Has Pain Management in Cancer Patients with Bone Metastases Improved? A Seven-Year Review at An Outpatient Palliative Radiotherapy Clinic

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1 Vol. 37 No. 1 January 2009 Journal of Pain and Symptom Management 77 Original Article Has Pain Management in Cancer Patients with Bone Metastases Improved? A Seven-Year Review at An Outpatient Palliative Radiotherapy Clinic Andrea M. Kirou-Mauro, BHSc (C), Amanda Hird, BSc (C), Jennifer Wong, BSc (C), Emily Sinclair, BSc, MRT (T), Elizabeth A. Barnes, MD, FRCPC, May Tsao, MD, FRCPC, Cyril Danjoux, MD, FRCPC, and Edward Chow, MBBS, PhD, FRCPC Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada Abstract The primary objective of this study was to determine the prevalence of underdosage of analgesics for pain associated with bone metastases in outpatients referred to the Rapid Response Radiotherapy Program at the Odette Cancer Centre from 1999 to A prospective database containing data for all patients with bone metastases who were referred to the Rapid Response Radiotherapy Program for palliative radiotherapy from 1999 to 2006 was analyzed. The database included patient demographic information, including age at referral for radiation to the bone, gender, primary cancer site, and Karnofsky Performance Status; information on treatment-related factors, such as worst pain ratings and analgesic consumption in the past 24 hours (recorded as oral morphine equivalent doses); pain intensity ratings (none [rating ¼ 0], mild [rating ¼ 1e4], moderate [rating ¼ 5e6] or severe [rating ¼ 7e10]; and analgesic consumption (rated as none, nonopioids, weak opioids [e.g., codeine] and strong opioids [e.g., morphine and hydromorphone]). Patients who experienced moderate or severe pain and were prescribed no pain medication, nonopioids, or weak opioids were considered to be undermedicated. Between January 1999 and December 2006, 1,038 patients were included in the study database. Approximately 56% of patients were male and 44% were female. The median age was 68 years (range 28e95) and the median Karnofsky Performance Status was 70 (range 10e100). The percentages of undermedicated patients were 40% in 1999, 34% in 2000, 29% in 2001, 37% in 2003, 39% in 2004, 36% in 2005, and 48% in No appreciable decline was noted in the proportion of patients with moderate-to-severe pain who received no pain medication, nonopioids, or weak opioids during the study period. Despite the publication of pain management guidelines and the dissemination of data regarding the proportion of patients with bone metastases who are being prescribed inadequate analgesics, our findings suggest that a significant proportion of patients This study was generously supported by the Michael and Karyn Goldstein Cancer Research Fund. Address correspondence to: Edward Chow, MBBS, PhD, FRCPC, Department of Radiation Oncology, Odette Ó 2009 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. edward.chow@sunnybrook.ca Accepted for publication: January 2, /09/$esee front matter doi: /j.jpainsymman

2 78 Kirou-Mauro et al. Vol. 37 No. 1 January 2009 continue to be undermedicated. J Pain Symptom Manage 2009;37:77e84. Ó 2009 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Pain, palliative radiotherapy, undermedication Introduction Approximately 70% of patients with carcinomas of the breast or prostate will experience metastases to the bone. In fact, the bone is the most frequent site of metastasis and is associated with significant morbidity, including pain severe enough to require opioids, radiotherapy, and/ or surgery, as well as hypercalcemia, pathologic fracture, and compression of the spinal cord or nerve root. 1 Unfortunately, despite the availability of strong opioids, the existence of various other treatment options for bone pain, and the publication of pain management guidelines, most patients with bone metastases have traditionally received inadequate treatment of their pain. 2e4 Analgesics used in the management of cancer-related pain can be categorized as nonopioids, so-called weak opioids (e.g., codeinecontaining analgesics) and so-called strong opioids (e.g., morphine or hydromorphone). 3 Patients with cancer that has metastasized to the bone are treated with palliative intent. Given that the focus of palliative care is to promote quality of life and reduce symptoms resulting from disease or its treatment, adequate pain management is a critical issue for patients receiving palliative care. 5 An assessment of whether there have been changes in the prevalence of underdosage of analgesics for cancer bone pain over a number of years can help determine whether palliative care is improving in this population and may be beneficial in determining the efficacy of pain relief in advanced cancer patients. The primary objective of this study was to determine the prevalence of underdosage of analgesics for pain associated with bone metastases in outpatients referred to the Rapid Response Radiotherapy Program (RRRP) at the Odette Cancer Centre from 1999 to Patients and Methods Ethics approval was obtained from the Hospital Research Ethics Board. A prospective database containing data for all outpatients with bone metastases who were referred to the RRRP for palliative radiotherapy to the bone during the years from 1999 to 2006 was analyzed. The RRRP is one of two programs offering timely access to palliative radiotherapy to patients in the Greater Toronto Area. Patients are referred to the program by community medical oncologists and