ORIGINAL ARTICLE
Clinical Experience With Strong Opioids in Pain Control of Terminally ill Cancer
Patients in Palliative Care Settings in Taiwan
Ming-Hsien Li
1, En-Tien Yeh
2,3, Shu-Cheng Huang
4, Huei-Mee Wang
1, Wei-Ru Su
5,
Yuen-Liang Lai
5,6,7,8,9,*1Department of Radiation Oncology, Taipei Medical UniversitydShuang Ho Hospital, Taipei, Taiwan 2Department of Family Medicine, Cardinal Tien Hospital, Taipei, Taiwan
3Department of Hospice and Palliative care, Cardinal Tien Hospital, Taipei, Taiwan 4Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan 5Graduate Institute of Humanities in Medicine, Taipei Medical University, Taipei, Taiwan 6Department of Radiation Oncology, Taipei Medical UniversitydShuang Ho Hospital, Taipei, Taiwan 7Education Center for Humanities and Social Sciences, National Yang-Ming University, Taipei, Taiwan 8Mackay Medical College, Taipei, Taiwan
9Hospice and Palliative Care Center, Mackay Memorial Hospital, Taipei, Taiwan
a r t i c l e i n f o
Article history: Received: Apr 23, 2010 Revised: Jul 12, 2010 Accepted: Aug 2, 2010 Available online 20 October 2010 KEY WORDS:
oncologic pain; palliative care; strong opioids; Taiwan
Background: Strong opioids have been recommended as the mainstay of therapy for moderate-to-severe pain, which is highly prevalent in terminally ill cancer patients.
Purposes: The aims of this study were to collect valuable data on the clinical use of strong opioid anal-gesics in the management of pain in terminally ill cancer patients receiving palliative care in Taiwan and disseminate the knowledge gleaned from these data to guide practical opioid treatment and improve pain control in end-of-life care.
Methods: This study retrospectively reviewed 150 cancer patients who received palliative care in a Taiwanese medical center between July 2005 and August 2008. Information regarding medications for pain control (opioid type, daily dosage, frequency, and route), adverse events, and pain assessments in the last 2 weeks before death was analyzed.
Results: In the second-last week of life, 97 (64.6%) patients were prescribed morphine only and 43 (28.7%) of them received two or more different opioids. In the last week, patients tended to prefer morphine to other opioids. The mean (standard deviation) daily morphine dosage was significantly higher in the last week [96.79 mg (110.55 mg)] than in the second-last week [88.08 mg (100.87 mg)]. The mean daily dose differed significantly between the gender and the three age groups (50, 51e70, and 71 years) in the last week of life but did not show difference in the second-last week of life. Subcutaneous injection (114 of 150, 76%) was the most frequent route of opioid administration. In the second-last week before death, patients with an improvement in their usual breakthrough pain level had taken a significantly higher dose of opioids than those who showed no improvement.
Conclusion: Overall, through appropriate dose adjustments, strong opioid regimens, and appropriate routes, strong opioids can be administered as extremely effective analgesics in the palliative care of patients with intractable cancer pain.
CopyrightÓ 2010, Taipei Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
1. Introduction
Cancer is becoming a leading cause of death, with increasing inci-dence and prevalence worldwide. Pain, one of the most feared and burdensome symptoms of cancer, has an enormously negative effect on the quality of life. Recent reports indicated that 56%e72%
of cancer patients suffer from pain.1,2The prevalence of pain among the population receiving palliative care was as high as 75%e88%,3e6 suggesting that pain management should not only be a substantial component of cancer therapy but also befirmly integrated into the framework of palliative care.
Cancer metastasis, effects of comorbidity in delivering cancer treatments, and persisting pain complicate pain management for the terminally ill cancer patients. Persistent pain causes unneces-sary suffering and can be psychologically devastating for a cancer patient. This often results in physical and mental anguish, a feeling
* Corresponding author. Department of Radiation Oncology, Taipei Medical University-Shuang Ho Hospital, 235 Zhongzheng Road, Zhonghe 291, Taipei County, Taiwan.
