Use of large doses of morphine in hospice facilities

Study of the database of patients, their characteristics and impact on life prognosis

Key words: hospice, cancer pain, life expectancy, morphine

Pain is the symptom most feared by patients with advanced forms of cancer. There are estimates that 65-85% of patients with cancer experienced pain during the illness [1] , [2] . Treatment of chronic cancer pain is often difficult and may require large doses of oral morphine; also, many clinicians suffer from "opiophobia" and refrain from prescribing large doses of morphine. [3] This may be the reason why there is so little information on the subject. 2,4-7. We were unable to find any detailed study in the English-language literature describing the extent or circumstances of high-dose morphine use in the classic hospice setting or the possible relationship between VDM and life expectancy. Many studies have addressed the life expectancy of hospice patients and found median survival periods of 11 to 36 days, but none have compared the life expectancy of patients receiving "standard" doses with that of patients receiving high doses of morphine.

These life expectancy data are important because many physicians believe that VDMs inevitably cause serious side effects and may actively hasten the death of their patients. Moreover, the estimation of life spans for patients on VDM can provide useful information regarding hospice programs and the satisfaction of their funding criteria, as well as overcome inaccuracies in "expert" estimates of patient life expectancy. This study aims to highlight the characteristics of patients requiring VDM, the relationship between the types of primary malignancy and metastatic development on the one hand and the dosage of morphine, the frequency of associated side effects and the duration of life of patients receiving high doses of morphine on the other.

PATIENTS AND METHODOLOGY

We reviewed the medical records of all consecutive patients admitted to Tel Hashomer Hospice during a two-year period beginning January 1, 1996. Most of these patients came simply from their homes, others were referred from various medical institutions. The authors of the study provided medical care to all of them during the last period of their lives.

All patients and caregivers were interviewed on the day of admission. A detailed medical history was obtained, including a complete medication history and a description of the pain syndrome, including onset, nature, intensity, and duration of pain. Data on conclusions from the letters of oncologists and general practitioners who referred patients were also collected.

For each patient included in the study, we recorded: 1) demographic parameters (age, gender, ethnic origin, social status, etc.), 2) tumor localization and metastatic development, 3) pain characteristics depending on morphine doses, 4) need for "rescue" doses associated with different dosage levels of morphine, 5) other drugs (concomitant analgesics) and non-pharmacological therapy used to control pain, 6) length of life in a hospice facility, especially for patients receiving VDM. Patients receiving morphine were classified according to the Edmonton classification for mean daily dose of oral morphine. 8Patients who received VDM were divided into two categories: 1) those who required doses in the range of 300 mg to 599 mg during the day and 2) those who required doses higher than 599 mg during the day. Pain was assessed on a five-point categorical scale (no pain, mild, moderate, severe, unbearable). 9Morphine doses were initially prescribed by the hospice physician, taking into account the severity and characteristics of pain reported at admission and previous morphine doses. During the hospital stay, decisions regarding dose adjustments were based on daily patient reports during morning rounds, nurses' reports, and the volume of "rescue" doses administered during the previous 24 hours. The increase in the dose in cases of insufficient reduction of pain occurred in accordance with the accepted scheme in the amount of 30-50%.

STATISTICAL ANALYSIS

Statistical analysis was performed using BMDP software. 10 A logarithmic transformation was used to obtain a Gaussian distribution for the analysis of morphine dosage. We looked for linear relationships between age, gender, patient ethnicity, and morphine dose using the Pearson correlation test. Different values ​​of morphine doses for different groups were tested using analysis of variance. The survival curve for patients receiving VDM was compared with that of patients receiving lower doses of morphine using the univariate (product-limit) Kaplan-Meier method.

RESULTS

A total of 651 medical records were processed. Using the criteria of the Edmonton system of degrees of previous exposure to morphine, we concluded that 453 patients (69.58%) required morphine as a first-choice drug with a stable dosage ("round-the-clock dosage"). The characteristics of these patients are described in Table I. 55 patients required doses greater than 299 mg per day, of which 19 received doses between 300 and 599 mg per day and 36 received doses greater than 599 mg per day.

Age, Sex, Ethnicity, and Dose of Morphine

Analysis of demographic data of patients receiving VDM showed a negative correlation between age and morphine dose (r = -0.35, P=0.01; Fig. 1). Female patients received a mean (+/- standard deviation) of 748.5 +/- 398 mg per day (range 320 - 1800), while male patients received 1120 +/- 1113 (range 300 - 5400). We decided to recognize this difference as insignificant. No difference in morphine use was found between Caucasian and non-Caucasian patients (Caucasian patients 1024 mg +/- 997 and non-Caucasian patients 910+/-804, respectively). Married patients required a mean (+/- standard deviation) of 1,104 mg +/- 1,058 mg per day (range, 300 - 5,400), while unmarried patients required 751 +/- 550 (range, 320 - 2,700). This was surprising in light of the classic concept of the "pain-killing effect" of immediate caregivers. 

