Palliative patients who may benefit from intranasal delivery of symptomatic drugs: a two-center observational study evaluated the administration of morphine and dexamethasone in Polish hospices.

Introduction

The number of people living with serious illnesses is increasing annually, and there is improving institutional support for both patients and their families [ 1 ] . This support is provided in inpatient hospice facilities and as part of home hospice care at the patients’ residences. The medical care of these patients poses numerous challenges, with a key focus on administering appropriate medications to manage end-of-life symptoms [ 2 ]. Opioids and steroids play a crucial role in palliative care as they help alleviate distressing symptoms without hastening death [ 3 ].

Morphine is a commonly used opioid [ 4 ] that acts to relieve severe pain and inhibit the sensation of dyspnea [ 5 ], especially when the respiratory system is involved in the disease process [ 6 ]. When administered orally, morphine is metabolized in the liver to produce M6G (morphine-6-glucuronide) and M3G (morphine-3-glucuronide). M3G is mainly responsible for causing nausea, vomiting, and cognitive decline [ 7 ]. Parenteral administration, which bypasses the liver’s first-pass effect, reduces the accumulation of toxic morphine metabolites. Morphine is commonly used to relieve dyspnea in conditions such as severe chronic obstructive pulmonary disease (COPD), idiopathic interstitial pneumonia [ 8 ], and heart failure [ 9 ].

Dexamethasone is the most widely used steroid in palliative care [ 10 ]. Its action is based on a glucocorticosteroid and residual mineralocorticosteroid mechanism [ 11 ]. It exhibits a long duration of action of 36 to 54 h [ 12 ]. Dexamethasone helps alleviate many problems burdening the patient during the dying period. It improves appetite [ 13 ], relieves pain and dyspnea, increases psychomotor drive, and improves mood [ 14 ]. It significantly reduces swelling of neural tissue caused by primary brain tumors, tumor metastasis to the brain, or tumor lesions within the spinal cord [ 15 ]. Additionally, studies support dexamethasone’s effectiveness in intestinal obstruction [ 16 ], superior vena cava syndrome, upper airway stenosis, and lymphangitis carcinomatosis [ 17 ].

The standard way to administer morphine and dexamethasone is through oral delivery [ 18 ]. However, patients at the end of life may face challenges with this method. Issues with oral delivery can arise from various factors such as consciousness disorders, gastrointestinal tract obstruction, the presence of a gastric fistula or nasogastric tube, and difficulty swallowing. In addition, liver failure in palliative patients can impact the effectiveness of orally administered drugs due to the absence or excessive effect on first-pass metabolism. In cases of difficulty swallowing or gastrointestinal obstruction, the preferred option for drug delivery is the subcutaneous route, both inpatient and at home, by caregivers [ 19 ]. The presence of significant edema in the subcutaneous tissue or cachexia may restrict subcutaneous drug delivery. Patients at the end of life often suffer from cachexia, associated hypoalbuminemia, and generalized edema. Patients at the end of life often present with cachexia, and the associated hypoalbuminemia often takes on the clinical presentation of a cachectic patient but with generalized edema present. In such a patient, the administration of subcutaneous injections may be ineffective as the administered drug will not be adequately absorbed via the subcutaneous tissue route. Furthermore, the insertion of a subcutaneous injection into swollen subcutaneous tissue is accompanied by pain greater than into normal subcutaneous tissue. Hence, the idea in the article that administering the drug via the intranasal route could help avoid this problem. Additionally, the willingness and engagement of the patient and their carers to accept the challenges of injecting are crucial. Some caregivers may not feel comfortable administering the drug via injection due to concerns about potentially harming the patient, uncertainty, or other psychological issues [ 20 ].