E-mail:enochlai49@yahoo.com(Y.-L. Lai).
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of hopelessness, and the loss of will to survive.7Keeping in mind the importance of effective pain management for cancer patients, the World Health Organization (WHO) developed guidelines for cancer pain relief and recommended opioids as the mainstay therapy for moderate-to-severe cancer pain.8Although the nega-tive attitudes toward using strong opioids exist,9 the rational prescription of opioids is the key to pain control.
Palliative care, an approach toward supporting and enhancing the quality of life of terminally ill cancer patients and their families,10 has spread worldwide over the past 2 decades.11Pain management is integral to palliative care to effectively improve patients’ quality of life. Taiwan’s hospice palliative care is among the best in the world.12 The aim of this study was to collect valuable data on the use of strong opioid analgesics in the management of pain in terminally ill cancer patients receiving palliative care in a Taiwanese medical center. This detailed analysis of drug usage should help in making decisions on opioid treatment in palliative care.
2. Methods
This registry study was designed as a noninterventionist study, based on therapeutic strategy and a retrospective patient chart review. The study was conducted in accordance with the Declara-tion of HelsinkidGood Clinical Practice. The protocol and study-related forms were reviewed and approved by the institutional review board.
The records of terminally ill cancer patients in need of standard palliative care (including inpatient care, home care, outpatient care, and shared care programs) and who were administered strong opioids during the period from July 2005 to August 2008 were collected from a medical center in Taiwan and reviewed retro-spectively with a focus on opioid medication and management of pain. The data consisted of thefinal 14 days of standard palliative care before the patient expired. Patient records were selected if they were diagnosed with terminal cancer, administered strong opioids for at least 14 days before death, and under standard palliative care for at least 14 days before they expired. However, patients were excluded from the study if their death was not related to cancer, the pain management received was not because of cancer pain, or they withdrew from palliative care during the observational period (14 days).
For systematical data documentation, a case report form, which included demographic characteristics (gender, age, primary tumor site, and place of primary care) and living performance [Eastern Cooperative Oncology Group (ECOG) performance status at commencement of palliative care, activity of daily living function, cognitive performance, overall quality of life during the last month of life, use of feeding tube, and bedriddenness] at baseline, was developed. The ECOG performance status scale comprises six grades, from 0 to 5, with 0 indicating an asymptomatic state and 5 indicating the death. Physicians evaluated the patients’ ECOG performance status to assess functional status.13Quality of life was rated by the patients themselves on an 11-point Likert sca-ledranging from 0 ¼ poor to 10 ¼ excellentdonce a week during the last month of life. On the basis of the results of self-evaluation, physicians assessed the patient’s overall quality of life during the final month. For patients receiving home-based care, personal interviews were conducted weekly to determine their quality of life. If the patients lost their consciousness, their caregivers would answer for them. Activity of daily living function and cognitive performance were assessed using four levels (none, mild, moderate, and severe impairment) according to evaluation by the physician.
Medications for pain control were recorded in terms of kind, daily dosage, frequency, and administration route. The incidence of
adverse effects (such as sedation, nausea/vomiting, constipation, drowsiness, cognitive impairment, and dry mouth), possibly asso-ciated with strong opioids, was also documented. The daily opioid dose was determined by calculating the morphine equivalent daily dose (MEDD) in milligrams,14according to the MEDD conversion table.15
Pain assessment was performed using two indicators: usual breakthrough pain level and pain intensity. The daily frequency of breakthrough pain in cancer patients was recorded at observed time points. Pain intensity was measured using a 10-point verbal numeric rating scale, between 0¼ pain-free and 10 ¼ worst pain, which relied on self-evaluation. Drug treatment and pain assess-ment were docuassess-mented weekly during the 14 days before patients expired.
Descriptive summaries were provided for patient demo-graphics, medication for pain management, and adverse effects related to strong opioids. In the case of ordinal scales, nonpara-metric rank tests (Wilcoxon rank sum test, Wilcoxon signed rank test, and Kruskal-Wallis test) were used; a p value of<0.05 was considered significant.
