced by approximately 25%–50% to account for incomplete cross‐tolerance, with further dose adjustment according to frailty, organ function, and symptom response. The CDC opioid prescribing guideline provides useful general safety principles but does not directly apply to cancer‐related pain, palliative care, or end‐of‐life care; therefore, its principles should be adapted to the goals of end‐of‐life symptom relief.

Clinical Question 3: Use, Dosing, and Safety Considerations of Nonsteroidal Anti‐Inflammatory Drugs (NSAIDs) in Geriatric Palliative Care

Recommendation 5

For patients with mild‐to‐moderate pain, acetaminophen is recommended as first‐line therapy at an oral dose of 1–2 g/day. Caution is advised in patients with hepatic impairment or chronic alcohol use (1A).

Recommendation 6

In patients with contraindications to acetaminophen who experience mild‐to‐moderate joint, muscle, or soft tissue pain, topical NSAIDs, such as diclofenac sodium gel (applied three to four times daily), are recommended (1B).

Recommendation 7

Before initiating oral NSAIDs, comprehensive assessment of cardiovascular, thrombotic, gastrointestinal bleeding, renal, heart failure, blood pressure, and drug‐interaction risks is required. Nonselective NSAIDs and COX‐2 selective NSAIDs differ in their balance of gastrointestinal and cardiovascular risks, but both classes may increase serious cardiovascular thrombotic events, gastrointestinal bleeding or perforation, renal injury, fluid retention, and heart failure exacerbation. Routine or scheduled oral NSAID use should generally be avoided in patients receiving anticoagulants or at high bleeding risk unless no safer alternative is available and the expected benefit clearly outweighs the risk. If an NSAID is used, the lowest effective dose for the shortest possible duration should be prescribed, with gastroprotection and close monitoring when appropriate (1A).

Rationale and Evidence Summary

These recommendations are supported by four meta‐analyses [33, 34, 35, 36], one narrative review [37], one RCT [38], two cohort studies [39, 40], and one case–control study [41]. Although acetaminophen has weaker anti‐inflammatory and analgesic effects compared with NSAIDs, it is associated with greater gastrointestinal and renal safety, fewer drug–drug interactions, and pharmacokinetics that are not substantially influenced by aging. Hepatotoxicity should be considered mainly in relation to acetaminophen overdose or high‐risk patients, including very old, malnourished, low‐body‐weight, or chronic alcohol‐consuming patients. By contrast, NSAID safety concerns should focus primarily on cardiovascular, renal, gastrointestinal, and bleeding risks. NSAIDs may exacerbate hypertension, heart failure, and renal dysfunction and should generally be avoided in patients with end‐stage heart failure, severe renal impairment, active gastrointestinal bleeding, or concurrent anticoagulation unless the benefit clearly outweighs risk and safer alternatives are unavailable. When nonselective NSAIDs are prescribed, co‐administration of proton pump inhibitors (PPIs) or misoprostol is recommended for gastrointestinal protection. Clinicians should also be vigilant regarding drug interactions with aspirin, diuretics, warfarin, and other commonly prescribed medications.

A systematic review [36] demonstrated that acetaminophen is effective for osteoarthritis pain, with fewer adverse effects compared with oral NSAIDs. A meta‐analysis of 10 RCTs (n = 1712) [34] showed that NSAIDs were associated with higher clinical response rates than acetaminophen for osteoarthritis pain (relative risk [RR] = 1.24, 95% CI: 1.08–1.41), but also higher rates of adverse events. An RCT by Simon et al. (n = 775) [38] reported that topical diclofenac provided analgesic efficacy comparable to oral diclofenac, with fewer systemic adverse effects. A meta‐analysis of 14 studies (n = 1502) [35] found that topical NSAIDs were significantly more effective than placebo (relative benefit [RB] = 1.9, 95% CI: 1.7–2.2), with no statistically significant difference compared with oral NSAIDs. A prospective cohort study (n = 1756) [40] reported that NSAIDs accounted for 23.5% of hospitalizations due to adverse drug reactions among older adults. A meta‐analysis (n = 754) [33] found that selective COX‐2 inhibitors (RR = 1.37, 95% CI: 1.14–1.66) and diclofenac (RR = 1.41, 95% CI: 1.12–1.78) were associated with approximately one‐third increased risk of major vascular events. All NSAIDs approximately doubled the risk of heart failure and increased the risk of upper gastrointestinal complications. A case–control study by Griffin et al. [41] reported that NSAID use increased the risk of acute kidney injury by 58% (adjusted OR = 1.58; 95% CI: 1.34–1.86). In a cohort study of 82,955 post–myocardial infarction patients receiving antithrombotic therapy [39], concomitant use of PPIs was associated with reduced gastrointestinal bleeding risk (HR = 0.72, 95% CI: 0.54–0.95). Pickering et al. [37] emphasized that in high‐risk patients receiving long‐term NSAIDs (age >75 years, concomitant use of glucocorticoids, anticoagulants, antiplatelets, or prior ulcer disease), co‐prescription of PPIs is essential. Overall, whereas NSAIDs may provide superior analgesic efficacy in certain conditions, their use in geriatric palliative care requires careful risk stratification and proactive prevention of cardiovascular, gastrointestinal, and renal complications.

Clinical Question 4: Use, Dosing, and Safety Considerations of Common Adjuvant Analgesics in Geriatric Palliative Care

Recommendation 8

For neuropathic pain in older adults receiving palliative care, gabapentin is recommended (1B). A suggested titration schedule is 100 mg once daily on Day 1, 100 mg twice daily on Day 2, and 100 mg three times daily on Day 3. The dose may then be gradually titrated according to pain intensity, up to a maximum of 900–1800 mg/day as tolerated. Pregabalin may be used as an alternative, initiated at 75 mg twice daily, with titration up to a maximum of 300 mg/day. During treatment, adverse effects should be closely monitored, and the regimen should be dynamically adjusted on the basis of clinical response and tolerability. In cases of refractory pain, multidisciplinary consultation involving pain specialists, anesthesiologists, and clinical pharmacists is recommended. Common adverse effects include fatigue, dizziness, somnolence, cognitive impairment, and ataxia. Other possible reactions include headache and nausea. Rarely, rash, peripheral edema, or respiratory depression may occur and require careful monitoring (1B).

Rationale and Evidence Summary

This recommendation is supported by two systematic reviews and four RCTs. Current evidence suggests that adjuvant analgesics are effective in non‐cancer pain; however, whether they provide additional benefit within comprehensive palliative care pain regimens remains uncertain. After comprehensive evaluation of the available data, the working group concluded that gabapentin demonstrates adjunctive analgesic effects, although existing studies are limited by small sample sizes and require confirmation in larger trials. Combination therapy with pregabalin and opioids or NSAIDs may be an option.

In patients with renal impairment, dose adjustment based on creatinine clearance is required to avoid drug accumulation. During treatment, adverse effects should be actively monitored. Gabapentin and pregabalin are gabapentinoids and are not typically classified as anticholinergic drugs; however, they contribute to central nervous system depressant burden and require careful monitoring in older adults. Clinicians should monitor for dizziness, somnolence, cognitive impairment, gait instability, falls, edema, and respiratory depression. Concomitant use with opioids, benzodiazepines (BZDs), Z‐drugs, or other central nervous system depressants should be avoided when possible or undertaken only with close monitoring, particularly in patients with chronic respiratory disease or severe frailty. If mild cognitive decline occurs, dose escalation should be paused or dose reduction considered. In cases of significant somnolence or cognitive impairment, dose reduction or discontinuation should be considered, alongside integration of non‐pharmacological interventions.

If mild cognitive decline occurs, dose escalation should be paused or dose reduction considered. Concomitant use with other sedative medications should be avoided whenever possible. In cases of significant somnolence or cognitive impairment, dose reduction or discontinuation should be considered, alongside integration of non‐pharmacological interventions. A meta‐analysis [42] reported a standardized mean difference (SMD) of 0.16 (95% CI: −0.19, 0.51) for gabapentin in cancer‐related pain, suggesting limited overall effect. However, a systematic review of three RCTs [43, 44, 45] demonstrated that in palliative care patients with neuropathic pain, gabapentin was associated with a mean difference (MD) of −1.47 (95% CI: −2.37, −0.57), indicating potential benefit. A meta‐analysis [46] showed that pregabalin reduced neuropathic pain in cancer patients (weighted MD [WMD] = −1.00, 95% CI: −1.29, −0.70). In contrast, one RCT evaluating pregabalin during radiotherapy in cancer patients found no significant difference compared with placebo [47]. Overall, gabapentinoids may provide benefit in neuropathic pain among geriatric palliative care patients, but the magnitude of effect varies, and careful titration and safety monitoring are essential, particularly in frail older adults.

Clinical Question 5: Principles of Pharmacological Management of Dyspnea in Geriatric Palliative Care

Recommendation 9

For dyspnea in older adults receiving palliative care, a stepwise and stratified management approach is recommended as follows:

• (1) Comprehensive assessment and etiologic management

Assessment should include dyspnea severity, precipitating factors, oxygenation, anxiety, secretions, bronchospasm, pulmonary edema, pleural effusion, infection, anemia, and other potentially reversible contributors. Etiology‐directed treatments, such as bronchodilators for bronchospasm, diuretics for pulmonary edema, corticosteroids for selected inflammatory or obstructive conditions, antibiotics for infection when consistent with goals of care, oxygen for hypoxemia, and noninvasive ventilation for selected patients with hypercapnia, should be considered before or alongside symptom‐directed treatment.

• (2) Non‐pharmacological interventions

Non‐pharmacological strategies should be implemented according to clinical condition. These may include supplemental oxygen (for hypoxemic patients), airway clearance (e.g., suctioning), fan therapy, positional adjustments, improving room ventilation, reducing ambient temperature, stress management, relaxation techniques, and other comfort‐focused measures.

• (3) Pharmacological management

If non‐pharmacological interventions provide insufficient relief, opioids (e.g., morphine) are recommended for symptomatic control. If dyspnea is accompanied by significant anxiety and remains inadequately controlled despite optimized non‐pharmacological measures and opioid therapy, BZDs may be used cautiously. For patients with suspected airway obstruction or inflammatory components, systemic corticosteroids may be considered. At present, there is insufficient evidence to support or refute the use of antidepressants or antipsychotics for dyspnea in end‐of‐life patients (GPS).

Rationale and Evidence Summary

This recommendation is based on eight national and international guidelines [8, 17, 20, 22, 48, 49, 50, 51]. Management of dyspnea in palliative care should be conducted by a multidisciplinary team, with the primary goal of relieving subjective breathlessness and improving comfort rather than solely correcting oxygen saturation levels. Although not all non‐pharmacological interventions are supported by high‐certainty evidence, they are generally low risk, inexpensive, and feasible. Given the heightened susceptibility of older palliative care patients to medication‐related adverse effects and the limited therapeutic options available, non‐pharmacological measures are prioritized as first‐line strategies. Comprehensive assessment of dyspnea should include evaluation of severity, etiology, precipitating factors, associated symptoms, emotional distress, and functional impact [48]. Identification and treatment of underlying causes are essential components of management [49]. Clinicians should actively assess for potentially reversible conditions, such as pulmonary edema or pleural effusion, and intervene appropriately [51]. For patients approaching the end of life, non‐pharmacological measures—including fan therapy, supplemental oxygen in hypoxemic individuals, environmental cooling, stress reduction, relaxation techniques, and physical comfort measures—should be prioritized [22, 48]. Existing guidelines recommend implementing these strategies before initiating pharmacological therapy and continuing them alongside drug treatment [50]. If non‐pharmacological interventions fail to provide adequate relief, opioids, such as morphine, are recommended for refractory dyspnea in terminally ill patients. Evidence supporting opioid use is most robust in chronic obstructive pulmonary disease (COPD) [8, 17, 20, 22, 49]. However, opioids are associated with adverse effects, including constipation, nausea, somnolence, pruritus, and, rarely, bronchospasm. Preventive measures and careful monitoring are required [48, 49, 50]. In end‐of‐life patients with anxiety‐related dyspnea that remains uncontrolled despite optimized non‐pharmacological and opioid therapy, BZDs may be considered [17, 20, 22, 48, 49]. For dyspnea related to malignant lymphangitic carcinomatosis, radiation pneumonitis, superior vena cava syndrome, inflammatory processes, or tumor‐related airway obstruction, systemic corticosteroids may provide benefit, although evidence remains limited [8, 48, 49, 50]. Sertraline is not recommended for chronic breathlessness, and the use of other antidepressants or antipsychotics for dyspnea should be limited to clinical trial settings [48, 49, 50]. Overall, dyspnea management in geriatric palliative care should prioritize symptom relief, individualized care planning, and careful balancing of benefits and harms.