palliative care physicians, as well as by other oncologists and palliative care physicians from the Odette Cancer Centre. Patients included in the analysis had radiographic evidence of bone metastases, were able to speak English, were over the age of 18 years, and were able to provide informed consent at time of inclusion in the study database. An explanation of the research was provided to all competent patients following their initial consultation at the RRRP and verbal consent was obtained from all participants. Patients were excluded from the database and subsequent analysis if they were confused or declined participation. Data included in the analysis consisted of patient demographic information, including age at referral for radiation for bone metastases, gender, primary cancer site, and Karnofsky Performance Status score. Information relating to treatment-related factors, including date of initial consultation with the radiation oncologist, worst pain rating, and analgesic consumption in the past 24 hours (recorded as oral morphine equivalent doses), was also analyzed. Pain intensity was stratified as none (rating ¼ 0), mild (rating ¼ 1e4), moderate (rating ¼ 5e6), or severe (rating ¼ 7e10), 6,7 and analgesic consumption was rated as none, nonopioids, weak opioids (e.g., codeine-containing analgesics) and strong opioids (e.g., morphine and hydromorphone). The proportions of patients with none, mild, moderate, and severe pain who received no pain medication, nonopioids, weak opioids, and strong opioids were determined. Patients who experienced moderate or severe pain and were prescribed no pain medication, nonopioids, or weak opioids were

3 Vol. 37 No. 1 January 2009 Pain Management in Patients with Bone Metastases 79 considered to be undermedicated. This classification is consistent with the Pain Management Index first proposed by Cleeland et al., 8 which considers the congruence between the severity of a patient s pain and the efficacy of the prescribed analgesics, based on World Health Organization guidelines for the management of cancer-related pain. 9,10 Results were expressed as the mean SD for quantitative variables and as proportions for categorical findings. The Pearson correlation (r) was calculated between rates of undermedication and age, gender, and primary cancer site. Chi-squared tests or two-sample independent t-tests were used to compare the rates of undermedication in gender, primary cancer site, or age. To search for the changes over time in the primary cancer site or in the undermedication rate, Chi-squared tests were applied as well. Results were considered significant at the 5% critical level (P < 0.05). All calculations were performed using the SAS (version 9.1, SAS Institute, Cary, NC) statistical software package. Table 1 Descriptive Statistics for Patients Seen in the RRRP from January 1999 to December 2006 (n ¼ 1,038) Sex Male 584 (56.3%) Female 454 (43.7%) Age n 1,038 Mean SD Median (range) 68 (28e95) Karnofsky Performance Status n 997 Mean SD Median (range) 70 (10e100) Worst pain score n 1,033 Mean SD Median (range) 7 (0e10) Total morphine equivalence n 971 Mean SD Median (range) 30 (0e3,600) Primary cancer site Breast 257 (24.7%) Prostate 228 (22.0%) Lung 248 (23.9%) Gastrointestinal 80 (7.7%) Other 225 (21.7%) Results Between January 1999 and December 2006, 1,038 patients were included in the study database. Approximately 56% of patients were male and 44% were female. The median age of patients was 68 years (range 28e95) and the median Karnofsky Performance Status was 70 (range 10e100). The most common primary cancer sites were breast (25%), lung (24%), and prostate (22%). There was no significant change in the proportions of patients with different malignancies during the seven-year study period. The mean total morphine equivalent dose used by patients was mg (range 0e3,600) (Table 1). From the 1,038 patients enrolled in the study, 38 (4%) had missing data in terms of worst pain rating or analgesic consumption. Therefore, this group was excluded from further analysis. In 2002, a change occurred in the database used to collect patient demographic and pain information; therefore, there are not sufficient data available to present the proportion of patients in this cohort who were undermedicated. Individuals seen during this time were not included in this analysis and have been excluded from Table 1. During the study period, the proportion of evaluable patients experiencing moderate-tosevere pain was calculated. Furthermore, the number of patients within this subgroup who were undermedicateddthose prescribed no pain medication, nonopioids, or weak opioidsdwas determined. In 1999, a total of 149 of 233 patients (67%) experienced moderate or severe pain. In 2000, 141 of the 223 patients (63%) also fell in this pain category. In 2001, the proportion of patients experiencing moderate-to-severe pain had increased slightly to 104 of 159 (65%). From these subgroups, 60 of 149 (40%), 48 of 141 (34%), and 30 of 104 (29%) patients were considered undermedicated in 1999, 2000, and 2001, respectively. Within this three-year time period, the mean oral morphine equivalent doses of prescribed weak opioids were 16.4, 13.7, and 10.8 mg, in 1999, 2000, and 2001, respectively, and 193.8, 209.4, and mg for strong opioids in the same years (Table 2). Following the reconstruction of the database, evaluation of undermedication resumed in 2003 and continued until In 2003, 2004, 2005, and 2006, the proportion of patients presenting with moderate-to-severe pain was 86 of 94 patients (91%), 111 of 124