Intranasal drug administration avoids most of these challenges [ 21 ]. The human nasal cavity is lined mainly with respiratory epithelium (about 130 cm 2 ) and olfactory epithelium (about 10 cm 2 ) [ 22 ]. Both types of nasal cavity epithelium have capacity for drug absorption. The respiratory epithelial area allows drugs to be transported mainly through blood vessels into the systemic circulation and through neuronal transport via the trigeminal nerve endings. The area of the olfactory epithelium allows drug absorption through various types of transport related to the presence of olfactory nerve endings and partly through absorption via the vascular route into the central circulation [ 23 ]. In a healthy nasal cavity mucosa, drugs can be non-invasively administered using a suitable atomizer applied to a syringe. This enables direct transport into the bloodstream and the brain’s nerve tissue [ 24 ]. As the drugs are absorbed through the mucosa into the systemic circulation, they naturally bypass the gastrointestinal tract and hepatic metabolism. Thus, the irritating effect of steroids on the gastric mucosa can be nullified, and the trajectory of the adverse metabolism of morphine and the formation of its neurotoxic metabolites can be altered. Numerous publications point to potential additional positive effects of intranasal administration of drugs [ 25 ]. A particular portion of the intranasally administered drug is absorbed directly into the brain via the neuronal pathway, involving the olfactory and trigeminal nerve, reaching therapeutic concentrations there (Fig. 1 ).

Intranasal drug delivery has been successfully used for years for potent opioids such as fentanyl [ 26 ]. This drug, administered intranasally or transmucosal, has proven efficacy in relieving breakthrough pain associated with cancer. It continues to be researched for the treatment of dyspnea in palliative patients [ 27 ]. In addition, intranasal drug delivery can enhance the patient’s comfort with medication and improve cooperation with caregivers [ 28 ]. The proposed method of administration does not cause any serious side effects [ 29 ].

The published papers to date suggest a potential beneficial effect of morphine, specifically its metabolite diamorphine, when administered intranasally [ 30 , 31 , 32 ]. This route of administration results in a rapid onset of action, comparable to that of intravenous injection [ 33 ]. In pediatric populations, a proposed dosing regimen for diamorphine has been suggested, with the dose potentially being one-third of the equivalent oral morphine dose [ 34 ]. Scientific reports suggest intranasal doses of morphine (0.1 mg/kg) and diamorphine (1.25–2.5 mg) 34 may be effective in pain management. Furthermore, studies indicate that the tolerability of intranasally administered diamorphine is generally well tolerated by patients.

Recent studies have shown promising results for the intranasal administration of dexamethasone in the treatment of various conditions, including COVID-19. Serum concentrations of dexamethasone after intranasal delivery were shown to be comparable to those observed after intravenous application, suggesting similar bioavailability and systemic absorption [ 35 ]. Furthermore, it was found that the therapeutic effect of intranasally applied dexamethasone was similar to that achieved by the intravenous route, offering an alternative, non-invasive method of administration. The recommended dose of dexamethasone is 0.06–0.12 mg/kg. Intranasal drug administration does not require the patient’s cooperation other than to allow the drug to be administered. Deep unconsciousness or coma are not a problem for intranasal drug administration [ 36 ].

The ECOG PS (Eastern Cooperative Oncology Group Performance Status) scale was initially developed as a prognostic tool and to assess the tolerability of therapy in chemotherapy patients. Currently, it is one of the most commonly used and straightforward methods for evaluating the functional status of an oncology patient. The scale consists of 6 grades, where 0 indicates full function with no signs of disease, and 5 indicates death [ 37 ].

Only a few published papers address the use of intranasal delivery of morphine and/or dexamethasone for palliative care patients [ 30 , 34 , 36 ].

Aim of the study

This study aims to identify the characteristics of patients who may benefit from switching from the standard method of administering opioids and steroids to the intranasal route. The authors also evaluated the condition of patients receiving hospice care using the Eastern Cooperative Oncology Group Performance Status scale, a validated tool for this purpose. The study also aimed to determine the feasibility of changing the delivery method of the drugs in question to the intranasal form.

Material and methods

Two hospices in the Pomeranian region of Poland participated in an observational study, which included patients receiving inpatient and home hospice care in either urban or rural areas. These hospices have provided comprehensive care for patients needing palliative treatment for many years. The majority of their patients (almost 98%) have been diagnosed with advanced and/or disseminated cancer. At any given time, 130–160 patients receive home care, and 30 patients receive inpatient care, based on the contract with the national insurer that funds the treatment.