Clinical Question 6: Use, Dosing, and Safety Considerations of Opioids for Dyspnea in Geriatric Palliative Care

Recommendation 10

For refractory dyspnea in older patients receiving end‐of‐life palliative care, low‐dose immediate‐release oral morphine may be considered after potentially reversible causes have been assessed and treated according to goals of care. An initial dose of 2.5 mg every 4 h may be considered, with additional doses as needed. Once symptoms are stabilized, conversion to an equivalent total daily dose administered twice daily in a sustained‐release formulation may be appropriate. If morphine is ineffective or not tolerated, opioid rotation to oral oxycodone, hydromorphone, or transdermal fentanyl may be considered, with individualized dose adjustment. Opioids are intended to relieve the subjective sensation of breathlessness rather than correct hypoxemia or replace disease‐specific therapy. Extra caution is required in acute unstable asthma, untreated acute respiratory failure, severe hypercapnia, rapidly reversible airway obstruction, or when opioids are combined with other sedatives. Routine nebulized administration of opioids (e.g., morphine or fentanyl) is not recommended (2C).

Recommendation 11

During opioid therapy for dyspnea, clinicians should monitor for respiratory rate, oxygen saturation, level of consciousness, delirium, constipation, nausea, vomiting, falls, and overall comfort after initiation and dose escalation (1B).

Rationale and Evidence Summary

These recommendations are supported by 29 studies, including four systematic reviews and meta‐analyses. Study populations primarily included older adults with advanced cancer, COPD, or heart failure, with mean ages ranging from 65 to 78 years. The direction of effect was consistent across studies, supporting cautious extrapolation to geriatric palliative care populations. Prior to initiation of opioid therapy, comprehensive assessment should include frailty status, renal function, and comorbid conditions. Constipation is common and should be prevented proactively, for example, through co‐prescription of stimulant laxatives (e.g., senna plus docusate) or polyethylene glycol (PEG). Nausea and sedation are dose‐dependent and often improve within 48 h. Neither RCTs nor large cohort studies have reported severe respiratory depression requiring naloxone reversal; however, close monitoring remains essential.

Monitoring is recommended at approximately 4 and 24 h after the initial dose, including respiratory rate, oxygen saturation (SpO₂), and level of consciousness. If respiratory rate falls below 8 breaths per minute or SpO₂ decreases below 88% in the absence of other reversible causes, the next dose should be withheld and dose reduction of 25%–50% considered. Oral and subcutaneous routes are preferred to minimize invasive procedures and reduce infection risk. Low‐dose opioids improve the subjective sensation of breathlessness rather than directly correcting oxygen saturation, aligning with patients’ and families’ goals of rapid symptom relief without increasing distress. Immediate‐release oral morphine 5 mg typically has an onset of action within approximately 30 min, meeting expectations for timely symptom control. If oral administration becomes impractical (e.g., dysphagia), seamless conversion to subcutaneous morphine or oxycodone is recommended, consistent with the palliative care principle of minimizing invasive interventions. Seven cohort studies [52, 53, 54, 55, 56, 57, 58] demonstrated clinically meaningful dyspnea relief with opioids, corresponding to an absolute effect of 654 per 1000 patients experiencing symptom improvement. A systematic review, including 15 RCTs [59], found that in non‐cancer chronic respiratory disease, low‐dose morphine significantly reduced worst dyspnea in patients with modified Medical Research Council (mMRC) dyspnea grade ≥3 and improved exercise‐induced breathlessness.

Multiple non‐randomized controlled studies suggest that opioids may effectively relieve dyspnea in terminally ill patients [60, 61, 62, 63, 64, 65, 66, 67, 68]. Fentanyl has shown potential benefit in case series and observational studies, but high‐quality RCT evidence remains limited [69]. If oral morphine is ineffective or poorly absorbed, conversion to equianalgesic oxycodone or continuous subcutaneous infusion of morphine or oxycodone may be considered. Three prospective observational studies [70, 71, 72] reported additional dyspnea relief in 56%–73% of patients following opioid rotation. Routine nebulized opioids are not recommended. Two systematic reviews [73, 74] found no significant difference in visual analog scale (VAS) dyspnea scores between nebulized opioids and placebo. Charles et al. [65] reported that subcutaneous hydromorphone produced faster and more profound relief compared with nebulized administration. Constipation is the most common adverse effect. A meta‐analysis of four RCTs [75, 76, 77, 78] showed an increased risk of constipation of approximately 138 per 1000 patients (OR = 2.09, 95% CI: 1.28–3.41). Prophylactic laxatives may reduce constipation rates to below 15%. Serious adverse events are rare; two large cohort studies [79, 80] (n = 18,539) reported no cases of respiratory depression requiring naloxone reversal. Nonetheless, vigilance for respiratory compromise remains essential.

Clinical Question 7: Use, Dosing, and Safety Considerations of Benzodiazepines for Dyspnea in Geriatric Palliative Care

Recommendation 12

For end‐of‐life patients experiencing acute exacerbation of dyspnea or dyspnea accompanied by significant anxiety, short‐term use of BZDs may be considered. Oral midazolam may be initiated at 0.5–1 mg, with a maximum total dose not exceeding 10 mg within 24 h (1B).

Recommendation 13

In patients whose dyspnea is inadequately relieved by opioids and is accompanied by anxiety, adjunctive benzodiazepine (B) therapy may be considered. Lorazepam 0.5–1 mg may be administered orally or sublingually as needed or two to three times daily (1C).

Recommendation 14

For terminal patients with refractory dyspnea unresponsive to optimized therapy, proportionate palliative sedation may be considered. Continuous midazolam infusion should be individualized, with infusion rates not exceeding 1.5 mg/h (1C).

Rationale and Evidence Summary

Although opioids remain the first‐line pharmacological treatment for dyspnea in end‐of‐life patients, BZDs may serve as adjunctive therapy in selected situations. The evidence supporting BZDs for dyspnea relief is limited and of low quality; therefore, they are not recommended as first‐line treatment [81]. BZDs may be considered when opioid therapy alone is insufficient, in cases of acute exacerbation of dyspnea, or when dyspnea is accompanied by significant anxiety. When used in combination with opioids, clinicians must remain vigilant for additive respiratory depression. Short‐term use at the lowest effective dose is advised, with close monitoring of respiratory rate, level of consciousness, and fall risk. If excessive sedation, cognitive impairment, or other adverse effects occur, dose reduction or discontinuation should be considered. These recommendations are based on four studies, including one RCT [82], one non‐randomized controlled study [83], one retrospective cohort study [84], and one case–control study [85]. In a study by Navigante et al. (n = 63) [82], midazolam demonstrated superior reduction in intensity and frequency of acute dyspnea episodes compared with morphine in patients with advanced disease. A retrospective cohort study [84] reported that combined use of BZDs and opioids significantly improved dyspnea compared with opioid monotherapy or no pharmacological treatment (OR = 5.5, 95% CI: 1.4–21.3). Prado et al. (n = 374) [85] found that patients receiving palliative sedation for refractory dyspnea had a median hospital survival approximately twice that of the comparison group (33.6 vs. 16 days), suggesting that proportionate sedation did not shorten survival. A non‐randomized controlled clinical study [83] suggested that in patients with dyspnea accompanied by anxiety, combined opioid and BZD therapy (lorazepam 1 mg sublingually) significantly reduced dyspnea severity. It should be noted that the use of lorazepam for anxiety‐associated dyspnea represents off‐label use. Overall, BZDs may be considered in carefully selected patients with anxiety‐related or refractory dyspnea; however, given limited high‐quality evidence and potential safety concerns, their use should be individualized, time‐limited, and closely monitored.

BZDs should not be used as first‐line pharmacological treatment for dyspnea in older adults. Consistent with geriatric prescribing safety principles, routine use should generally be avoided because of risks of sedation, cognitive impairment, delirium, falls, fractures, dependence, and respiratory depression, particularly when combined with opioids. In end‐of‐life palliative care, short‐term use may be considered only for carefully selected patients with severe anxiety‐associated dyspnea, acute terminal distress, or refractory dyspnea requiring proportionate palliative sedation, with the lowest effective dose and close monitoring.

Clinical Question 8: Combined Pharmacological and Non‐Pharmacological Interventions for Dyspnea in Geriatric Palliative Care

Recommendation 15

For patients with terminal dyspnea, airflow interventions—such as directing a handheld or bedside fan toward the face—are recommended (1B).

Recommendation 16

Standard oxygen therapy is recommended for dyspneic patients with documented hypoxemia (oxygen saturation ≤90% on room air). Routine oxygen therapy is not recommended for patients with oxygen saturation >90%, as current evidence suggests limited improvement in subjective dyspnea and potential for increased dependence and financial burden. However, clinical symptoms should be considered comprehensively, and oxygen saturation should not be used as the sole determinant for treatment decisions (1B).

Recommendation 17

For patients whose dyspnea is not adequately relieved by standard oxygen therapy, short‐term high‐flow nasal cannula (HFNC) oxygen may be considered where available. For patients with concomitant hypercapnia, noninvasive positive pressure ventilation (NIPPV) may be used (1B).

Recommendation 18

On the basis of patient preference, additional non‐pharmacological interventions may be considered, including acupressure, reflexology, acupuncture, breathing training, music therapy, relaxation techniques, or psychological interventions (2C).

Rationale and Evidence Summary

Airflow interventions, commonly referred to as fan therapy, typically involve lightweight handheld battery‐operated fans directed toward the face. If patients are unable to hold the device, tabletop or floor‐standing fans may be used. Fan therapy is simple, low‐cost, and minimally invasive. Eight RCTs (n = 371) [86, 87, 88, 89, 90, 91, 92, 93] demonstrated that fan therapy significantly alleviates dyspnea. A meta‐analysis [94] reported significant improvement in resting dyspnea in terminally ill patients (MD = −1.31, 95% CI: −1.79 to −0.83). Evidence regarding oxygen therapy remains mixed. A systematic review (n = 83) [95] suggested that oxygen therapy may improve resting dyspnea in selected terminal patients. However, a meta‐analysis (n = 134) [96] and a multicenter RCT [97] found no significant difference between oxygen and control interventions in dyspnea relief. Many studies were limited by small sample sizes, case‐series designs, and the lack of matched controls, resulting in low overall certainty of evidence. Given the high sensitivity of older palliative care patients to medication‐related adverse effects and limited therapeutic options, non‐pharmacological interventions—despite heterogeneous evidence quality—are recommended because they are simple, low‐risk, and supported by preliminary data.