4 80 Kirou-Mauro et al. Vol. 37 No. 1 January 2009 Table 2 Oral Morphine Equivalent Doses for Patients Seen in the RRRP from 1999 to 2001 and 2003 to 2006 Year Mean SD (mg) Range (mg) 1999 Weak opioids e86.4 Strong opioids e3, Weak opioids e43.2 Strong opioids e1, Weak opioids e43.2 Strong opioids e2, Weak opioids e36 Strong opioids e1, Weak opioids e36 Strong opioids e2, Weak opioids e18 Strong opioids e2, Weak opioids e56 Strong opioids e648 (90%), 85 of 107 (79%), and 54 of 70 (77%), respectively. From these subgroups, 32 of 86 (37%), 43 of 111 (39%), 31 of 85 (36%), and 26 of 54 patients (48%), respectively, were not receiving adequate opioids despite reporting moderate or severe pain (Table 3). The mean oral morphine equivalent doses for weak opioids used by patients in 2003, 2004, 2005, and 2006 were 12.8, 14.0, 6.5, and 23.2 mg, respectively. Strong opioid users among patients seen during this four-year period used, on average, the equivalent of 192.6, 206.7, 281.9, and mg of oral morphine, respectively (Table 2). Additional correlational analyses were conducted using Chi-squared tests and two-sample independent t-tests. There was no significant difference in the rates of undermedication based on age or gender. Patients with breast cancer were more likely than all other patients to be undermedicated (P < ) and patients with lung cancer were less likely than all other patients to experience moderate or severe pain without the prescription of strong opioids (P ¼ 0.019). Sensitivity tests were also carried out using the definitions of mild (1e3), moderate (4e7), and severe (8e10) pain used in the previous investigations by Chow et al. 3 and Yau et al. 4 There were no significant changes in the results using these alternative pain intensity definitions (results not shown). Finally, a Chi-square analysis revealed a significant difference in the proportion of undermedicated patients over the study period; there was a decrease in the prevalence of poorly treated pain from 1999 to 2001, followed by a rise beyond the baseline level (P ¼ ). Although the majority of patients assessed in the RRRP consistently presented with moderate-to-severe pain, there was no appreciable decline in the proportion of undermedicated patients over the sevenyear study period. Discussion This investigation used definitions of mild, moderate, and severe pain consistent with those determined by Li et al. 6 and Serlin et al. 7 when optimal cutpoints for pain intensity ratings were determined through correlation with functional interference ratings; mild pain was defined as a worst pain rating of 1e4, moderate pain was characterized as a pain intensity of 5e6, and patients who reported a worst pain rating of 7e10 were considered to have severe pain. Using these definitions, the analysis determined that there was no appreciable decline in the proportion of undermedicated patients seen in the RRRP from 1999 to These findings are generally consistent with those of previous publications by our group outlining trends in analgesic utilization by patients with painful bone metastases. 3,4 With the knowledge that pain is a significant issue for advanced cancer patients, the World Health Organization, in 1986, proposed a three-step analgesic ladder approach for the management of cancer pain. According to this algorithm, patients should first be prescribed a nonopioid (such as a nonsteroidal anti-inflammatory drug [NSAID]). If the patient then experiences persisting or increasing pain, he or she should be prescribed an opioid drug for mild-to-moderate pain (i.e., a so-called weak opioid such as codeine). If or when the patient no longer receives adequate pain relief for mild or moderate pain, he or she should be prescribed an opioid for moderate-to-severe pain (i.e., a so-called strong opioid such as morphine). 9,10 A randomized controlled trial conducted by Marinangeli and colleagues 11 found that strong opioids were safe and well tolerated, with no development of tolerance or serious adverse events, even when used as first-line

5 Vol. 37 No. 1 January 2009 Pain Management in Patients with Bone Metastases 81 Table 3 Number of Patients with Various Degrees of Worst Pain Intensity Stratified by Type of Analgesic Prescribed (Based on RRRP Data from 1999 to 2001 and 2003 to 2006) Pain Intensity Analgesic Intake None Mild Moderate Severe Total 1999 No pain medication (16.6%) Nonopioids (5.8%) Weak opioids (22.9%) Strong opioids (54.7%) Total 17 (7.6%) 57 (25.6%) 40 (17.9%) 109 (48.9%) No pain medication (14.8%) Nonopioids (13.9%) Weak opioids (12.6%) Strong opioids (58.7%) Total 15 (6.7%) 67 (30.0%) 55 (24.7%) 86 (38.6%) No pain medication (10.1%) Nonopioids (8.2%) Weak opioids (20.1%) Strong opioids (61.6%) Total 13 (8.2%) 42 (26.4%) 38 (23.9%) 66 (41.5%) No pain medication (2.1%) Nonopioids (20.2%) Weak opioids (17.0%) Strong opioids (60.7%) Total 1 (1.1%) 7 (7.4%) 15 (16.0%) 71 (75.5%) No pain medication (12.1%) Non-opioids (16.9%) Weak opioids (9.7%) Strong opioids (61.3%) Total 0 (0%) 13 (10.5%) 23 (18.5%) 88 (71.0%) No pain medication (16.8%) Nonopioids (10.3%) Weak opioids (15.0%) Strong opioids (57.9%) Total 0 (0%) 22 (20.6%) 21 (19.6%) 64 (59.8%) No pain medication (30.0%) Nonopioids (10.0%) Weak opioids (8.6%) Strong opioids (51.4%) Total 0 (0%) 16 (22.8%) 10 (14.3%) 44 (62.9%) 70 treatment of pain in patients with terminal cancer. This finding suggests the potential utility of strong opioids at all stages for patients with painful bone metastases. Interestingly, Eisenberg et al. 12 reported that NSAIDs provided as many as 60% of patients with pain relief, even though the baseline pain intensity was moderate to severe in the majority of these patients. This result suggests that weak opioids may be no better than NSAIDs alone and calls into question the efficacy of the second step of the analgesic ladder. 