3. Results
The medical records of 150 patients, from July 2005 to August 2008, were reviewed and included in this retrospective analysis. Patient demographics and baseline characteristics are shown inTable 1. The study group comprises 71 men (47.3%) and 79 women (52.7%), with a mean age of 60.3 (14.1) years (range, 27e90 years). Gastrointestinal cancers were the most common (50%), followed by cancers of the respiratory system (12%). Most participants (84.7%) had received standard palliative care at hospice rather than in a home setting (15.3%).
Table 1 Clinical characteristics of patients in the study
Characteristics (n¼ 150) N % Gender Male 71 47.3 Female 79 52.7 Age (yr) 50 37 24.7 51e70 72 48.0 71 41 27.3 Mean age (SD) 60.3 (14.1) Cancer type
Head and neck 17 11.3
Respiratory 18 12.0
Gastrointestinal, hepatobiliary system 76 50.7
Breast 13 8.7
Urogential system 17 11.3
Hematopoietic-lymphatic system 1 0.7
Skin, sarcoma, connective tissue 4 2.7
Other 4 2.7
Place of primary care within 14 days before death
Home 23 15.3
Hospice 127 84.7
ECOG at palliative care start
2 10 6.7
3 100 66.7
4 40 26.7
Severe compromised activities of daily living function 40 26.7
Bedriddenness 84 56.0
Suffering impaired cognitive performance 80 53.3
Feeding tube 50 33.3
3.1. Use of strong opioids
Table 2shows the types of opioid treatment the patients under-went. In the second-last week, 97 (64.6%) patients used only morphine, with the mean MEDD being 75.67 mg (95.62 mg), and 43 (28.7%) were administered two or more different types of strong opioid. The most common opioid combination was that of morphine and fentanyl. In the week preceding death, the patients tended to reduce the use of opioid combinations (26, 17.3%) and preferred the use of morphine alone (120, 80.0%). Mean dosages of strong opioids prescribed in the last 2 weeks are summarized in
Table 3. Overall, the mean daily dosage [96.79 mg (110.55 mg)] in the last week of life was significantly higher than that in the second-last week (Wilcoxon signed rank test, p < 0.0001). Male patients received a mean dosage of 115.56 mg (129.76 mg), whereas female patients received a significantly different dose of 79.92 mg (87.32 mg) during the last week. Furthermore, the mean daily dose also differed significantly among the three age groups (50, 51e70, and71 years) during the last week. Over the last 2 weeks of life, the mean daily dose differed significantly among three score groups (6, 7, and 8) of overall quality of life during the last month of life, and between patients with and without impaired cognitive performance, based on a Wilcoxon rank sum test and Kruskal-Wallis test at a significance level of 0.05.
3.2. Route of administration
Forty-two percent of patients needed more than one administra-tion route. In the last 2 weeks of life, as shown inTable 4, the most frequent route of administration was injection. Strong opioids were administered via injection to 146 patients (97.3%); the subcuta-neous route was used for 114 patients (76.0%). The transdermal route (30%) was used more frequently than the oral route (22.0%). For patients receiving palliative care at home, subcutaneous route (91.3%) was most used, followed by the transdermal (43.5%) and oral routes (34.8%).
3.3. Association between pain control and strong opioids
As shown inTable 5, during the second-last week before death, patients who improved in their usual breakthrough pain level took a 104.80-mg MEDD, which is approximately 1.5 times higher than the dose of unimproved patients; patients who improved in terms of pain intensity had taken a 96.12-mg MEDD, which is around 1.4 times higher than the dose of unimproved patients. There was a statistically significant difference in mean MEDD of transition of usual breakthrough pain level between improved and unimproved patients during the second-last week, based on a Wilcoxon rank sum test with a significance level equal to 0.05, whereas the rela-tionships during the last week are not statistically significant.