Two RCTs (n = 47) [98, 99] demonstrated that high‐flow nasal oxygen reduced dyspnea scores compared with control, with improvements of −1.83 on the numerical rating scale (95% CI: −2.69 to −0.97) and −1.90 on the modified Borg scale (95% CI: −2.75 to −1.05). Another RCT (n = 200) showed that noninvasive ventilation provided more rapid dyspnea relief than standard oxygen therapy (MD = −0.58, 95% CI: −0.92 to −0.23), with the greatest benefit observed in patients with hypercapnia during the first treatment hour. Total morphine consumption within 48 h was also lower in the noninvasive ventilation group (MD = −32.4 mg, 95% CI: −47.5 to −17.4) [100]. Evidence supporting complementary therapies is limited and heterogeneous. Studies suggest that acupressure may reduce dyspnea severity and improve QoL [101, 102], and foot reflexology has demonstrated benefit compared with usual care [103]. However, Vickers et al. [104] reported no significant improvement in dyspnea scores with acupuncture. Multiple observational studies [105, 106, 107, 108] indicate that music therapy may improve dyspnea, pain, anxiety, and overall psychological well‐being in patients with advanced illness. Johnson et al. [109] found that structured breathing training may alleviate dyspnea, although repeated sessions did not demonstrate significantly greater benefit than a single session. Psychological interventions—including hypnosis, mindfulness‐based breathing, and guided listening—have been associated with reductions in dyspnea and psychological distress [110, 111]. Overall, non‐pharmacological interventions play a central supportive role in dyspnea management for geriatric palliative care patients. Although evidence quality varies, these interventions are generally safe, accessible, and aligned with patient‐centered care principles.

Clinical Question 9: Use, Dosing, and Safety Considerations of Centrally Acting Antitussive Agents for Cough and Sputum in Geriatric Palliative Care

Recommendation 19

For chronic cough associated with idiopathic pulmonary fibrosis (IPF), low‐dose sustained‐release morphine (5 mg twice daily) may be considered (2C).

Recommendation 20

For chronic cough due to other underlying conditions, centrally acting antitussive agents may be considered, including the following points:

• Dextromethorphan 20 mg twice daily (2C).

• Codeine 15 mL three times daily (2D).

• Pholcodine 15 mL three times daily (2D).

Rationale and Evidence Summary

International and national guidelines emphasize that cough severity should be assessed systematically and underlying causes should be actively managed [112, 113]. The present recommendations focus specifically on centrally acting antitussive agents. The available evidence is limited and primarily derived from RCTs with small sample sizes, precluding reliable assessment of heterogeneity or publication bias. In geriatric palliative care patients, therapeutic decisions should prioritize safety and tolerability. Morphine has been shown to reduce cough frequency and intensity; however, adverse effects—including constipation, dizziness, and nausea—are common and require careful risk–benefit evaluation. Data specific to geriatric palliative populations remain scarce, and further research is needed to clarify the dose–response relationship of morphine for cough in this setting. Most studies evaluating other centrally acting antitussive agents have focused on cough associated with COPD, lung cancer, or interstitial lung disease. These studies represent indirect evidence for palliative care populations, as underlying etiologies and patient characteristics may differ. Overall evidence quality is low, and safety data are limited; therefore, recommendations are weak. Special caution is warranted in older adults or those with chronic respiratory disease. Centrally acting antitussives should not be combined with other central nervous system depressants, and periodic reassessment of cough etiology and treatment response is essential to avoid masking infection or aspiration risk.

A crossover RCT (n = 43) [114] demonstrated that in patients with IPF, sustained‐release morphine (5 mg twice daily) significantly reduced daytime cough frequency (SMD = −39.4%, 95% CI: −54.4% to −19.4%), cough severity (SMD = −14.6, 95% CI: −22.8 to −6.5), and Leicester IPF cough scores (SMD = −11.9, 95% CI: −18.7 to −5.1). However, adverse events were significantly more frequent (RR = 2.77, 95% CI: 1.21–6.33), primarily nausea and constipation [114]. Two RCTs (n = 70) [115, 116] found that codeine did not significantly reduce cough frequency or severity in older adults compared with control. In contrast, one RCT (n = 60) [117] reported that both pholcodine and codeine reduced cough episodes in older patients with lung cancer, with comparable efficacy between agents. However, the absence of placebo control limits interpretability. Another randomized trial (n = 16) [115] showed that dextromethorphan significantly reduced nighttime cough frequency (SMD = −1.91, 95% CI: −2.78 to −1.04) and cough severity (SMD = −1.25, 95% CI: −2.04 to −0.46). Overall, although certain centrally acting antitussive agents may provide symptomatic benefit, evidence remains limited and heterogeneous. Treatment decisions should be individualized, cautiously implemented, and regularly reassessed.

Clinical Question 10: Use, Dosing, and Safety Considerations of Other Antitussive and Expectorant Agents for Cough and Sputum in Geriatric Palliative Care

Recommendation 21

Mucolytic agents, such as ambroxol or carbocisteine, may be considered to reduce sputum viscosity and facilitate airway clearance. Concomitant use of strong antitussive agents should be avoided during mucolytic therapy, as suppression of the cough reflex may increase the risk of airway obstruction by thinned secretions (2B).

Rationale and Evidence Summary

These recommendations are primarily based on 10 RCTs [118, 119, 120, 121, 122, 123, 124, 125, 126, 127]. Although direct studies in geriatric palliative care populations are limited, extrapolation from RCTs conducted in older patients with COPD is considered reasonable, given similar pathophysiological mechanisms and consistent treatment effects. The safety profile and simplicity of administration align with the needs of older patients receiving palliative care. Evidence suggests that ambroxol demonstrates clinically meaningful improvement in cough and sputum symptoms, although the number of trials specifically conducted in palliative populations remains limited. Carbocisteine has also shown benefit in reducing sputum viscosity and improving symptom control. In addition to pharmacological treatment, the management of weak or ineffective cough in palliative care should incorporate supportive non‐pharmacological strategies aimed at improving comfort and QoL. These may include postural drainage in lateral or semi‐recumbent positions combined with gentle chest percussion, meticulous oral care and gentle oropharyngeal suctioning to clear secretions [127], and humidification therapy such as nebulized normal saline [128]. All interventions should prioritize symptom relief while respecting patient tolerance and subjective comfort.

A meta‐analysis conducted by the working group, including eight RCTs (n = 203) [118, 120, 121, 122, 125, 126, 127, 129], showed that ambroxol significantly improved cough and sputum symptoms compared with placebo (OR = 4.32, 95% CI: 2.27–8.22). No serious adverse events were reported in these trials. Similarly, a pooled analysis of two RCTs (n = 142) [122, 123] demonstrated that carbocisteine significantly improved cough and sputum symptoms compared with placebo (OR = 4.04, 95% CI: 1.56–10.45), with no major adverse effects reported. Overall, although direct evidence in geriatric palliative care populations remains limited, mucolytic therapy may provide symptomatic benefit when individualized and integrated with supportive care measures.

Clinical Question 11: Use, Dosing, and Safety Considerations of Common Hemostatic Agents for Hemoptysis in Geriatric Palliative Care

Recommendation 22: Mild‐to‐Moderate Hemoptysis

• (1) Treat the underlying cause whenever possible; tranexamic acid is recommended as first‐line therapy

Oral tranexamic acid is recommended: an initial dose of 1.5 g, followed by 1 g three times daily for maintenance. If hemostasis is inadequate, the dose may be increased to 1.5–2.0 g three times daily. After hemoptysis has ceased for 1 week, the dose may be reduced to 1 g three times daily or discontinued as appropriate. Tranexamic acid is contraindicated in patients with thromboembolic disease. Before initiation, clinicians should balance expected hemostatic benefit against thrombotic risk, and thromboembolic events should be monitored during treatment (1B).

• (2) For patients unable to take oral or intravenous therapy

Nebulized tranexamic acid 0.5 g three times daily may be considered (1B). For terminal patients with hemoptysis who cannot receive oral, nebulized, or intravenous therapy, subcutaneous injection or continuous subcutaneous infusion (via syringe driver) of tranexamic acid may be considered for palliation, with a commonly used dose of 0.5–1.5 g/24 h. Both nebulized and subcutaneous tranexamic acid are off‐label; they should be used cautiously after adequate informed consent and careful assessment of benefits and risks (2D).

• (3) If tranexamic acid provides insufficient hemostasis

Adjunctive Yunnan Baiyao may be considered at 0.5 g orally three times daily; if response remains inadequate, the dose may be increased to 1 g three times daily (2C).

Recommendation 23: Massive Hemoptysis

• (1) Vasopressin (posterior pituitary extract) may be considered

A volume of 5–10 U diluted and administered by slow intravenous injection, with close monitoring of blood pressure and heart rate to avoid precipitating angina or arrhythmias. This may be followed by 10–20 U added to 250 mL of 5% glucose and administered as a slow continuous intravenous infusion. After hemoptysis stops, treatment may be continued for 1–2 days and then discontinued (2C).

• (2) Phentolamine may be considered

A volume of 10–20 mg added to 250 mL of 5% glucose and administered by intravenous infusion once daily for 5–7 days. Blood pressure should be closely monitored to prevent hypotension. Use with caution in older adults and in patients with cardio‐cerebrovascular disease (2C).

Rationale and Evidence Summary

These recommendations are supported by four systematic reviews/meta‐analyses [130, 131, 132, 133] and one retrospective cohort study [134]. Most evidence is derived from studies, including children, adults, and some older patients; therefore, application to geriatric palliative care populations is largely based on indirect evidence and cautious extrapolation. Management should prioritize safety, effectiveness, comfort, and feasibility. Tranexamic acid is recommended as the preferred hemostatic agent given its demonstrated effectiveness and acceptable safety profile. Dose adjustment according to renal function is advised, and thromboembolic events should be monitored; tranexamic acid is contraindicated in patients with thrombotic disease. Yunnan Baiyao may be used as an adjunctive therapy. For massive hemoptysis, vasopressin is considered a preferred option; both vasopressin and phentolamine require close monitoring of heart rate and blood pressure, with infusion rate adjustment as needed. Caution is warranted in patients with underlying cardiac disease or thrombotic risk. High‐quality evidence specific to geriatric palliative care remains limited, and further studies are needed.

A meta‐analysis by Tsai et al., including two RCTs (n = 93), showed that, compared with placebo, tranexamic acid reduced bleeding volume (MD = −56.21, 95% CI: −94.70 to −17.72) and shortened length of hospital stay (MD = −1.62, 95% CI: −2.93 to −0.31) [132]. A meta‐analysis by Mahalingam et al., including three RCTs (n = 203), reported that nebulized tranexamic acid (500 mg three times daily) significantly improved hemoptysis control (OR = 3.85, 95% CI: 1.25–11.88) without increasing adverse events [131]. Another systematic review found that nebulized tranexamic acid is safe and effective for non‐massive hemoptysis, enabling rapid bleeding control and reducing the need for invasive procedures [133].

A retrospective cohort study of emergency admissions for hemoptysis (n = 19,866; mean age 72 years) reported that tranexamic acid use was associated with lower in‐hospital mortality (RD = −2.5%, 95% CI: −3.5 to −1.6), shorter length of stay (RD = −2.4 days, 95% CI: −3.1 to −1.8), and reduced hospitalization costs [130]. Another meta‐analysis (n = 1379) found that adding Yunnan Baiyao to conventional hemostatic therapy significantly improved hemostasis rates (RR = 1.18, 95% CI: 1.13–1.23), reduced hemoptysis volume (MD = −107.37, 95% CI: −121.69 to −93.06), shortened duration of hemoptysis and hospitalization, and was associated with fewer adverse events [134].