Table 1. Characteristics of patients receiving morphine

Primary tumor and VDM

The types of primary tumors associated with high doses of morphine were as follows: breast (23.63%), gastrointestinal tract (23.36%), lung (20.0%), genitourinary system (16.36%), and head and neck (3.6%) . The relationship between primary tumor and mean morphine doses is presented in Chart 2.

The chart shows that patients with genitourinary cancers required the highest doses of morphine (1469+/-1546 mg), as did those with breast carcinoma (1262+/-1004 mg). Patients with lung, gastrointestinal, head and neck cancer, and other types of cancer needed lower doses. We believe that patients with cancer of the genitourinary system were more in need of VDM due to the high degree of innervation of the pelvic floor.

Metastases and VDM

Metastatic lesions of the spine were diagnosed in 8 (14.5%) patients who received VDM. It required the highest doses of morphine (1519 +/-971 mg per day; range, 420 - 3600). This dose was statistically different from the dose for patients without spinal metastases (P = 0.02); in the second and third places in terms of the volume of the dose, metastatic damage to the organs of the abdominal cavity (1289 +/-1536 mg during the day; range 320 - 5400) and bone damage (1221 +/-1237 mg during the day; range, 300 - 3600) were found ( diagram 3). Patients with lung metastases received a significantly lower daily dose of morphine (525 +/- 253 mg per day) than those without lung metastases (P = 0.03).

Characteristics of pain associated with VDM

Using the simple classification of cancer pain described above 11, we identified 29 patients (52.7%) with bone pain, 24 (43.6%) with visceral pain, and 13 (23.6%) with neuropathic pain. One patient had pain unrelated to cancer. 12 patients had 2 types of pain at the same time. According to a 5-point scale of pain intensity (at the time of hospitalization), the majority of patients had severe (27 patients, 49%) or unbearable (20 patients, 36%) pain. Only 8 patients (27%) characterized their pain as moderate. No patient described their pain as mild. Men were more likely to experience severe or excruciating pain that required VDM (35 patients, 63.6%) than women (20 patients, 36.4%). A small number reported two or more types of pain, mostly caused by the primary tumor and/or multiple metastatic spread.

Rescue doses during VDM therapy

All 55 patients who received VDM had a 24-hour schedule of taking the drug. The majority of patients received orally (41 patients, 74.5%) controlled-release morphine. Twenty-five patients (45.5%) received morphine subcutaneously in later stages. Fourteen of these patients received injections of morphine subcutaneously and 11 used special devices for the injection of morphine - "pumps" (analgesia that is controlled by the patient himself). The last group consisted mostly of patients with terminal dysphagia. Intravenous injections were used only for 8 patients (14.5%); for 7 of them, the main goal was to calm down. In accordance with the recommendations of the World Health Organization for the stabilization of the usual treatment schedule and the treatment of acute breakthrough pain, we used additional doses, which were provided "as needed" (rescue doses). Chart 4 illustrates a positive correlation between the total number of rescue doses and the maximum dosage of morphine (P = 0.025, r = 0.307).

Examples of the use of concomitant painkillers and non-pharmacological treatment

During their stay in hospice, patients who received VDM also used various types of concomitant analgesics. Patients with bone metastases received nonsteroidal anti-inflammatory drugs (NSAIDs) in addition to morphine (33 patients, 60%). All 13 patients with neuropathic pain were treated with tricyclic antidepressants or anticonvulsants. Patients with visceral pain required less adjuvant drugs and lower doses of morphine. Corticosteroids were used for analgesia in 38 (69%) VDM patients. Despite VDM and concomitant analgesia, 11 patients had refractory pain, of which 4 required more aggressive therapy, such as chordotomy (2 patients), radiation therapy (1 patient), or conversion to methadone (1 patient). Another 7 patients (12. 7%) did not benefit from therapy with large doses of morphine, as a result of which there was a need to use sedatives (benzodiazepines, barbiturates or neuroleptics) for appropriate analgesia. When fully controlling the pain syndrome, we found 3 patients (5.5%) who had symptoms of clinical depression, while 8 patients (14.5%) had symptoms of anxiety. These patients received anxiolytics and antidepressants as concomitant analgesic therapy.

Frequency of side effects of VDM

The most common side effects when using VDM were relatively mild. Among them: constipation (41 patients, 74.6%), the treatment of which was a prophylactic combination of such laxatives as lactulose and bisacodyl. Nausea was reported by 23 patients (41.8%), vomiting by 20 (36.3%). Seven patients (12.7%) developed coprostasis and required the use of enemas. In five patients (9.1%)

ichuria developed, requiring the use of indwelling indwelling catheters. One patient developed symptoms of mild myoclonus, but morphine was not discontinued. No rash or pruritus was observed in any patient. None of the 55 patients discontinued VDM because of adverse effects, although some dose adjustments occurred for some patients. Clinically significant depression of respiratory function did not occur in any of the patients receiving VDM.