13 This finding is consistent with the definition of undermedication used in this investigation, as patients using NSAIDs (nonopioids) in addition to those using weak opioids were considered to have been prescribed inadequate analgesics. Interestingly, a decrease in the proportion of undermedicated patients was observed from 1999 to 2001, followed by a rise beyond the baseline level from 2003 to These findings suggest that there may have been an initial improvement in pain management practices, but cancer pain does not get as much

6 82 Kirou-Mauro et al. Vol. 37 No. 1 January 2009 attention as it did before and practitioners may have forgotten about this significant issue. Without a persistent focus on analgesic prescription practices, patients cancer pain may have evaded notice in clinical practice. Given that there was no significant and perpetual decrease in the proportion of undermedicated patients over the seven-year study period, it is important to consider reasons for the continual underdosage of analgesics for patients with moderate-to-severe pain from bone metastases. One plausible explanation for the persistence of pain management deficiencies for patients referred to the RRRP would be that the same set of physicians consistently referred undermedicated patients to this practice. Palliative radiotherapy may be viewed as an alternative to the treatment of cancerrelated bone pain with opioids and this may account for the high proportion of patients being referred to the RRRP without optimal prescription of strong opioids. An alternative explanation for the perpetuation of undermedication of patients with bone pain would be structural barriers to prescription of analgesics by physicians caring for these patients. Surveys of Canadian palliative care physicians and oncologists, however, have indicated that regulatory issues, cost factors, and access to analgesics and opioids are not regarded as major contributors to the undertreatment of cancer-related pain. 14,15 In fact, medications such as opioids are widely available for use in the management of pain for patients with cancer. 15,16 The persistence of undermedication despite the availability of opioids and other analgesics for the treatment of cancer pain may point to limitations in current pain management guidelines. For instance, a study by Mularski et al. 17 found that even with the implementation of routine documentation of pain intensity in the United States, the quality of pain management did not appear to improve significantly. The authors concluded that additional interventions were required to facilitate greater awareness of patients pain and to increase the rates at which patients received appropriate therapy according to the intensity of pain they were experiencing. Apfelbaum et al. 18 provided a similar critique of the current pain management guidelines in their study of the postoperative pain experience. Given that most patients were found to experience moderate-to-severe pain at some point during their postoperative recovery period, the authors suggested that the current pain management guidelines alone were not sufficient to provide optimal treatment for patients pain. Instead, the authors called for changes to current medical practice models, further research, and development of potent, yet tolerable, analgesics to allow for more successful pain management. Further, a large body of research has been conducted to determine additional causes of undermedication of patients pain. Through these investigations, barriers such as misconceptions from health care providers about medications and side effects from the medications, insufficient knowledge and training in pain management, and insufficient pain measurement procedures have been identified. 19e32 Moreover, various patient and primary caregiver concerns, including fear of addiction to pain medication or concern about side effects of treatment, may prevent patients from using strong opioids. Poor communication with health care providers, the notion that reporting pain is inappropriate, and a misconception of the inevitability of pain among patients may contribute to the inadequate treatment of pain in advanced cancer patients. 33e40 On account of the persistence of the undermedication issue, research has emerged investigating potential interventions to improve pain management practices. For instance, a study by Ury et al. 41 investigated the effectiveness of a case-based pain management and palliative care curriculum in improving the opioid prescribing practices of medical residents. The curriculum was found to be associated with a sustained improvement in opioid prescribing practices, and thus the authors concluded that a well-planned educational intervention may be an effective way to improve patient care through appropriate opioid prescription. From a Canadian perspective, higher levels of expertise and access, as well as a revised national action plan, have been identified as potential vehicles for the improvement of cancer pain management beyond the present status. 16 In addition, patient and caregiver education has been considered as a potential intervention to improve pain management practices.