Clinical Question 12: Use, Dosing, and Safety Considerations of Other Medications for Hemoptysis Management in Geriatric Palliative Care

Recommendation 24

Antitussive agents are not routinely recommended for hemoptysis in palliative care patients. For hemoptysis triggered by severe coughing, judicious antitussive therapy may be considered to reduce cough‐related bleeding (GPS).

Recommendation 25

Sedative agents are not routinely recommended for hemoptysis in palliative care patients. For hemoptysis accompanied by marked anxiety or emotional distress, low‐dose sedatives may be considered (GPS).

Rationale and Evidence Summary

A comprehensive search did not identify systematic reviews, RCTs, or cohort studies evaluating antitussive or sedative medications specifically for hemoptysis management. Therefore, these recommendations are based on expert clinical experience and formulated as GPS. In palliative care patients with hemoptysis, treatment generally focuses on hemostatic therapy and comfort‐oriented care. Beyond hemostatic agents, moderate cough suppression may be considered for hemoptysis clearly triggered by violent coughing. During antitussive treatment, clinicians should closely monitor consciousness and respiratory status and remain vigilant for impaired clearance of blood‐tinged sputum or clots, which may increase the risk of airway obstruction and asphyxia.

For patients with hemoptysis accompanied by anxiety or emotional distress, low‐dose sedatives may help stabilize mood and potentially reduce recurrence of hemoptysis by decreasing sympathetic activation, suppressing excessive cough reflexes, and improving overall comfort. When sedatives are used in palliative care, the intent should be explicit—namely, palliative (proportionate) sedation rather than disease‐directed treatment. In critically ill patients with massive hemoptysis requiring respiratory support (e.g., endotracheal intubation), sedation is an integral component of standard ICU practice [135]. However, in palliative care settings, sedative use should remain symptom‐focused and proportional.

An expert consensus statement [136] suggests that for hemoptysis triggered by severe cough, oral codeine (15–30 mg, two to three times daily) or dextromethorphan (15–30 mL, three times daily) may be considered, with dose reduction in older adults as appropriate. Related international recommendations are also largely based on expert opinion [137], reflecting a lack of high‐quality evidence. For hemoptysis accompanied by anxiety, diazepam may be considered (2.5 mg orally, two to three times daily). For patients unable to take oral medications, intramuscular administration (5–10 mg) may be used; however, diazepam is contraindicated in patients with respiratory failure. The Palliative Care Practice Guideline (2025 edition) [138] notes that patients with bleeding events (including hemoptysis) require reassurance, and sedatives may be used when necessary, although no specific agents or dosing regimens are recommended. In palliative care, sedatives, such as midazolam, are more commonly used for palliative sedation [139] rather than as direct treatment for hemoptysis.

Overall, the use of antitussive and sedative medications in palliative care patients with hemoptysis remains insufficiently supported by high‐quality evidence and should be individualized, carefully monitored, and aligned with a symptom‐relief and comfort‐oriented care approach.

Clinical Question 13: Pharmacological Principles and Medication Use for Anorexia in Geriatric Palliative Care

Recommendation 26

Megestrol acetate may be considered to improve appetite in older adults receiving palliative care. The recommended dose is 160–800 mg/day, typically administered for 1–3 months. Doses exceeding 800 mg/day have not been shown to provide additional benefit (2B).

Recommendation 27

Short‐term use of systemic corticosteroids (e.g., dexamethasone, methylprednisolone, or betamethasone) may be considered to improve appetite in geriatric palliative care patients (2C).

Rationale and Evidence Summary

These recommendations are based on 22 RCTs and three systematic reviews. Most studies enrolled adult patients with advanced cancer, rather than specifically older palliative care populations; therefore, these recommendations are based on indirect evidence and cautious extrapolation. Existing RCTs evaluating appetite stimulants are generally small and of limited methodological quality. Shared decision‐making with patients and families is essential prior to initiating therapy. Further high‐quality research is needed to provide more definitive guidance for geriatric palliative populations.

Four RCTs [140, 141, 142, 143] demonstrated that megestrol acetate improved appetite compared with placebo. However, assessment methods for appetite varied across studies, limiting the feasibility of pooled quantitative analysis. Six RCTs [144, 145, 146, 147, 148, 149] compared different doses of megestrol acetate, but results were inconsistent and did not establish a clear dose–response relationship. A systematic review by Talebi et al. [150] reported that each 200 mg/day increase in megestrol acetate was associated with a modest but statistically significant weight gain (MD = 0.44 kg; 95% CI: 0.13–0.74). However, the magnitude of effect was relatively small and may not translate into meaningful functional improvement. Another systematic review [151] suggested that megestrol acetate may increase the risk of thromboembolic events and edema, although no clear dose‐related difference in adverse events was observed. Most studies administered megestrol acetate for durations of 1–3 months. A systematic review by Miller et al. [152] reported that corticosteroids (including dexamethasone, methylprednisolone, and betamethasone) may provide short‐term improvement in anorexia symptoms. However, the number of studies is limited, and heterogeneity in dosing regimens and administration routes precludes definitive conclusions. Three RCTs [153, 154, 155] showed that dexamethasone and methylprednisolone improved appetite. Comparative data indicate that dexamethasone and megestrol acetate may provide similar appetite improvement, although corticosteroids are associated with a higher incidence of adverse effects and are therefore best used short term [156, 157]. One RCT [158] suggested that combining megestrol acetate with olanzapine may enhance appetite‐stimulating effects compared with megestrol acetate alone. Overall, pharmacological treatment of anorexia in geriatric palliative care should be individualized, time‐limited, and aligned with patient‐centered goals of care, recognizing the modest efficacy and potential adverse effects of available agents.

Clinical Question 14: Recommended Medications, Dosing, and Safety Considerations for Nausea and Vomiting in Geriatric Palliative Care

Recommendation 28

Routine prophylactic use of dopamine receptor antagonists does not reduce opioid‐related nausea and vomiting and is therefore not recommended (1B).

Recommendation 29

For nausea and vomiting associated with malignant bowel obstruction, octreotide is recommended as first‐line therapy. The recommended initial dose is 300 µg/day. It may be combined with other antiemetics for additive benefit (1A).

Recommendation 30

For chemotherapy‐ or radiotherapy‐induced nausea and vomiting, 5‐hydroxytryptamine Type 3 (5‐HT3) receptor antagonists may be used as first‐line therapy, including the following points:

• Ondansetron 8 mg once or twice daily.

• Granisetron 2 mg once daily.

Combination with other antiemetic agents may enhance efficacy (1B).

Recommendation 31

For general management of nausea and vomiting, oral agents may be initiated with one of the following:

• Haloperidol 1–2 mg/day.

• Olanzapine 2.5–5 mg/day.

• Metoclopramide 5–10 mg, three to four times daily.

These agents may be used as first‐line therapy based on symptom pattern and underlying etiology (1B).

Rationale and Evidence Summary

These recommendations are based on one systematic review/meta‐analysis, seven RCTs, and five non‐randomized controlled studies. Most studies enrolled middle‐aged and older adults with advanced cancer or end‐of‐life conditions. As such, the evidence is indirectly extrapolated to geriatric palliative care populations. Dose recommendations have been refined to enhance safety and feasibility in older patients.

Antiemetic agents are categorized according to mechanism of action, including dopamine D2 receptor antagonists, 5‐HT3 receptor antagonists, NK1 receptor antagonists, prokinetic agents, corticosteroids, anticholinergics, antihistamines, and opioid receptor antagonists. In geriatric palliative care, treatment should prioritize non‐pharmacological measures when appropriate and avoid unnecessary polypharmacy. Clinicians should evaluate underlying causes and symptom patterns, adopting an etiology‐driven rather than empiric single‐drug approach.

An RCT (n = 120) [159] demonstrated that prophylactic chlorpromazine added to oxycodone did not reduce opioid‐related nausea and vomiting but increased sedation. A retrospective study (n = 619) [160] similarly found that dopamine D2 receptor antagonists did not reduce opioid‐induced nausea and vomiting in cancer pain patients [170]. Two RCTs (n = 115) [161, 162] showed that octreotide 300 µg/day significantly reduced vomiting in malignant bowel obstruction. A prospective study (n = 46) [163] further demonstrated reduced vomiting frequency following subcutaneous octreotide 300 µg/day. A systematic review [164] and two RCTs [165, 166] demonstrated that 5‐HT3 receptor antagonists (ondansetron 8 mg once or twice daily; granisetron 2 mg/day) effectively control chemotherapy‐ or radiotherapy‐induced nausea and vomiting. In highly emetogenic chemotherapy regimens, combination therapy with NK1 receptor antagonists, olanzapine, or corticosteroids further improves efficacy [165]. An RCT (n = 121) [167] and a pharmacovigilance report (n = 150) [168] demonstrated that haloperidol (1.5 mg/day) relieved nausea and vomiting in 75%–79% of palliative care patients. Another RCT (n = 30) [169] showed that olanzapine 5 mg/day significantly improved nausea and vomiting in advanced cancer patients and also enhanced appetite. A retrospective analysis (n = 20) [170] reported that olanzapine reduced nausea severity scores from 2.4 to 0.2 in advanced cancer patients with incomplete bowel obstruction.

A pharmacovigilance report by Currow et al. (n = 53) [171] found that metoclopramide (30 mg/day) provided antiemetic benefit in 43% of patients, whereas 17% experienced lack of efficacy and potential harm. Overall, the management of nausea and vomiting in geriatric palliative care should be mechanism‐based, individualized, and cautious with respect to polypharmacy and drug‐related adverse effects.

Clinical Question 15: Use, Dosing, and Safety Considerations of Hemostatic Agents for Hematemesis and Melena in Geriatric Palliative Care

Recommendation 32

For acute upper gastrointestinal bleeding due to peptic ulcer disease, PPIs are recommended (1B).

Common regimens include

• Omeprazole 40 mg intravenously every 12 h.

• In cases of massive gastrointestinal bleeding: an initial 80 mg intravenous bolus followed by continuous infusion at 8 mg/h until bleeding is controlled.

• Alternatively, omeprazole 40 mg orally every 12 h for 5 days.

• Or lansoprazole 60 mg orally once daily for 6 days.

Recommendation 33

For massive non‐variceal gastrointestinal bleeding, somatostatin may be administered at an initial dose of 250 µg by intravenous bolus, followed by continuous infusion at 250 µg/h for 72 h. If rebleeding occurs, infusion may continue for an additional 72 h. The intensity of treatment should be individualized on the basis of patient comfort, expected survival, and family preferences, consistent with palliative care principles (2B).

Rationale and Evidence Summary

The guideline working group included five systematic reviews evaluating PPIs for gastrointestinal bleeding, all based on RCTs. However, high‐quality evidence specific to geriatric palliative care populations is scarce. Therefore, the evidence base was expanded to include pharmacologic management of gastrointestinal bleeding in general older populations. Important limitations should be acknowledged: Many studies included broader adult populations rather than strictly older adults; patients with advanced malignancy, hepatic or renal failure, or coagulopathy—common in palliative care—were frequently excluded. Additionally, study participants generally had less severe disease than typical geriatric palliative patients. Thus, conclusions represent indirect evidence and should be applied cautiously. Older palliative care patients often present with critical illness, multiple comorbidities, and complex medication regimens, making management more challenging. Treatment decisions should consider the patient's clinical condition, route feasibility, and goals of care, with priority given to rapid bleeding control and comfort. For acute non‐variceal massive bleeding, continuous somatostatin infusion may reduce the need for surgical intervention but has not demonstrated significant mortality benefit. Evidence regarding somatostatin in acute variceal bleeding remains inconsistent.