3.4. Adverse effects
In this retrospective study, four major adverse effects, including sedation (1 patient, 0.7%), constipation (86 patients, 57.3%), drowsiness (7 patients, 4.7%), and dry mouth (6 patients, 4%), were noted. Constipation was more frequently recorded in patients prescribed morphine (81) and fentanyl (14).
4. Discussion
Palliative care services have spread throughout Asia over the past 10 years,11and those of Taiwan are among the best in the world.12 This study aims to describe a practical pain management option, using strong opioids for terminally ill cancer patients receiving palliative care, so as to facilitate optimal pain management.
As recommended by the WHO analgesic ladder, oral morphine should be considered as afirst-line opioid for patients in need of Step 3 treatment. Our study reflected the fact that morphine was thefirst choice for controlling cancer pain, as reported by other studies, which focused on either the entire cancer population16,17or the children and young patients.18Fentanyl, the second choice of strong opioid, based on our study, was not frequently prescribed alone but was combined with morphine. Patients nearing the end of life often suffer from complicated pain symptoms; therefore, terminally ill cancer patients would use morphine alone because of its clinical efficacy, variable formulations, and convenient dosage adjustment.
Table 2 Type and combinations of strong opioid prescribed Medication Period before death
Second-last week Last week
N (%) MEDD* N (%) MEDD* Fentanyl 7 (4.7) 58.78 (31.85) 4 (2.7) 60.00 (0.00) Morphine 97 (64.6) 75.67 (95.62) 120 (80.0) 80.78 (93.13) Fentanylþ morphine 28 (18.7) 140.35 (109.40) 21 (14.0) 199.46 (161.82) Demerolþ morphine 12 (8.0) 100.69 (119.28) 4 (2.7) 95.10 (15.23) Fentanylþ demerol þ morphine 3 (2.0) 107.73 (120.27) 1 (0.6) 14.86 (NA) None 3 (2.0) e e e
MEDD¼ morphine equivalent daily dose; NA ¼ not applicable.
*Data are presented as mean (standard deviation).
Table 3 Summary of mean MEDD during the last 2 weeks before death*
Determinants Period before death
Second-last week Last week
(N¼ 150) (N¼ 150)
Mean daily dose 88.08 (100.87) 96.79 (110.55)
Gender Male (N¼ 71) 101.05 (115.02) 115.56 (129.76) Female (N¼ 79) 76.43 (85.30) 79.92 (87.32) p Value 0.1169 0.0223 Age group 50 (N ¼ 37) 104.16 (128.82) 108.12 (119.45) 51e70 (N ¼ 72) 97.90 (105.15) 112.58 (127.97) 71 (N ¼ 41) 56.33 (43.57) 58.81 (39.61) p Value 0.0704 0.0297
Place of primary care
Home (N¼ 23) 108.10 (142.15) 114.19 (129.89)
Hospice (N¼ 127) 84.46 (91.75) 93.63 (106.96)
p Value 0.4977 0.3293
Overall quality of life during the last month of life
6 (N¼ 21) 223.00 (181.50) 254.28 (203.26)
7 (N¼ 104) 67.80 (56.12) 73.38 (54.44)
8 (N¼ 25) 59.13 (60.18) 61.87 (58.07)
p Value <0.0001 <0.0001
Impaired cognitive performance
None (N¼ 70) 110.39 (119.17) 119.99 (129.48) Mild/moderate/severe (N¼ 80) 68.56 (77.21) 76.48 (86.66) p Value 0.0177 0.0154 Feeding tube No (N¼ 100) 79.25 (89.02) 90.63 (110.25) Yes (N¼ 50) 105.74 (120.23) 109.10 (111.22) p Value 0.1359 0.0389 Cancer type GI system cancer (N¼ 76) 74.49 (76.89) 87.79 (98.37) Non-GI system cancer (N¼ 74) 102.04 (119.61) 106.03 (121.78)
p Value 0.0738 0.1665
MEDD¼ morphine equivalent daily dose; GI¼gastrointestinal.