The observation period was from February 1, 2024, to April 30, 2024. The inclusion criteria involved adult patients who received home (Home Hospice Care) or inpatient (Hospice Unit Care) hospice palliative care, irrespective of the duration of that care. Patients were included if they were prescribed morphine in any form, corticosteroids in any form, or both. Oral delivery involved taking the drugs as tablets, drops, or solutions, while subcutaneous delivery was administered as bolus injections. The seriousness of the condition was evaluated using the ECOG PS scale on the first day of the study. We determined the characteristics of a patient who would likely benefit from intranasal drug administration by considering clinical and psychological/social criteria. These criteria were evaluated during the initial qualifying examination and then during hospice care using self-created questionnaire (Table 1 ). During the initial medical visit, the medical interview covered topics such as medication preferences, concurrent illnesses, and symptoms of the underlying disease. Additionally, the patient’s past medical records were reviewed to gather more information about any issues related to standard (oral or subcutaneous) drug administration. When evaluating disturbances of consciousness, we considered any quantitative disruptions that hindered a patient’s ability to swallow effectively (e.g., significant weakness, abnormal drowsiness). Patients and their caregivers were informed at the initial trial that they could or should be switched to the subcutaneous route when the patient’s condition changed (prognosis of swallowing difficulty, significant weakness, confusion). Where the patient did not consent to injections at this step or was unsure whether they would be able to tolerate the administration of injections, patient non-cooperation was noted. Respectively, where at any point the caregivers were reluctant to give the injection due to fear of harming a loved one, lack of competence, or their own psychological barriers, a non-cooperation on the part of the caregivers was reported.

Results

Two hundred eighty-two patients were analyzed, with 206 receiving home hospice care and 76 receiving inpatient hospice care. Ninety-five patients met the inclusion criteria representing 33.7% of all patients from the two centers at the time of the analysis. Of these, 43.2% were male (41 patients) and 56.8% female (54 patients). The mean age was 72.9 years (SD ± 12.4). There were 48 patients (50.5%) in inpatient care and 47 patients (49.5%) in-home care. The study found that nearly half of the patients (45%) passed away before the end of the study, with 73% of these deaths occurring in inpatient care. According to the ECOG PS scale, patients in home hospice care had slightly better performance status than those in inpatient hospice care (ECOG 4–41% vs. 65%) (Table 2 ).

The most common reasons for hospice care were advanced lung cancer (over 23%) and breast cancer (over 10%) (Table 3 ).

In the study group, 28 patients were taking corticosteroids only, including 20 patients taking dexamethasone only. Additionally, 51 patients were taking morphine only, while 13 patients were taking both drugs (morphine and dexamethasone) simultaneously during the study. The majority of patients taking steroids used them orally (39 patients—87%), whereas morphine was prescribed orally to a smaller percentage of patients (23 patients—45%). Subcutaneous administration was more common for morphine (44 patients) than for dexamethasone (4 patients). Intravenous administration of both study drugs was rare, occurring in only 1% of the study group.

In the 44 patients taking steroids, dexamethasone was the most commonly prescribed steroid, with 33 patients (75%) using it. Of these, 28 patients (85%) took it orally, four patients (12%) took it subcutaneously, and one patient (3%) took it intravenously. Eleven patients (25%) took a different steroid (prednisone or methylprednisolone) orally. Overall, steroids were taken mainly orally by 39 patients (89%). The primary reasons for taking steroids were dyspnea (30%) and brain metastasis (20%).

The study observed that the method of administering morphine varied depending on the care setting. In-home care, the oral form was used more frequently (68%) than the subcutaneous form (32%). Conversely, in inpatient hospice, the subcutaneous form was much more common (90%) than the oral form (10%). Notably, intravenous morphine was not used in any of the palliative care settings (Table 4 ).

The main reasons for administering morphine were severe pain and shortness of breath (Table 5 ).

During the study, 13 out of 92 patients (14%) received both steroids and morphine at the same time. This was particularly common among patients with lung cancer (39%), bowel cancer (15%), and breast cancer (15%). These patients generally had the most severe clinical conditions, see Fig. 2 .

In 83 patients (87%), we demonstrated at least one reason why the intranasal route of drug administration might be preferable to the standard route. The most common reasons were impaired consciousness (66%), lack of caregiver cooperation (20%), and reluctance to inject (19%). Less common reasons included generalized edema and/or cachexia (13%), liver failure (11%), vomiting (6%), presence of a PEG (percutaneous endoscopic gastrostomy) 5%, and gastrointestinal obstruction (1%) (Fig. 3 ). More than two difficulties were observed in 16% of the patients, while more than three were observed in 6%.