A systematic review (n = 4670) [172] demonstrated that for acute non‐variceal upper gastrointestinal bleeding, PPIs significantly reduced rebleeding (OR = 0.48, 95% CI: 0.40–0.57) and surgical intervention rates (OR = 0.61, 95% CI: 0.48–0.76), but did not significantly reduce all‐cause mortality. Another systematic review [173] confirmed reductions in rebleeding (OR = 0.49, 95% CI: 0.37–0.65) and surgical intervention (OR = 0.61, 95% CI: 0.48–0.78). In subgroup analysis of high‐risk Asian patients with adverse endoscopic findings, PPIs were associated with reduced mortality (OR = 0.53, 95% CI: 0.31–0.91). A systematic review [174] showed no significant difference between high‐dose PPI regimens (80 mg bolus followed by 8 mg/h infusion for 72 h or >192 mg/day continuous infusion) and non‐high‐dose regimens in terms of rebleeding, surgical intervention, or mortality. Another review [175] found no significant difference between oral and intravenous PPI administration in rebleeding, transfusion requirement, surgical intervention, or mortality. Oral PPI therapy was associated with shorter hospitalization (−0.74 days, 95% CI: −1.10 to −0.39). Similar findings were reported in another review [176], demonstrating no difference in 30‐day rebleeding, mortality, transfusion need, or hospital stay between oral and intravenous PPIs. An RCT (n = 95) [177] evaluating somatostatin in massive non‐variceal bleeding showed reduced need for surgical intervention (somatostatin: 5/46 vs. placebo: 14/49), without significant differences in transfusion requirements or mortality. In acute variceal bleeding, one RCT (n = 22) [178] found that somatostatin‐controlled bleeding more effectively than vasopressin within 18–24 h. However, another RCT [177] reported no significant difference between somatostatin and placebo in bleeding cessation or mortality during a 30‐h observation period. Overall, PPIs remain the cornerstone of therapy for peptic ulcer‐related bleeding, with demonstrated reductions in rebleeding and surgical intervention but limited impact on mortality. Somatostatin may reduce the need for surgery in selected cases, though survival benefit has not been consistently demonstrated. In geriatric palliative care, treatment decisions should balance bleeding control with patient comfort, overall prognosis, and goals of care.

Clinical Question 16: Other Pharmacological Interventions for Hematemesis/Melena in Geriatric Palliative Care

Recommendation 34

For patients experiencing life‐threatening or catastrophic bleeding accompanied by severe distress or anxiety, early use of sedative medication is recommended. Midazolam is preferred as first‐line therapy. A single dose of 510 mg (or 0.2 mg/kg) may be administered, preferably via intravenous route. For nonfatal bleeding episodes, a lower dose (e.g., 2.55 mg) may be considered. During sedation, supplemental oxygen and airway management equipment should be readily available to ensure patient safety (1B).

Recommendation 35

For patients with BZD allergy, hemodynamic instability, or high risk of respiratory depression, ketamine may be considered an alternative agent, with individualized dosing. Administration should strictly adhere to the principles of palliative (proportionate) sedation, with the primary goal of relieving suffering and avoiding excessive sedation (2B).

Rationale and Evidence Summary

These recommendations are based on five systematic reviews/meta‐analyses. Most included patients with advanced malignancies experiencing catastrophic bleeding due to tumor invasion of major vessels. Although not entirely equivalent to hematemesis or melena in geriatric palliative populations, clinical presentation and symptom burden are comparable. Therefore, recommendations represent indirect extrapolation based on pharmacologic consistency and similar therapeutic direction. Current domestic and international guidelines [8, 138, 179] and textbooks [180, 181] recommend midazolam as the core medication for catastrophic hemorrhage and other terminal emergencies. In geriatric palliative care, medication selection should prioritize safety, simplicity, and rapid symptom control. Intravenous midazolam is preferred for its rapid onset and titratability. For patients with BZD hypersensitivity, significant hemodynamic instability, or high risk of respiratory depression, ketamine has been suggested as an alternative in certain guidelines [179] and handbooks [181], although high‐quality evidence remains limited.

A meta‐analysis [182] demonstrated that in patients with catastrophic hemorrhage or refractory symptoms accompanied by severe distress, midazolam as first‐line palliative sedation can rapidly relieve anxiety and reduce suffering. Regarding safety, a systematic review (n = 1509) [183] reported that midazolam may increase the risk of delirium (RR = 2.39, 95% CI: 1.75–3.26), although it was associated with reduced bradycardia (RR = 0.52, 95% CI: 0.36–0.76). Another systematic review (n = 838) [184] found higher rates of adverse events with midazolam compared to other sedatives (OR = 5.25, 95% CI: 2.64–10.45). Therefore, in older adults, careful risk–benefit assessment, individualized dosing, and close monitoring of vital signs are essential. In critically ill mechanically ventilated patients, a systematic review (n = 805) [185] found that ketamine was associated with a lower incidence of delirium compared with midazolam (RR = 0.71, 95% CI: 0.51–0.99). Another large study (n = 8105) [186] reported fewer respiratory adverse events with ketamine compared to midazolam or opioids (RR = 0.55, 95% CI: 0.32–0.96). Overall, sedative use in catastrophic bleeding should be guided by the principle of proportionate palliative sedation. The primary objective is relief of intolerable suffering rather than life‐shortening. Decisions should align with patient preferences, family discussions, and established palliative care ethics.

Clinical Question 17: Principles, Dosing, and Safety Considerations for the Management of Diarrhea in Geriatric Palliative Care

Recommendation 36

After excluding fecal impactionrelated “overflow diarrhea,” and while addressing reversible causes, nonspecific antidiarrheal agents are recommended for symptom control. For infection‐related diarrhea, antimicrobial therapy should be selected on the basis of susceptibility testing. In the absence of infection, loperamide may be administered orally at an initial dose of 4 mg, followed by 2 mg after each loose stool, with a maximum of 16 mg/day. In older adults, especially those with advanced age, hepatic impairment, or marked frailty, a reduced starting dose (2 mg initially) is recommended, with a daily maximum of 812 mg. Liquid formulations or orally disintegrating capsules may be used in patients with swallowing difficulties (1B).

Recommendation 37

The combination preparation diphenoxylate‐atropine may be used for symptomatic relief of diarrhea. Recommended dosing: 5 mg (based on diphenoxylate content) orally every 6 h as needed, up to a maximum of 20 mg/day. This combination may cause central opioid‐related and anticholinergic adverse effects, including flushing, tachycardia, confusion, headache, and fluid retention. Caution is advised in older adults; dose reduction should be considered. It is contraindicated in patients with glaucoma, benign prostatic hyperplasia (BPH), or cognitive impairment (2B).

Recommendation 38

Octreotide may be considered severe noninfectious diarrhea refractory to standard therapy, particularly when associated with neuroendocrine tumors, pancreatic fistula, short bowel syndrome, or bleeding (2B).

Recommended dosing are as follows:

• Subcutaneous injection: 50–100 µg, two to three times daily; maximum 200 µg per dose.

• Continuous intravenous infusion: 10–80 µg/h until symptom relief.

Blood glucose should be closely monitored during therapy.

Rationale and Evidence Summary

These recommendations are based on eight RCTs [187, 188, 189, 190, 191, 192, 193, 194] and one cohort study [195]. The cornerstone of diarrhea management in geriatric palliative care is identification and treatment of underlying causes, including medication effects (e.g., laxatives and antibiotics), infection, radiation injury, chemotherapy, or post‐obstructive overflow diarrhea. Symptom‐directed pharmacologic therapy should be combined with hydration and nutritional support. Several adult guidelines for fecal incontinence and diarrhea management, though not specifically focused on palliative populations, also recommend loperamide as first‐line therapy after exclusion of reversible causes [196, 197].

Loperamide is the most widely used antidiarrheal agent in clinical practice. Studies have demonstrated improvement in stool consistency [192], reduction in stool weight, and overall symptom improvement [193]. It has also shown efficacy in bile acid diarrhea [198], radiation enteritis [199], and chemotherapy‐ or radiotherapy‐induced diarrhea [200]. A comparative study [194] demonstrated that in patients with chronic diarrhea, loperamide increased the proportion of solid stools and resulted in fewer adverse effects and less urgency compared with diphenoxylate–atropine. Regarding chemotherapy‐induced diarrhea, three RCTs reported inconsistent findings. Two studies [188, 189] showed that octreotide was superior to loperamide, achieving faster symptom control and reducing hospitalization rates. However, another study [190] in patients with leukemia or undergoing bone marrow transplantation found that loperamide had a higher 48‐h response rate (92%) compared with octreotide (78%). Although octreotide has been explored as a nonspecific antidiarrheal agent, results remain heterogeneous. High‐quality, large‐scale studies in geriatric palliative populations are lacking. Differences in etiology and outcome measures limit generalizability. Further research is needed to optimize diarrhea management strategies in older palliative care patients.

Clinical Question 18: Recommended Laxatives, Dosing, and Safety Considerations for Constipation in Geriatric Palliative Care

Recommendation 39

For short‐term or refractory constipation, stimulant laxatives are recommended (1B).

• Senna may be initiated at a low dose (1–3 g infusion once daily), for no longer than 1 week.

• Alternatively, bisacodyl 10 mg orally once daily may be used for up to 4 weeks.

Long‐term use of stimulant laxatives may lead to electrolyte imbalance and melanosis coli. Regular reassessment is recommended, and discontinuation should be considered when appropriate.

Recommendation 40

For chronic constipation, osmotic laxatives are recommended (1B).

• PEG is preferred at 10–30 g once daily for up to 4 weeks.

• Lactulose may be used as an alternative but may cause bloating or abdominal discomfort; dose reduction or discontinuation should be considered if intolerance occurs.

Recommendation 41

If monotherapy with either osmotic or stimulant laxatives is insufficient, combination therapy may be considered.

Alternatively, addition of a stool softener, such as docusate sodium (100–300 mg orally once daily), may be used (2C).

Rationale and Evidence Summary

These recommendations are based on seven systematic reviews [201, 202, 203, 204, 205, 206, 207] and one RCT [208]. Most evidence originates from adult patients with advanced disease or receiving palliative treatment. Therefore, the evidence should be considered indirect when applied to geriatric palliative care populations. Clinical decisions must account for multimorbidity, frailty, and age‐related physiological decline. In geriatric palliative care, non‐pharmacological interventions (e.g., hydration, mobility support, and bowel routine optimization) should be prioritized whenever feasible. When pharmacologic therapy is required, medication selection should consider tolerability and safety. Magnesium‐ and phosphate‐containing enemas should be used cautiously due to the risk of electrolyte disturbances, particularly in frail older adults [209]. Anthraquinone derivatives (e.g., senna) may be used temporarily to soften stools and stimulate colonic motility [209]. However, long‐term safety data are limited, and regular reassessment with timely discontinuation is recommended. Lactulose undergoes fermentation in the intestinal lumen and is commonly associated with bloating and abdominal discomfort. In contrast, PEG has a more favorable tolerability profile and is recommended as first‐line therapy for chronic constipation [206]. Docusate sodium, a mild stool softener, is generally safe but has limited efficacy and may be considered an initial or adjunctive option [202, 210]. These recommendations primarily apply to slow‐transit and mixed‐type constipation. For defecatory (outlet) dysfunction, specialist evaluation is recommended, and management may include biofeedback therapy or surgical intervention.

Multiple systematic reviews have demonstrated that senna improves opioid‐induced constipation in patients with advanced illness or cancer [203], increasing complete spontaneous bowel movement (CSBM) response rates [206]. Bisacodyl (5–10 mg orally once daily) has demonstrated efficacy and good tolerability in chronic constipation [205, 206].