Interindividual variability in the analgesic dosage required for pain relief is high, as reported by Brooks et al.19Gender and age were reported to be associated with the dosage of strong opioids.17,20In terms of gender, our data showed that males in the last week of life received significantly higher doses of strong opioids than did females, but not in the second-last week, indicating that gender differences became significant as the patients neared death. This might be partly because of the relatively larger number of
m
-opioid receptors in females than in males, that is, females are more sensi-tive to morphine than males.21Males required elevated doses of morphine as pain increased with approaching death, whereas females, who are more sensitive to morphine, maintained an almost constant dose during the same period. The result was that, in the last week, males required significantly higher doses of morphine than did females. Apart from gender, our data indicate that age also affected the use of strong opioids. This is in accordance with previous studies reporting that elderly patients required lower doses to control pain than did young patients, because of a lower volume of drug distribution, reduced hepatic and renal function, and lower protein-binding capacity, and a difference in pain perception to that of younger patients.20,22In addition to interindividual vari-ation, opioid doses have often been reported to increase markedly as death approaches,23,24which was also observed in this study.Generally, hospices are more successful than home care at controlling pain because of the experience and knowledge of health professionals on opioid use. Patients considered to be highly dependent, with a high symptom burden and complicated pain control, are more likely to be admitted to hospices. Therefore, it is not surprising that patients referred to palliative care in hospices required higher doses than those cared for at home.24,25However, our data did not show a significant difference in analgesic dose between patients at home and those in hospice. This result was attributed to the limitations of the retrospective review process, which could not confirm the amount of “as required” medication that patients at home actually consumed. The total opioid dose for
patients at home was calculated as the sum of regular opioid dose (around the clock) and total“as required” dose, which might over-estimate the use of opioid for patients at home.
The most commonly reportedly used route of administration is oral.26However, the subcutaneous routedused by 76% of patient-sdwas the most frequently used route in this study, which focused on terminally ill cancer patients who might suffer unstable pain or impaired cognitive performance prior to death. One study found that the intravenous route was used more frequently than the oral as the disease progressed because rapid and precise titration could be achieved more easily through intravenous routes.18Furthermore, in our study, patients referred to palliative care at home also used opioids, mainly through injection. Thefirst likely explanation is that patients tend to be admitted to hospitals, when pain is uncontrolled, because of the reimbursements of the National Health Insurance system and high hospital densities in Taiwan; so patients will often be prescribed a rescue dose through injection for immediate pain relief. Second, the home-care group is partially composed of patients following the Chinese custom of dying at home, and who are willing to discharge themselves because of terminal illness, with the provision of prescribed analgesic injections. In this study, the transdermal route, another relatively recent development in cancer pain control, was less frequently used than injection. The advantages of the transdermal route include simplicity of use and high patient compliance; however, it is often not efficacious in the treatment of terminally ill cancer patients because of difficult titration in unstable pain18,26 and inefficient absorption of patches in far-advanced patients often suffering from sweating and cachexia.27Overall, the injection route is recommended for terminally ill cancer patients approaching the end of life.
