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

doi:10.21203/rs.3.rs-5271335/v1

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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

https://doi.org/10.21203/rs.3.rs-5271335/v1

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Introduction: Patients who are receiving hospice care often have various ailments and may need to take medications to relieve symptoms for the rest of their lives. The most common and recommended way to take morphine and streoids is orally, less frequently, subcutaneous or intravenous routes are used in palliative care. The intranasal route is a relatively uncommon but interesting alternative for administering drugs.

Aim: The study aims to identify palliative patients who may benefit from changing the standard opioid and steroid administration route to intranasal delivery.

Material and methods: The electronic medical records of all home and inpatient hospice patients were analyzed between February and April 2024. The study focused on the magnitude and type of problems associated with taking medications via standard routes and assessed the potential for changing to an intranasal route of administration.

Results: Out of 282 patients who met the inclusion criteria, 95 (43%) were eligible for analysis. According to a survey, 87% of patients experienced issues with taking medications through the standard route. Among the problems related to oral medicines, consciousness disorders were the most significant at 66%. For subcutaneous administration, the main issues were reluctance to inject at 19% and lack of cooperation from caregivers at 20%. Conclusion: The profile of a palliative patient who may benefit from intranasal administration of symptomatic drugs includes patients with impaired consciousness, aversion to subcutaneous injections, and inadequate support from caregivers.

palliative patient

morphine

dexamethasone

intranasal route

hospice

The number of palliative care patients is increasing annually, and there is improving institutional support for both patients and their families¹. This support is provided in inpatient hospice facilities and as part of home hospice care at the patients' residences. The medical care of palliative patients poses numerous challenges, with a key focus on administering appropriate medications to manage end-of-life symptoms². Opioids and steroids play a crucial role in palliative care as they help alleviate distressing symptoms without hastening death³.

Morphine is a commonly used opioid^4,5 that acts to relieve severe pain and inhibit the sensation of dyspnea, especially when the respiratory system is involved in the disease process⁶. 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 decline⁷. Parenteral administration, which bypasses the liver's first-pass effect, reduces the accumulation of toxic morphine metabolites. Morphine is being studied for its potential to relieve dyspnea in conditions such as severe chronic obstructive pulmonary disease (COPD), idiopathic interstitial pneumonia⁸, and heart failure⁹.

Dexamethasone is the most widely used steroid in palliative care^10,11. Its action is based on a glucocorticosteroid and residual mineralocorticosteroid mechanism. It exhibits a long duration of action of 36 to 54 hours¹². Dexamethasone helps alleviate many problems burdening the patient during the dying period. It improves appetite, relieves pain and dyspnea, increases psychomotor drive, and improves mood^13,14. It significantly reduces swelling of neural tissue caused by primary brain tumors, tumor metastasis to the brain, or tumor lesions within the spinal cord¹⁵. Additionally, evidence supports dexamethasone's effectiveness in intestinal obstruction¹⁶, superior vena cava syndrome, upper airway stenosis, and lymphangitis carcinomatosis¹⁷.

The standard way to administer morphine and dexamethasone is through oral delivery¹⁸. 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 probe, 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 of the first-pass effect. In cases of difficulty swallowing or gastrointestinal obstruction, the preferred option for drug delivery is the subcutaneous route, both inpatient and at home, by caregivers¹⁹. The presence of significant edema in the subcutaneous tissue or cachexia may restrict subcutaneous drug delivery. Additionally, the willingness and cooperation of the patient and their caregivers is crucial. Some caregivers may refuse to administer the drug via injection due to concerns about potentially harming the patient, uncertainty, or other psychological issues²⁰.

Intranasal drug administration avoids most of these challenges²¹. The human nasal cavity is lined mainly with respiratory epithelium (about 130 cm²) and olfactory epithelium (about 10 cm²)²². Both types of nasal cavity epithelium are involved in 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 circulation²³. 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 tissue²⁴. 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 drugs²⁵. 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 there²⁶ (Fig. 1).

Intranasal drug delivery has been successfully used for years for potent opioids such as fentanyl²⁷. 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 patients²⁸. In addition, intranasal drug delivery can enhance the patient's comfort with medication and improve cooperation with caregivers²⁹.

The ECOG PS 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 death³⁰.

Only a few published papers address the use of intranasal delivery of morphine and/or dexamethasone for palliative care patients^31–33. This article aims to evaluate the patient population who are prescribed morphine and/or dexamethasone. The study seeks to identify the characteristics of palliative care patients who may benefit from switching the administration of these drugs to the intranasal route.