PEG increases CSBM response rates in chronic constipation [204] and has shown superiority over lactulose in improving stool frequency and consistency. A systematic review [202] found that, compared with placebo, docusate sodium did not demonstrate significant benefit in improving stool frequency or consistency. High‐quality evidence supporting its benefit in geriatric palliative care remains lacking.Recommended laxatives and their dosages for elderly patients receiving hospice care are summarized in Table 2.

TABLE 2.

Recommended laxatives for constipation in geriatric palliative care.

Clinical indication	Recommended medication	Dosage and administration	Recommendation strength
Short‐term or refractory constipation	Senna	An amount of 1–3 g infusion orally once daily; duration should not exceed 1 week	1B
	Bisacodyl	An amount of 10 mg orally once daily; may be used for up to 4 weeks	1B
Chronic constipation	Polyethylene glycol	An amount of 10–30 g orally once daily; may be continued for up to 4 weeks	1B
Inadequate response to single‐agent osmotic or stimulant laxative	Docusate sodium	An amount of 100–300 mg orally once daily	2C

Clinical Question 19: Recommended Pharmacologic Management, Dosing, and Safety Considerations for Urinary Frequency, Urgency, and Incontinence in Geriatric Palliative Care

Recommendation 42

In patients with overactive bladder (OAB) characterized by urinary frequency, urgency, or urgency urinary incontinence, and after exclusion of reversible causes, a β3‐adrenoceptor agonist (mirabegron) is recommended as first‐line therapy. Mirabegron should be initiated at 25 mg once daily and may be increased to 50 mg once daily on the basis of efficacy and tolerability (1A).

Recommendation 43

If mirabegron is insufficient or if patients prefer anticholinergic therapy, the following agents may be considered (1B):

• Solifenacin 5–10 mg once daily.

• Extended‐release tolterodine 2–4 mg once daily.

• Fesoterodine 4–8 mg once daily.

• Trospium 20 mg twice daily.

• Oxybutynin transdermal patch (36 mg/39 cm²), replaced every 3–4 days.

Recommendation 44

If monotherapy is inadequate and the patient can tolerate combination therapy, solifenacin (5 mg once daily) may be combined with mirabegron (25–50 mg once daily) (2B).

Recommendation 45

In postmenopausal women with genitourinary syndrome of menopause, topical estrogen therapy (e.g., estradiol cream or vaginal estrogen suppositories) may be added (2B).

Recommendation 46

In men with BPH and postvoid residual (PVR) ≤150 mL, β3‐adrenoceptor agonists or anticholinergic agents may be added to existing α‐blocker therapy, with periodic reassessment of PVR to reduce the risk of urinary retention (1B).

Rationale and Evidence Summary

These recommendations are based on 22 RCTs and one systematic review. Most OAB trials enrolled middle‐aged and older adults but did not specifically focus on geriatric palliative care populations; therefore, the evidence should be considered indirect.

On the basis of relevant international guidelines [8, 211, 212], and given pharmacologic consistency and similar efficacy trends, cautious extrapolation of RCT evidence was performed. Clinical decision‐making should consider cognitive function, life expectancy, functional status, and goals of care. When pharmacologic therapy is required, mirabegron should be preferred in order to minimize anticholinergic burden. If anticholinergic agents are used, treatment should begin at the lowest effective dose, with preference given to long‐acting or transdermal formulations to reduce peak‐related adverse effects. Treatment response and tolerability should be reassessed within 2–4 weeks, and unnecessary long‐term combination therapy should be avoided.

A pooled analysis of three large RCTs demonstrated that mirabegron significantly reduced urinary incontinence episodes and micturition frequency compared with placebo [213].

A Phase II dose‐ranging study [214] suggested that 50 mg once daily provided optimal balance of efficacy and safety. A crossover study [215] showed higher treatment satisfaction and better tolerability compared with extended‐release tolterodine. In geriatric palliative care, a starting dose of 25 mg daily is recommended, with possible escalation to 50 mg after 2–4 weeks based on response and tolerability. Blood pressure and heart rate should be monitored, and potential drug interactions and hepatic/renal function should be considered. Mirabegron is contraindicated in patients with severe uncontrolled hypertension or significant arrhythmias.

Multiple RCTs [216, 217, 218, 219, 220, 221, 222, 223] demonstrated that anticholinergic agents significantly reduce urgency and incontinence episodes. In patients with inadequate response to tolterodine, fesoterodine 8 mg/day provided additional benefit. Solifenacin has demonstrated improvement in nocturia. Transdermal oxybutynin significantly reduced incontinence episodes and micturition frequency compared with placebo, while increasing voided volume per micturition [224, 225]. Trospium showed similar efficacy to oxybutynin but with lower incidence of dry mouth and better overall tolerability [226]. Multicenter RCTs [227, 228, 229] demonstrated that in patients partially responsive to solifenacin 5 mg, combination therapy with mirabegron resulted in greater reductions in incontinence and micturition frequency compared with monotherapy. An RCT (n = 104) found that in postmenopausal women with OAB, adding local vaginal estrogen to solifenacin improved subjective symptoms and QoL, although urinary frequency was not significantly changed [230]. In men with BPH and OAB, combination therapy with tamsulosin and either mirabegron or solifenacin significantly reduced micturition and incontinence episodes and improved QoL [231, 232, 233]. Combination therapy with tamsulosin and mirabegron demonstrated greater improvement in OAB symptom scores with low incidence of serious adverse events [234]. Overall, pharmacologic management of OAB in geriatric palliative care should prioritize symptom relief while minimizing cognitive burden, cardiovascular risk, and urinary retention. Regular reassessment and alignment with patient goals of care remain essential.

Clinical Question 20: Pharmacologic Management of Anxiety and Depression in Geriatric Palliative Care—Recommendations on Psychotropic Medications, Dosing, and Safety Considerations

Recommendation 47

For geriatric palliative care patients with significant depressive symptoms and relatively longer life expectancy, selective serotonin reuptake inhibitors (SSRIs) are recommended, following the principle of “start low, go slow, and reassess regularly”. Sertraline is preferred. The recommended starting dose is 25 mg once daily, which may be increased to 50 mg once daily after 12 weeks if tolerated. On the basis of efficacy and tolerability, the dose may be further adjusted to 50100 mg once daily (2D).

Recommendation 48

For geriatric palliative care patients with significant depressive symptoms and life expectancy less than 8 weeks, methylphenidate may be considered. Treatment may begin at 2.55 mg twice daily, with gradual titration to 10 mg twice daily based on tolerability. The maximum daily dose generally should not exceed 40 mg/day. Methylphenidate is not recommended for patients with isolated anxiety disorders. Cardiovascular adverse effects should be monitored, and the drug is contraindicated in patients with marked agitation or excessive excitability (2C).

Rationale and Evidence Summary

These recommendations are based on 28 RCTs. However, high‐quality studies specifically addressing anxiety and depression in geriatric palliative care patients are lacking. Most available evidence derives from adult palliative or oncology populations and therefore represents indirect and low‐certainty evidence when applied to older palliative patients. For depressive symptoms, SSRIs are generally well tolerated, have manageable drug–drug interactions, and align with longer term remission goals. In patients with relatively longer life expectancy, SSRIs may therefore be considered first‐line therapy [8]. Sertraline is preferred due to its stable pharmacokinetic profile, relatively low potential for drug interactions, and favorable cardiovascular safety profile [235]. Treatment decisions should be individualized, taking into account comorbid conditions, hepatic and renal function, polypharmacy, and patient‐centered therapeutic goals. Methylphenidate may improve depressive symptoms in geriatric palliative care patients and is generally well tolerated. However, the available evidence is limited by small sample sizes and high risk of bias. Many trials primarily evaluated cancer‐related fatigue (CRF), and evidence for direct improvement of depressive or anxiety symptoms remains indirect and of low certainty. As a central nervous system stimulant, methylphenidate is contraindicated in patients with prominent anxiety, tension, or agitation and is therefore not recommended for isolated anxiety disorders. Its use for depression in terminal or palliative settings is considered off‐label and requires careful risk–benefit assessment; it should not be administered to patients with marked excitability. Although certain guidelines [236] recommend mirtazapine for depression accompanied by anorexia, evidence in geriatric palliative patients with coexisting depression and anorexia remains inconsistent [237, 238], and routine use is not recommended. Current evidence does not support any pharmacologic therapy specifically for anxiety symptoms in this population, and therefore no medication is recommended solely for anxiety management. Given the high prevalence of multimorbidity and polypharmacy in geriatric palliative care, comprehensive medication review is essential prior to initiating antidepressant treatment.

In quantitative analyses, a meta‐analysis of 22 RCTs (n = 2350) conducted by the working group demonstrated that antidepressants significantly improved depressive symptoms at 4–12 weeks compared with placebo (SMD = −0.22, 95% CI: −0.37 to −0.08) [238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259]. A separate meta‐analysis of seven RCTs (n = 588) showed that sertraline reduced depression scale scores (SMD = −0.31, 95% CI: −0.61 to −0.01) [8, 235, 236, 241, 259, 260]. In contrast, a meta‐analysis of five RCTs (n = 382) found no significant difference between antidepressants and placebo in improving anxiety symptoms [246, 247, 255, 256, 257]. A meta‐analysis of three RCTs (n = 226) showed that methylphenidate significantly improved depressive symptom scores at 2–6 weeks (SMD = −0.36, 95% CI: −0.63 to −0.10) and anxiety scores (SMD = −0.47, 95% CI: −0.73 to −0.20) [261, 262, 263], although the overall certainty of evidence remains limited.

Clinical Question 21: Recommended Pharmacologic Management, Dosing, and Safety Considerations for Sleep Disturbances in Geriatric Palliative Care

Recommendation 49

Management of insomnia in older patients receiving end‐of‐life palliative care should prioritize non‐pharmacological sleep interventions, treatment of reversible causes, and the principle of “start low and use short‐term therapy,” with symptom control as the primary goal while addressing both physical and psychological needs (1A). If longer term pharmacologic therapy is required, intermittent dosing strategies may be considered once therapeutic efficacy is achieved and stable (1A).

Recommendation 50

The following pharmacologic options may be considered only when insomnia causes substantial distress, non‐pharmacological measures are insufficient, expected benefit is aligned with goals of care, and short‐term use at the lowest effective dose with reassessment is feasible (1A):

• (1)
  Non‐BZD hypnotics (Z‐drugs)

  • Zolpidem 5 mg once nightly.
  • Eszopiclone 2 mg once nightly.

These agents may improve sleep quality and daytime functioning, but non‐BZD BZD receptor agonist hypnotics (Z‐drugs) should generally be avoided for routine insomnia treatment in older adults because of risks of delirium, cognitive impairment, falls, fractures, next‐day sedation, dependence, and limited improvement in sleep outcomes. If used in end‐of‐life palliative care, clinicians should monitor for next‐day residual sedation, fall risk, and potential dependence.

• (2)
  Melatonin or melatonin receptor agonists

  • Prolonged‐release melatonin 2 mg once nightly.
  • Ramelteon 8 mg once nightly.

These agents may improve sleep onset latency and circadian rhythm disturbances and are generally well tolerated.

• (3)
  Orexin receptor antagonists

  • Lemborexant 5 mg once nightly.

These agents may reduce sleep latency, increase total sleep time, and decrease wake after sleep onset, with favorable tolerability.

• (4) BZDs

Due to risks of cognitive impairment, delirium, falls, and dependence, BZDs should generally be avoided for routine insomnia treatment in older adults. In end‐of‐life palliative care, use should be restricted to selected patients with severe distress after careful risk–benefit assessment and discussion of goals of care.