Helping patients to enhance their quality of life by relieving symptom distress is a primary goal of palliative care. Of all symp-toms, pain is a major influence on quality of life and receives considerable research attention. Generally, to facilitate optimal pain management, a multidisciplinary approach is essential in
Table 4 Routes for medications by place of palliative care, cancer type and use of feeding tube
Route Overall (N¼ 150) Place of palliative care Cancer type Use of feeding tube
Home (N¼ 23) Hospice (N¼ 127) GI system (N¼ 76) Non-GI system (N¼ 74) No (N¼ 100) Yes (N¼ 50)
Injection 146 (97.3%) 23 (100.0%) 123 (96.9%) 74 (97.4%) 72 (97.3%) 98 (98.0%) 48 (96.0%) Intramuscular 14 (9.3%) 2 (8.7%) 12 (9.4%) 5 (6.6%) 9 (12.2%) 6 (6.0%) 8 (16.0%) Intravenous 58 (38.7%) 8 (34.8%) 50 (39.4%) 29 (38.2%) 29 (39.2%) 35 (35.0%) 23 (46.0%) Subcutaneous 114 (76.0%) 21 (91.3%) 93 (73.2%) 59 (77.6%) 55 (74.3%) 79 (79.0) 35 (70.0%) Oral 33 (22.0%) 8 (34.8%) 25 (19.7%) 19 (25.0%) 14 (18.9%) 23 (23.0%) 10 (20.0%) PO 31 (20.7%) 8 (34.8%) 23 (18.1%) 18 (23.7%) 13 (17.6%) 21 (21.0%) 10 (20.0%) Sublingual 2 (1.3%) 0 (0.0%) 2 (1.6%) 1 (1.3%) 1 (1.4%) 2 (2.0%) 0 (0.0%) Transdermal 45 (30.0%) 10 (43.5%) 35 (27.6%) 27 (35.5%) 28 (24.3%) 31 (31.0%) 14 (28.0%) GI¼ gastrointestinal; PO ¼ per os
Table 5 Association between mean MEDD and transition of pain control
Variable Period before death
Second-last week (N¼ 150) Last week (N¼ 150)
N (%) Mean* N (%) Mean*
Transition of usual breakthrough pain level
Improved 84 (56.0) 104.80 (120.30) 133 (88.7) 100.84 (114.73)
Unimproved 66 (44.0) 66.80 (63.45) 17 (11.3) 65.09 (63.25)
p Value 0.0396 0.0787
Transition of pain intensity
Improved 107 (71.3) 96.12 (111.17) 143 (95.3) 97.50 (112.02)
Unimproved 43 (28.7) 68.07 (65.82) 7 (4.7) 82.14 (79.06)
p Value 0.1412 0.5929
MEDD¼ morphine equivalent daily dose.
clinical care. In our study, the results demonstrated that patients who improved in their usual breakthrough pain level took signi fi-cantly higher doses of strong opioids than did the unimproved; specifically, pain relief is associated with the dose of strong narcotics. Appropriate prescriptions of strong opioids will assist patients to relieve pain and reduce the frequency of breakthrough pain, as well as to obtain higher levels of quality of life in palliative care. In addition to adequate opioid prescriptions, other non-pharmacological methods, such as neurosurgery, radiotherapy, and supportive measures, and spiritual, emotional, religious, and socioeconomic support also play important roles in pain manage-ment28for patients facing imminent death. Aflexible combination of pain therapies will be of significant help in relieving pain.
Constipation is prevalent in patients taking morphine but low in those prescribed fentanyl.22,26 However, this retrospective study showed that 14 of 46 patients (30.4%) who had been prescribed fentanyl encountered constipation. A reasonable explanation for the phenomenon might be that patients in our survey seldom received fentanyl alone, but rather, in a combination of fentanyl and morphine; the relatively high incidence of constipation might be attributable to concurrent use of morphine.
There are a few limitations of this research. The research was performed in a single medical center, which means that the study sample might not be representative of the population. Therefore, this study should not be considered as a comprehensive picture of opioid use in Taiwan but as a sharing of clinical experience from a specialized palliative care setting. Besides, owing to the limita-tions of retrospective study, it was assumed that all prescribed strong opioid medication had been taken when calculating the total opioids given to home-care patients, which may have resulted in an overestimation. Furthermore, this study focused on the 2-week period before death with only three observed time points. To incorporate more valuable experiences such as opioid switching and analgesic regimes, it is recommended that the study be carried out over a longer period of time and that the observations be more frequent.
This study was intended to provide useful insights into strong opioid use in cancer patients receiving palliative care in the last 2 weeks before death, using clinical experience from a medical center in Taiwan. The principles of treating cancer patients under palliative care in the study followed the fundamental assertions of the WHO guidelines. Nevertheless, more clinicallyflexible treatments should be applied as the disease progresses. Overall, through appropriate dose adjustments, strong opioid regimens, and appropriate routes, strong opioids can be administered as extremely effective analgesics in the palliative care of patients with intractable cancer pain. References
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