This publication aims to identify the characteristics of palliative care patients who may benefit from switching from the standard method of administering opioids and steroids to the intranasal route. The manuscript's 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.

Two hospices in the Pomeranian region of Poland participated in a two-center observational study, which included patients receiving inpatient and home hospice care. 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 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

(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).

Table 1

Proprietary questionnaire for assessing medication problems.
Route of drug delivery	Difficulties in administering medication	Tick if applicable
oral	obstruction of the gastrointestinal tract – symptoms or diagnosis
	feeding by nasogastric tube or PEG (percutaneous endoscopic gastrostomy)
	nausea and/or vomiting
	known liver failure
	decreased level of consciousness with swallowing difficulties
subcutaneous/intravenous	unwillingness of caregivers to be involved in treatment (medical interview)
	swelling of the subcutaneous tissue
	cachexia
	patient-reported aversion to injections

282 patients were analyzed, with 206 receiving home hospice care and 76 receiving inpatient hospice care. The group meeting the inclusion criteria represented 46% of all palliative care patients from the two centers at the time of the analysis. Ninety-five patients met the inclusion criteria, with 43.2% 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 outcomes than those in inpatient hospice care (ECOG 4–41% vs. 65%). For detailed data, please refer to Table 2.

Table 2

Table illustrating the distribution of patients on the ECOG PS scale. N – number of patients.
Patients description	Asymptomatic	Symptomatic but completely ambulatory	Symptomatic, < 50% in bed during the day	Symptomatic, > 50% in bed, but not bedbound	Bedbound	Death
ECOG PS score	0	1	2	3	4	5
Home Hospice Care N = 47	N = 0	N = 0	N = 10 (10,5%)	N = 19 (20%)	N = 18 (18,9%)	N = 0
Hospice Unit Care N = 48	N = 0	N = 0	N = 7 (7,4%)	N = 10 (10,5%)	N = 31 (32,6%)	N = 0

The most common reasons for hospice care are advanced lung cancer (over 23%) and breast cancer (over 10%). The exact distribution is illustrated in Table 3.

Table 3

Table showing the primary disease diagnoses in patients receiving hospice care.
Main diagnosis for hospice care	Main diagnosis (ICD-10)	Numer of patients	% of total patients
Lung cancer	C34	22	23,1
Breast cancer	C50	9	10,6
Colorectal cancer	C18	8	9,5
Prostate cancer	C61	6	6,3
Brain tumor	C71	6	6,3
Rectal cancer	C20	5	5,2
Unknown malignant neoplasm	C80	5	5,2
Ovarian cancer	C56	5	5,2
Pleural mesothelioma	C45	3	3,2
Pancreatic cancer	C25	2	2,1
Gallbladder cancer	C23	2	2,1
Multiple myeloma	C90	2	2,1
Malignant tumor of the lymphatic tissue	C96	2	2,1
Liver cancer	C22	2	2,1
Cancer of the urethra	C68	1	1
Non-Hodgkin’s lymphoma	C83	1	1
Oesophageal cancer	C15	1	1
Lymphatic leukemia	C91	1	1
Cardiomyopathy	I42	1	1
Oropharyngeal cancer	C10	1	1
Decubitus ulcers	L98	1	1
Stomach cancer	C16	1	1
Salivary gland cancer	C07	1	1
Biliary tract cancer	C24	1	1
Skin cancer	C44	1	1
Cancer of the cervix	C53	1	1
Bladder cancer	C67	1	1
Endometrial cancer	C54	1	1

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 a group of 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 mainly were taken 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, the subcutaneous form (90%) in inpatient hospice care was much more common than the oral form (10%). Notably, intravenous morphine was not used in any of the palliative care settings (Table 4).

Table 4

The table shows the number of patients receiving the studied drugs. MF – morphine, DXM – dexamethasone, p.o. – orally, s.c. – subcutaneously, i.v. – intravenous, n – number of patients
	MF p.o.	MF s.c.	DXM p.o.	DXM s.c.	DXM i.v.	A different steroid than DXM p.o.
Home hospice care	n = 19	n = 9	n = 19	n = 3	n = 0	n = 6
Hospice unit care	n = 4	n = 35	n = 9	n = 1	n = 1	n = 5

The main reasons for administering morphine were severe pain and shortness of breath. Detailed data is presented in Table 5.