Rationale and Evidence Summary

Four RCTs and two meta‐analyses were included. Evidence was supplemented by data from adult insomnia populations due to limited high‐quality studies specifically targeting geriatric palliative care patients. Non‐pharmacologic interventions (e.g., sleep hygiene optimization, environmental modification, pain control, and anxiety management) should be prioritized. When pharmacologic therapy is necessary, the decision should consider frailty, fall risk, delirium risk, respiratory status, drug–drug interactions, expected survival, and patient goals. BZDs and Z‐drugs should not be used routinely in older adults and should be reassessed frequently if used for end‐of‐life distress.

An RCT (n = 115) demonstrated that zolpidem 5 mg nightly significantly improved Pittsburgh Sleep Quality Index (PSQI) scores at Weeks 1 and 3 in older outpatients with insomnia [264].

Two RCTs (n = 625) showed that eszopiclone 2 mg nightly significantly increased total sleep time and reduced sleep latency and nocturnal awakenings, with sustained benefit after discontinuation compared with baseline [265, 266]. An RCT (n = 791) reported that prolonged‐release melatonin significantly shortened sleep onset latency in older adults, with sustained efficacy for up to 6 months [267]. A meta‐analysis (n = 2462) further demonstrated that melatonin and the melatonin receptor agonist ramelteon improved both subjective and objective total sleep time, sleep latency, and overall sleep quality in older adults with chronic insomnia [268]. A large meta‐analysis, including 111 RCTs (n = 25,923), evaluated seven commonly used hypnotics [269]. In older adults, BZDs, melatonin, and orexin receptor antagonists significantly reduced sleep latency and increased total sleep time. Z‐drugs and orexin receptor antagonists significantly improved sleep efficiency. BZDs, Z‐drugs, and melatonin reduced wake after sleep onset. However, BZDs were associated with a higher incidence of adverse events, and their use in older adults should therefore be cautious. Long‐term use of hypnotics should be minimized. If ongoing therapy is required, intermittent dosing strategies may reduce tolerance and adverse effects. Long‐acting sedative‐hypnotics should generally be avoided in frail older adults.

Clinical Question 22: Diagnosis, Management, and Pharmacologic Principles for Delirium in Geriatric Palliative Care

Recommendation 51

In patients with positive delirium screening results or suspected delirium, reversible causes should be promptly identified and addressed. Non‐pharmacologic interventions are recommended as first‐line management, including multisensory stimulation, environmental modification, family presence, circadian rhythm regulation, use of hearing aids or glasses, and early mobilization (2C).

Recommendation 52

In geriatric palliative care patients with delirium, antipsychotic medications such as haloperidol, risperidone, or olanzapine may be considered when symptoms cause significant distress or raise safety concerns (2C).

Recommendation 53

For opioid‐associated hyperactive delirium accompanied by uncontrolled pain, opioid rotation may be considered under specialist supervision. Substitution of morphine with methadone should be initiated at very low doses (e.g., 2.5 mg every 12 h), with close monitoring for respiratory depression and QT interval prolongation (2D).

Rationale and Evidence Summary

The evidence supporting these recommendations derives primarily from studies involving patients aged ≥65 years with life expectancy between 7 and 90 days, multiple comorbidities, and polypharmacy. Most of these patients had advanced cancer or end‐stage organ failure. Data are largely derived from middle‐ and high‐income countries. Non‐pharmacologic interventions are low‐cost, carry minimal risk, and demonstrate a favorable benefit–risk profile. Opioid rotation requires clinical expertise in analgesic and sedative management and is preferably initiated in inpatient or structured care settings.

Delirium is highly prevalent in geriatric palliative populations. Systematic identification and correction of reversible precipitants, including dehydration, infection, metabolic disturbances, medication effects, and uncontrolled pain, are essential. A retrospective study [270] showed that patients receiving structured non‐pharmacologic interventions (including correction of dehydration, infection control, and analgesic optimization) experienced greater improvement in delirium severity compared with those without systematic precipitant management. Non‐pharmacologic strategies, including environmental orientation, family involvement, circadian cues, sensory aids, early mobilization, and supportive modalities such as music and light therapy—constitute the cornerstone of delirium management. Routine addition of antipsychotic medications has not consistently demonstrated additional benefit and may, in some cases, worsen outcomes. An RCT (n = 247) [271] reported that compared with risperidone or haloperidol, placebo combined with non‐pharmacologic care was associated with greater reduction in delirium symptom scores and longer survival. A small prospective study (n = 22) [272] and a retrospective analysis (n = 65) [270] similarly suggested that adjunctive antipsychotics did not significantly improve delirium scores, reinforcing the central role of non‐pharmacologic management. Haloperidol remains one of the most used off‐label medications for delirium in palliative settings [273]. An RCT (n = 247) [271] suggested that in hospitalized palliative patients with life expectancy ≤3 months, haloperidol and risperidone reduced delirium symptom scores, with acceptable adverse event profiles. A systematic review [274] concluded that haloperidol, risperidone, or olanzapine may be used in terminal delirium for rapid control of agitation and improvement of comfort; however, overall evidence quality remains limited. In a small study of advanced cancer patients with pain and delirium (n = 20), rotation from morphine to methadone was associated with improvement in both pain and delirium symptoms [275]. Given the risks of QT prolongation and respiratory depression, methadone initiation should be undertaken cautiously with appropriate monitoring. Overall, delirium management in geriatric palliative care should prioritize identification and treatment of reversible causes and implementation of structured non‐pharmacologic strategies. Pharmacologic therapy should be reserved for cases involving severe agitation, distress, or safety risk, and decisions should be individualized according to patient goals of care.

Clinical Question 23: Use, Dosing, and Safety Considerations of Benzodiazepines in Delirium Among Geriatric Palliative Care Patients

Recommendation 54

BZDs should not be used as first‐line therapy for delirium in geriatric palliative care patients. Their use should be limited to specific end‐of‐life indications, such as refractory terminal agitation, severe anxiety‐associated distress, alcohol or BZD withdrawal, or proportionate palliative sedation, when non‐pharmacologic interventions and antipsychotic therapy have failed or are inappropriate (2C).

Recommendation 55

For refractory terminal hyperactive delirium unresponsive to non‐pharmacologic measures and haloperidol monotherapy, combination therapy with haloperidol and lorazepam (0.5–1 mg orally every 4–6 h as required) may improve symptom control (1A).

When rapid symptom control is required, intravenous lorazepam may be administered at an initial dose of 0.25–0.5 mg given slowly over at least 2 min, with careful monitoring of respiratory function and blood pressure. Dose escalation up to 1 mg may be considered only if symptoms persist and hemodynamically stability is maintained.

Recommendation 56

After multidisciplinary team discussion and informed consent from family members, proportional palliative sedation with midazolam may be considered for refractory terminal delirium causing intolerable distress. In older patients, continuous infusion should be initiated at a low rate (e.g., 0.5–1 mg/h) and titrated by 0.5–1 mg/h every 1–2 h according to symptom control and Richmond AgitationSedation Scale (RASS) targets (generally −2 to −3). Vital signs should be closely monitored during initiation (e.g., every 1530 min initially). Once sedation is stable, monitoring frequency may be reduced, prioritizing patient comfort and minimizing disturbance (2B).

Recommendation 57

For refractory terminal delirium accompanied by severe pain in patients for whom minimizing respiratory depression is a priority, dexmedetomidine may be considered in monitored settings. Infusion may be initiated at 0.2 µg/kg/h and titrated by 0.1 µg/kg/h every 30 min according to symptom control. Clinicians must monitor for hypotension and bradycardia and assess hemodynamic stability before and during administration (2C).

Rationale and Evidence Summary

These recommendations are based on two systematic reviews, three RCTs, and two non‐randomized studies. Available evidence indicates that BZDs should not be used as routine treatment for delirium, as they may worsen cognitive impairment and increase risks of oversedation and respiratory depression. Their use is generally restricted to refractory terminal hyperactive delirium after the failure of non‐pharmacologic strategies and antipsychotic therapy, or to selected patients requiring proportionate palliative sedation. Decisions should include informed consent where possible, explicit documentation of palliative intent, low starting doses, and close monitoring.

Systematic reviews and a retrospective cohort study [276, 277, 278] suggest that BZDs may be appropriate in end‐of‐life agitation unresponsive to standard therapy, provided risks are clearly communicated and dosing begins at the lowest effective level with close monitoring. An RCT (n = 58) [279] demonstrated that lorazepam combined with haloperidol significantly reduced RASS scores within 8 h and, compared with haloperidol alone, improved comfort in patients with advanced cancer and agitated delirium. Another randomized study [280] showed that haloperidol plus midazolam achieved higher agitation control rates (84% vs. 64%) and faster onset of action (median 15 vs. 60 min) compared with haloperidol alone. A prospective study [281] reported that continuous midazolam infusion effectively controlled refractory terminal delirium, although evidence quality remained limited and dosing varied across studies. An RCT (n = 52) [282] found that dexmedetomidine reduced delirium severity on the first treatment day compared with midazolam in hospice patients; however, the difference was not sustained on subsequent days. Dexmedetomidine may offer the advantage of lighter sedation with less respiratory depression but requires hemodynamic monitoring. Overall, BZDs should be reserved for refractory terminal delirium associated with severe distress. When sedation is required, it should be proportional, goal‐directed, ethically justified, and consistent with patient‐centered goals of care.

Clinical Question 24: Pharmacologic Principles, Dosing, and Safety Considerations for Fever in Geriatric Palliative Care Patients

Recommendation 58

In patients with limited life expectancy who experience fever‐related discomfort, acetaminophen or NSAIDs may be used for symptomatic relief. Acetaminophen may be administered orally or intravenously at 325–500 mg every 4–6 h, with a maximum daily dose of 2 g. For rectal administration, the maximum recommended dose is 1.2 g/day (2B).

Recommendation 59

In patients with suspected neoplastic (tumor‐related) fever, naproxen 250 mg twice daily may be considered. If fever does not improve within 3 days, reassessment of the underlying cause is recommended (2C).

Rationale and Evidence Summary

These recommendations are based on one systematic review/meta‐analysis, two RCTs, and five cohort studies. The included studies were conducted in adult populations and do not fully represent geriatric palliative care patients; therefore, the evidence is indirect. Recommendations are made through cautious extrapolation, considering pharmacologic consistency and directionally similar effects.

Two RCTs (n = 690) [283, 284] demonstrated that acetaminophen and ibuprofen were both effective in reducing fever, with no significant difference in temperature reduction between the two agents. A cohort study (n = 324) [285] in older adults showed no significant difference in antipyretic effect between acetaminophen 1000 mg and a combination preparation of acetaminophen/ibuprofen (500/150 mg). A meta‐analysis (n = 388) [286] reported that naproxen achieved symptom relief in 94.1% (95% CI: 87.6%–97.3%) of patients with tumor‐related fever. Evidence regarding potential risks of active fever reduction derives primarily from critically ill ICU populations and remains inconsistent. A large retrospective cohort study (n = 15,268) [287] found that among ICU patients with temperatures >39°C, any form of active temperature reduction (pharmacologic or physical) was associated with increased mortality (OR 1.29, 95% CI: 1.04–1.61). However, univariate analysis showed no significant mortality difference between patients receiving antipyretics and those who did not. In multivariable models, physical cooling was identified as an independent risk factor for mortality (OR 1.51, 95% CI: 1.23–1.84). Conversely, a prospective cohort study in ICU patients with sepsis (n = 1425) [288] suggested that the use of NSAIDs or acetaminophen was associated with increased mortality, whereas physical cooling was not. Discrepancies between studies likely reflect residual confounding, measurement bias, and heterogeneity in statistical modeling. Importantly, both investigations were conducted in critically ill septic ICU populations and cannot be directly extrapolated to terminal palliative care settings. In geriatric palliative care, fever management is primarily directed toward symptom relief rather than disease modification. Antipyretic therapy may not alter underlying prognosis but can improve comfort in selected patients. Clinical decisions should therefore prioritize relief of distress and overall comfort, while recognizing that potential long‐term risks observed in critical care populations may be less clinically relevant in end‐of‐life contexts.