Discussion

The study determined how often patients receiving hospice care took two commonly prescribed medications: morphine and dexamethasone. We found that almost half of the patients (43%) took one or both of these drugs simultaneously. This finding aligns with previous reports stating that morphine is the most frequently used opioid [ 38 ] and dexamethasone is the most commonly used steroid [ 39 ]. Both dexamethasone and morphine have been proven to relieve end-of-life symptoms effectively and are routinely used in palliative care [ 40 ]. However, both medications have many side effects. The most common noteworthy side effects of morphine include constipation, confusion, and possible post-opioid hyperalgesia. On the other hand, dexamethasone may lead to insomnia, muscle atrophy, susceptibility to infection, and hyperglycemia [ 41 , 42 ]. In the population of patients with advanced cancer, the benefits of oral opioids and steroids outweigh the potential drawbacks for effective treatment of severe terminal symptoms. However, there is a lack of comprehensive reporting on the side effects of these drugs in this patient group [ 39 ]. In addition, it is worth noting that most subcutaneously administered medications (including morphine, buscolysin, dexamethasone) in palliative care are not approved for such use and are used off-label [ 43 ].

The transmucosal route is not typically the first choice for treating hospice patients [ 33 ]. Intranasal administration of drugs in end-of-life care is most often used off-label, as are medications administered subcutaneously [ 43 ]. The exception to this is fentanyl, which has become a standard treatment for pain in palliative care. It is used not only for patients with cancer but also for those experiencing coronary artery pain [ 44 ] or pain during sickle cell disease (SCD) [ 45 ]. Methods of delivering fentanyl include sublingual, buccal, and intranasal routes. The intranasal route is considered the most convenient and easy to control, making it the most common choice for patients [ 46 ].

Numerous publications suggest that intranasal drug delivery is an intriguing alternative to traditional drug delivery methods, especially for specific patient groups [ 47 , 48 ]. Patients who could benefit from changing the route of administration of essential drugs from oral to intranasal are primarily those with obstructed gastrointestinal tracts, fistulas, or feeding tubes. This includes individuals with swallowing disorders due to nausea, vomiting, or disorders of consciousness, particularly among patients at the end of life [ 49 ]. An essential aspect of palliative care, particularly in a home setting, is the collaboration of medical personnel with the patient’s family or caregivers [ 50 ]. Caregivers’ reluctance to administer injections and the patient’s hesitancy to receive them are significant factors limiting the use of drugs for symptom management via the subcutaneous route [ 50 ].

On the other hand, the widespread use of fentanyl in intranasal form shows that there is no technical or mental problem with using this method [ 51 ]. The use of the intranasal route in treating patients under hospice care may enhance the effectiveness of symptomatic treatment for those who, for various reasons, cannot take medications orally or subcutaneously [ 52 ]. However, further comprehensive studies are required to examine patient preferences and to verify the effectiveness of these medications in a clinical setting.

Limitations

The study only included patients from two medical centers in one province of a single country. This could impact how medical professionals choose treatments for similar cases. The study had a relatively short follow-up period of 3 months. A significant number of patients (46%) died before the study concluded, which is a limitation often seen in research involving end-of-life patients. Difficulties with medication use were assessed in a non-standardized manner, based on interviews with the patient, family, or carers using a self-created questionnaire. For the purposes of clinical practice and further scientific research, we see the need to create a validated questionnaire to assess the indications for intranasal drug administration in palliative patients.

Conclusion

In patients receiving palliative care at home or in a hospice, many are prescribed morphine, corticosteroids, or both. However, there are obstacles to taking these drugs using standard methods. An alternative approach using intranasal delivery of these drugs for end-of-life symptom management is worth exploring. The authors suggest further research to understand patients’ preferences for intranasal drug administration and to evaluate the effectiveness of intranasal morphine and/or dexamethasone in palliative care patients through an experimental study.

Author contributions

Conceptualization: A.I., Z.B., M.S., and R.S.

Formal analysis: A.I.

Methodology: A.I., Z.B., M.S., and R.S.

Resources: A.I., Z.B., and R.S.

Supervision: R.S.

Writing—original draft: A.I., Z.B., M.S., and R.S.

Funding

Gdański Uniwersytet Medyczny,open access funding,open access funding,open access funding,open access funding

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

The paper was approved by the Bioethical Committee of Medical University of Gdansk (consent KB/12/2024). The ethical standard according to which the study was conducted: The Declaration of Helsinki.

Consent to participate

Not applicable.

Conflict of interest

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.