Time of life expectancy and VDM

Median life expectancy for patients receiving VDM was 15 days, while for patients receiving less than 300 mg per day, this time was 14 days. Patients with very large doses (more than 599 mg per day) lived an average of 13 days. The difference between these groups was not statistically significant (Chart 5). There was also no statistically significant correlation between the patient's life expectancy and the location of the primary tumor or the type of metastases.

DISCUSSION

Sometimes VDM is a necessary treatment for patients in the late stages of cancer to control chronic pain or to overcome tolerance. In Europe, more than 1 million patients suffer from pain caused by cancer 3 . Most of them do not have satisfactory pain control due to insufficient dosage regimen. Previous studies have neglected the role of VDM, and therefore there are only a few small descriptions of VDM in hospice settings. However, none of the previous publications investigated a large number of patients or had the opportunity to characterize these patients while looking for a possible effect of VDM on their life expectancy. Why do some hospice patients require much higher doses of morphine? One of the most important explanations is disease progression, which requires higher doses to control increasing pain.12,13 Moreover, it is clear that many other factors dependent on the individual characteristics of absorption, bioavailability, distribution and protein binding, hepatic and extrahepatic metabolism, and total elimination 4 are involved in the response to morphine use. The pharmacokinetics of morphine are influenced by the age of 14-15 and various painful conditions characteristic of middle and old age. In addition, variability in response to equivalent doses may represent differences in genetic factors as determinants of response to morphine.

Our findings support the current clinical understanding that elderly patients may require lower doses for pain control. A physiological explanation for this fact may be related to the existence of a difference in receptor binding or to a lower volume of distribution of the drug, a lower protein binding capacity, a longer period of elimination of the drug from the body, as well as a difference in the perception of pain compared to younger patients.

Marital status and ethnicity were also frequently associated with VDM, which was rather surprising given the concept of absolute pain and the role of family support in pain management. It also appears that, in addition to cultural factors, ethnicity may be a factor in the patient's presentation of pain symptoms and intensity of treatment.

Acute breakthrough pain occurred relatively frequently 17 in patients with controlled general pain. When this occurred, an additional rescue dose identical to the usual opioid dose was given. We did not examine the number of rescue doses given each day, but our findings demonstrate a positive correlation between the total number of rescue doses and the maximum daily dose of morphine. It was also found that despite increased morphine doses and better analgesia, rescue doses were still required to improve pain control.

In this group of patients using VDM, we found a surprisingly small number of adverse events that required dose limitation. One patient had to switch to another opioid (methadone), and three others we had to provide non-pharmacological care. We did not note any aggravation of side effects despite high doses and were also unable to confirm an increase in the incidence of myoclonus 7 despite concomitant use of psychoactive drugs and nonsteroidal anti-inflammatory drugs with morphine. These results correspond to the conclusions of Radbruch et al. 6, who did not observe any serious side effects or myoclonus in 12 patients receiving more than 600 mg of morphine per day with concomitant analgesics. Therefore, we believe that, despite the obvious need for VDM in some patients, analgesia in cases of severe terminal cancer should also include concomitant non-opioids to treat the specific type of pain the patient is suffering from without fear of myoclonus.

The absence of clinically significant depression of respiratory function in all patients treated with VDM provides strong evidence that the possibility of provoking this complication and thus hastening the death of patients was exaggerated. It should also encourage doctors who are still reluctant to use VDM not to deprive their end-stage patients of this type of treatment.

The question of life expectancy for patients who used VDM is extremely important from a practical and ethical point of view. In addition, predicting life expectancy for hospice inpatients remains imprecise, posing significant challenges for hospice programs and policymakers.

However, in the existing literature on the issue, among the parameters that are associated with reduced life expectancy, no source mentions drug treatment. 18,19 . General poor health was most strongly associated with shorter life expectancy. The use of patient status scales (such as the Karnofsky scale) to assess life expectancy has been suggested. The average life expectancy in our hospice was 15.6 days, much shorter than that reported by US Medicare hospice users, namely 36 days. 20 This difference may have arisen from the fact that our patients come to us at a later stage of the disease. However, we did not observe a significant difference in life expectancy between patients receiving low, moderate, high, and very high doses of morphine.

The conclusion is that VDMs are an adequate type of treatment for some hospice patients who do not respond well to conventional doses of opioids. Our results suggest that physicians can use higher doses of opioids when indicated for better analgesia without fear of hastening patient death.

LINK

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