Table 5

Reasons for prescribing medications in hospice care. N – numer of patients.
	Morphine N = 67	Steroids N = 44
Pain	N = 52 (78%)	N = 4 (9%)
Dyspnea	N = 15 (22%)	N = 13 (30%)
Brain metastases	N = 0	N = 9 (20%)
Brain tumor	N = 0	N = 6 (14%)
other	N = 0	N = 12 (27%)

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, as shown in Graph 1.

The study group found that 83 patients (87%) had at least one reason why using the intranasal route of drug administration might be better than 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 PEG (5%), and gastrointestinal obstruction (1%) (Graph 2). More than two obstructions were observed in 16% of the patients, while more than three were observed in 6%.

Graph 1. The severity of the patient's condition on the ECOG scale in the context of the medication being taken. MF – morphine, DXM – dexamethasone.

Graph 2. Difficulties with the intake of medicines using conventional routes.

The research examined how often patients in hospice care were taking two commonly prescribed drugs, morphine and dexamethasone. The authors 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 opioid³⁴ and dexamethasone is the most commonly used steroid³⁵. Both dexamethasone and morphine have been proven to relieve end-of-life symptoms effectively and are routinely used in palliative care³⁶. 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^37,38. In the population of patients with advanced cancer, the benefits of using solid opioids and steroids outweigh the potential drawbacks when it comes to effectively managing severe end-of-life symptoms. However, there is a lack of comprehensive reporting on the side effects of these drugs in this patient group³⁵. In addition, it is worth noting that most subcutaneously administered medications in palliative care are not approved for such use and are used off-label³⁹.

The transmucosal route is not typically the first choice for treating palliative patients⁴⁰. Intranasal administration of drugs in end-of-life care is most often used off-label, as are medications administered subcutaneously³⁹. 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 pain⁴¹ or pain during sickle cell disease (SCD)⁴². 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 patients⁴³.

Numerous publications suggest that intranasal drug delivery is an intriguing alternative to traditional drug delivery methods, especially for specific patient groups⁴⁴. 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 life⁴⁵. An essential aspect of palliative care, particularly in a home setting, is the collaboration of medical personnel with the patient's family or caregivers⁴⁶. Caregivers' reluctance to administer injections and the patient's hesitancy to receive them are significant factors limiting the use of symptomatic drugs via the subcutaneous route²⁰.

On the other hand, the widespread use of fentanyl in intranasal form shows that there is no technical or mental problem with using this method⁴⁷. 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 subcutaneously⁴⁸. However, further comprehensive studies are required to examine patient preferences and to verify the effectiveness of these medications in a clinical setting.

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. Medication difficulties were assessed non-standardized, based on interviews with the patient, their family, or caregivers, rather than using a formal scale or questionnaire. Additionally, the study did not provide clear patient feedback supporting the hypothesis that switching to intranasal medication would improve adherence.

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 researching 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.

Acknowledgments: None

Author Contributions: Conceptualization: Anna Ingielewicz, Zuzanna Brunka, Mateusz Szczupak, Robert Szymczak Formal analysis: Anna Ingielewicz Methodology: Anna Ingielewicz, Zuzanna Brunka, Mateusz Szczupak., Robert Szymczak Resources: Anna Ingielewicz, Zuzanna Brunka., Robert Szymczak Supervision: Robert Szymczak Writing – original draft: Anna Ingielewicz., Zuzanna Brunka, Mateusz Szczupak, Robert Szczupak

Funding sources: The authors did not receive support from any organization for the submitted work.

Conflict of interest: None

Consent to participate declarations: not applicable

The paper was approved by the Bioethical Committee of Medical University of Gdansk.

The ethical standard according to which the study was conducted: The Declaration of Helsinki

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Graphs 1 and 2 are available in the Supplementary Files section.

No competing interests reported.

graph1.pdf
Graph 1. The severity of the patient's condition on the ECOG scale in the context of the medication being taken. MF – morphine, DXM – dexamethasone.
graph2.pdf
Graph 2. Difficulties with the intake of medicines using conventional routes.

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Submission checks completed at journal
28 Oct, 2024
First submitted to journal
15 Oct, 2024

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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

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Abstract

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1. Introduction

2. Aim of the study

3. Material and methods

4. Results

5. Discussion

6. Restrictions

7. Conclusion

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Supplementary Files

Status:

Version 1