Clinical Question 25: Pharmacologic Management of Fatigue in Geriatric Palliative Care Patients

Recommendation 60

In patients with CRF, reversible causes should be systematically identified and corrected before initiating pharmacologic therapy. Non‐pharmacologic interventions, including physical activity, sleep optimization, nutritional support, and psychosocial interventions, should remain the foundation of fatigue management (2C).

Recommendation 61

For CRF patients who do not receive active anticancer therapy who have hemoglobin levels below normal and a life expectancy greater than 6 months, individualized treatment with recombinant human erythropoietin‐α may be considered. Routine use is not recommended in end‐of‐life patients (2C).

Recommendation 62

For CRF patients whose fatigue is accompanied by depressive symptoms and sleep disturbance, bupropion sustained release may be considered, starting at a low dose and titrating gradually according to response and tolerability (2C).

Recommendation 63

In older patients with advanced malignancy and moderate‐to‐severe fatigue, cautious use of methylphenidate may be considered, starting at a low dose, with close monitoring for cardiovascular symptoms, insomnia, and anxiety (2C).

Recommendation 64

Short‐term use of low‐dose corticosteroids (e.g., prednisone or dexamethasone, typically for no longer than 2 weeks) may be considered for moderate‐to‐severe CRF, provided no contraindications exist. Long‐term use is not recommended (2C).

Recommendation 65

In patients receiving traditional Chinese medicine (TCM)–integrated care, adjunctive use of qi‐tonifying herbal formulations may be considered on the basis of individualized syndrome differentiation. For patients with qi deficiency, formulations, such as Buzhong Yiqi pills or Shenmai injection (when oral administration is not feasible), may be considered (2B). For patients with combined qi and yin deficiency, American ginseng or Shengmai injection may be considered (2C).

Rationale and Evidence Summary

These recommendations are based on 15 studies, including two meta‐analyses, 12 RCTs, and one non‐randomized controlled study. The available evidence primarily derives from adult oncology or palliative populations and represents indirect evidence for geriatric palliative care patients. No dose‐finding studies have specifically targeted older adults. Given age‐related physiologic decline, multimorbidity, and polypharmacy, treatment should follow a “start low and titrate slowly” principle with close monitoring. In patients with anemia‐related CRF not receiving anticancer therapy, one RCT demonstrated that recombinant erythropoietin‐α improved hemoglobin levels and exercise capacity but did not significantly improve patient‐reported fatigue or QoL [289].

Two RCTs reported that bupropion significantly reduced fatigue severity and improved depressive symptoms compared with placebo [239, 258]. In contrast, multiple RCTs found no overall significant difference between methylphenidate and placebo for CRF [290, 291, 292, 293], although subgroup analysis suggested potential benefit in patients with moderate‐to‐severe fatigue [290]. Short‐term corticosteroid therapy may improve CRF. A non‐randomized study showed that prednisone improved fatigue and quality‐of‐life scores [294], and an RCT reported similar findings for dexamethasone without clear short‐term safety concerns [295]. Long‐term use is not recommended. Two meta‐analyses suggested that qi‐tonifying herbal therapies (e.g., Buzhong Yiqi pills, Shenmai injection, and American ginseng) may improve fatigue scores [286, 296]. Three RCTs reported that Shengmai injection improved fatigue and physical function without significant hepatic or renal toxicity [297, 298, 299]. However, overall evidence quality remains limited. Pharmacologic therapy for CRF should be individualized and used only after reversible causes have been addressed and non‐pharmacologic interventions optimized.

4. Discussion

This guideline provides a symptom‐focused medication framework for older patients receiving end‐of‐life or hospice‐oriented palliative care. Its strengths include prospective registration, use of GRADE and Reporting Items for Practice Guidelines in Healthcare (RIGHT) standards, multidisciplinary participation, incorporation of patient preferences, structured Delphi consensus, and external review. The guideline also highlights geriatric medication safety, including frailty, multimorbidity, renal and hepatic impairment, polypharmacy, drug–drug interactions, falls, delirium, constipation, and respiratory depression.

Several limitations should be acknowledged. First, high‐quality direct evidence in older end‐of‐life palliative care populations is limited, and some recommendations rely on indirect evidence from adult palliative care, advanced cancer, COPD, heart failure, or general geriatric populations. Second, some drugs or routes are off‐label in specific contexts and should be used only after careful risk–benefit assessment and informed consent. Third, this guideline does not address disease‐modifying management of chronic conditions across the full palliative care trajectory. Finally, availability of medications and care resources may vary across settings, and recommendations should be adapted to local practice and patient goals.

5.

In conclusion, this guideline aims to support safe, individualized, and goal‐concordant pharmacological management of distressing symptoms in older patients receiving end‐of‐life palliative care. Clinical decisions should be based on symptom severity, underlying etiology, prognosis, frailty, organ function, medication burden, patient and family preferences, and the balance between benefit and harm. Future research should prioritize high‐quality studies specifically enrolling older end‐of‐life palliative care patients and evaluating clinically meaningful outcomes, such as comfort, QoL, adverse drug events, treatment burden, and caregiver‐reported outcomes.

Working Groups for the Guideline for Medication Management of Distressing Symptoms in Older Patients Receiving End‐of‐Life Palliative Care

Members of the Steering Committee

Birong Dong (National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University), Huiping Chen (Department of Palliative Medicine, West China Xiamen Hospital, West China Fourth Hospital, Sichuan University), Jirong Yue (The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University)

Members of the Secretariat

Daiping Li (National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University), Yang Wang (National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University), Yiping Deng (National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University), Yixiao Chen (National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University)

Members of the Consensus Expert Group (listed in alphabetical order by surname)

Feng Cao (Hospice Care Center, Beijing Geriatric Hospital), Li Cao (The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University), Huiping Chen (Department of Palliative Medicine, West China Xiamen Hospital, West China Fourth Hospital, Sichuan University), Qian Chen (Geriatrics Center, Sichuan Provincial Key Laboratory of Nursing, West China Hospital, Sichuan University), Wenwu Cheng (Department of Integrated Care, Fudan University Shanghai Cancer Center), Birong Dong (National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University), Hongyan Duan (Department of Geriatrics, Henan Provincial People's Hospital), Qiukui Hao (The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University), Zhiyao He (Department of Pharmacy, West China Hospital, Sichuan University), Xiaomin Hou (Department of Geriatrics, Sichuan First Veterans Hospital), Xiaoli Huang (The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University), Yan Jiang (Department of Nursing/Evidence‐Based Nursing Center, West China Hospital, Sichuan University), Hongyi Li (Department of Geriatrics, Chengdu Fourth People's Hospital), Jinxiang Li (Department of Palliative Medicine, West China Fourth Hospital of Sichuan University), Xiaomei Li (Department of Geriatrics, The Second Medical Center of Chinese PLA General Hospital), Ying Li (The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University), Xuezheng Liu (Department of Geriatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine), Yanfang Long (Teaching and Research Section of Clinical Nursing, Xiangya Hospital, Central South University), Shichao Lv (Department of Geriatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine), Ke Ma (Palliative Medicine Center, Xin Kunhua Hospital, Yunnan First People's Hospital), Ben Niu (Department of Geriatrics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology), Ying Pang (Department of Psycho‐Oncology, Peking University Cancer Hospital), Yuan Qin (Department/Hospice Care Center of Palliative Care, Beijing Haidian Hospital), Li Song (Department of Pain Management, West China Hospital, Sichuan University), Lili Tang (Department of Psycho‐Oncology, Peking University Cancer Hospital), Yanyan Wang (West China School of Nursing, West China Hospital, Sichuan University), Yumei Wang (General Practice Palliative Care Ward, Shengjing Hospital of China Medical University), Yali Xu (Department of Palliative Care, Chongqing Thirteenth People's Hospital), Jirong Yue (The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University), Ying Zhang (Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University), Na Zhao (Department of Geriatrics, The People's Hospital of Yingkou), Linan Zeng (Department of Pharmacy, West China Second University Hospital, Sichuan University), Rujun Zheng (Department of Biotherapy Research, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University), Zhi Zhou (Department of Palliative Medicine, BenQ Hospital Affiliated to Nanjing Medical University)

Members of the Evidence Evaluation Group (listed in alphabetical order by surname):

Yingying Cai (Department of Geriatrics, The First Affiliated Hospital of Chengdu Medical College), Rui Cheng (Department of Palliative Medicine, West China Xiamen Hospital, Sichuan University), Tenzing Noryung (Integrated Care Management Center of Qinghai University Affiliated Hospital), Lu Fan (Department of Geriatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine), Meiling Ge (The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University), Duan Guo (Department of Palliative Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University), Jing He (Department of Geriatrics and Special Needs Medicine, General Hospital of Ningxia Medical University), Yan He (Department of Geriatrics, The second people's hospital of Yibin), Shuli Jia (The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University), Ting Jiang (Department of Geriatrics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology), Daiping Li (National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University), Dan Li (Second Department of Geriatrics, First Hospital of Shanxi Medical University), Leishen Li (Department of Geriatrics, Henan Provincial People's Hospital), Yaqin Li (Department of Geriatrics, Chengdu Fourth People's Hospital), Jufeng Luo (The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University), Ping Ni (Innovation Center of Nursing Research, West China Hospital, Sichuan University), Xuchao Peng (Department of Geriatrics, Sichuan Provincial People's Hospital), Runjuan Qiao (General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University), Shuang Song (Department of Geriatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine), Xiangping Tu (Department of Laboratory Medicine, West China Hospital, Sichuan University), Peng Wang (Department of Geriatrics, Nanchong Second People's Hospital), Yali Xu (Department of Geriatrics, Chongqing Academy of Medical Sciences, Chongqing General Hospital, Chongqing University), Yanwu Yang (Department of Emergency Medicine, West China Hospital, Sichuan University), Qihang Zhang (Department of Geriatrics, No. 925 Hospital), Yan Zhang (The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University), Youyou Zhang (Department of Geriatric Neurology, The Second Affiliated Hospital of Xi'an Jiaotong University), Yunxia Zhang (First Department of Geriatrics, Mianyang Third People's Hospital), Yanli Zhao (The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University), Wenjun Zeng (Department of Geriatrics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology)

Members of the External Review Group (listed in alphabetical order by surname)

Xinyu Chen (Department of Geriatrics, Zhejiang Hospital), Yun Fan (Department of Hematology, Beijing Hospital, National Center for Gerontology; National Clinical Research Center for Gerontology), Ling Li (Palliative and Hospice Care Center, Zhengzhou Third People's Hospital), Guanjian Liu (Clinical Epidemiology and Evidence‐Based Medicine Center, West China Hospital, Sichuan University), Yongming Liu (Department of Geriatrics, First Hospital of Lanzhou University), Lina Ma (Department of Geriatrics, Xuanwu Hospital Capital Medical University), Shiying Yu (Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology), Xuan Zhou (Hematology Center, Beijing Children's Hospital, Capital Medical University)

Funding

The study was supported by the National Key Research and Development Program of China (2023YFC3605900/02).