7 Vol. 37 No. 1 January 2009 Pain Management in Patients with Bone Metastases 83 The results of a randomized trial published by Wells et al. 42 indicate that whereas pain education does improve knowledge and beliefs about pain, this education alone does not translate into better pain outcomes. Thus, the authors suggest that educational interventions directed at either patients or health care providers alone are not of clear benefit, although interventions of a more multidimensional nature may be of greater utility. Evidently, there are a number of patient, caregiver, and health care provider-related factors that influence pain management practices. This analysis did not consider factors, such as patient preference, that may have contributed to undermedication. Thus, future prospective studies are warranted to further examine the prevalence of underdosage of analgesics, while taking into account reasons for strong opioid nonuse. Patients with bone metastases who are referred to the RRRP and treated with palliative radiotherapy demonstrate symptomatic bone pain. Therefore, these patients are not representative of all patients with bone metastases; individuals who are asymptomatic or obtain adequate pain relief through the use of pain medications would not warrant a referral to our clinic and would thus not be included in our sample. In addition, only English-speaking patients were included in this investigation. Given that Toronto and the surrounding area is a very multicultural region, patients included in this study may not be representative of all patients with painful bone metastases in this region. Thus, future studies should include patients from other care settings (i.e., inpatients) as well as outpatients receiving services aside from palliative radiotherapy, and non-english-speaking patients, to determine whether the proportion of undermedicated patients differs by treatment setting. Further, this study is limited in that specific information regarding the prescription of analgesics was not recorded. For example, it is unknown whether pain medications were being prescribed by oncologists or primary care physicians, and the length of time since prescription of analgesics was not elucidated. Thus, future studies should involve more detailed accounts of analgesic prescription history so that the causes of underdosage of pain medications may be explored. Conclusion The results of this study support the observation that despite the publication of pain management guidelines and in spite of the dissemination of data regarding the inadequate prescription of analgesics for patients with painful bone metastases, a significant proportion of these patients are still being undermedicated. Given that pain relief is a critical issue in the treatment of bone metastases, changes in practice in terms of prescription of analgesics will help to achieve the objective of reducing pain and suffering for these patients. References 1. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006;12:6243e Grossman S, Pain Sheidler V. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE, eds. Clinical oncology. New York: Churchill Livingstone, 1995: 357e Chow E, Connolly R, Franssen E, et al. Prevalence of under-dosage of analgesics for cancer bone pain in patients referred for palliative radiotherapy, and its potential implications in radiotherapy trials. Ann RCPSC 2001;34(4):217e Yau V, Chow E, Davis L, et al. Pain management in cancer patients with bone metastases remains a challenge. J Pain Symptom Manage 2004;27(1): 1e3. 5. Goldberg G, Morrison R. Pain management in hospitalized cancer patients: a systematic review. J Clin Oncol 2007;25:1792e Li KK, Harris K, Hadi S, Chow E. What should be the optimal cutpoints for mild, moderate and severe pain? J Palliat Med 2007;10(6):1338e Serlin RC, Mendoza TR, Nakamura Y, Edwards KR, Cleeland CS. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain 1995;61(2): 277e Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 1994;330(9):592e World Health Organization. Cancer pain relief and palliative care: a report of a WHO expert committee. World Health Organ Tech Rep Ser 1990;804: 1e World Health Organization. Cancer pain relief. In: With a guide to opioid availability, 2nd ed. Geneva: WHO, e Marinangeli F, Ciccozzi A, Leonardis M, et al. Use of strong opioids in advanced cancer:

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