Use of Opioid Analgesics Among Older Persons With Colorectal Cancer in Two Health Districts With Palliative Care Programs

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1 20 Journal of Pain and Symptom Management Vol. 46 No. 1 July 2013 Original Article Use of Opioid Analgesics Among Older Persons With Colorectal Cancer in Two Health Districts With Palliative Care Programs Judith Fisher, BSc (Pharm), PhD, Robin Urquhart, MSc, and Grace Johnston, PhD Pharmaceutical Services (J.F.), Department of Health and Wellness, Halifax; Cancer Outcomes Research Program (R.U.), Cancer Care Nova Scotia, Halifax; and School of Health Administration (G.J.), Faculty of Health Professions, Dalhousie University, Halifax, Nova Scotia, Canada Abstract Context. Prescription of opioid analgesics is a key component of pain management among persons with cancer at the end of life. Objectives. To use a population-based method to assess the use of opioid analgesics within the community among older persons with colorectal cancer (CRC) before death and determine factors associated with the use of opioid analgesics. Methods. Data were derived from a retrospective, linked administrative database study of all persons who were diagnosed with CRC between January 1, 2001 and December 31, 2005 in Nova Scotia, Canada. This study included all persons who 1) were 66 years or older at the date of diagnosis; 2) died between January 1, 2001 and April 1, 2008; and 3) resided in health districts with formal palliative care programs (PCPs) (n ¼ 657). Factors associated with having filled at least one prescription for a so-called strong opioid analgesic in the six months before death were examined using multivariate logistic regression. Results. In all, 36.7% filled at least one prescription for any opioid in the six months before death. Adjusting for all covariates, filling a prescription for a strong opioid was associated with enrollment in a PCP (odds ratio [OR] ¼ 3.18, 95% CI ¼ 2.05e4.94), residence in a long-term care facility (OR ¼ 2.19, 95% CI ¼ 1.23e3.89), and a CRC cause of death (OR ¼ 1.75, 95% CI ¼ 1.14e2.68). Persons were less likely to fill a prescription for a strong opioid if they were older (OR ¼ 0.97, 95% CI ¼ 0.95e0.99), male (OR ¼ 0.59, 95% 0.40e0.86), and diagnosed less than six months before death (OR ¼ 0.62, 95% CI ¼ 0.41e0.93). Conclusion. PCPs may play an important role in enabling access to end-of-life care within the community. J Pain Symptom Manage 2013;46:20e29. Ó 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Opioid, pain management, colorectal neoplasms, palliative care Address correspondence to: Judith Fisher, BSc (Pharm), PhD, Pharmaceutical Services, Department of Health and Wellness, 1690 Hollis Street, P.O. Box 488, Halifax, Nova Scotia, Canada B3J 2R8. Ó 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. judith.fisher@gov.ns.ca or judithellenfisher@ gmail.com Accepted for publication: July 11, /$ - see front matter

2 Vol. 46 No. 1 July 2013 Opioid Use in Persons With Colorectal Cancer 21 Introduction Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in Canada and accounts for approximately 11.9% of cancer-related deaths. 1 In the province of Nova Scotia (NS), CRC is the second most prevalent cancer for both men and women, with the reported declines in incidence rates at the national level not yet observed in the NS population; in 2011, the estimated age-standardized incidence rate in NS was 75 per 100,000 male population as compared with the estimated national incidence rate of Given the epidemiology, CRC has been a priority area for health system decision makers in the province, although little empirical evidence exists to understand the issues surrounding access to and quality of care, including access to medications in the community, for people diagnosed with this disease. Despite efforts to improve early detection of the disease and modest reductions in mortality rates over the past 20 years, 1 20%e25% of CRC cases continue to be metastatic (or advanced) at the time of diagnosis. 2e4 Pain is common among persons with advanced cancer, 5e7 with studies finding that 75%e90% of those with advanced cancer report severe pain throughout their illness. 8,9 In CRC, mechanisms of pain include tumor infiltration of nerves, bowel obstruction, treatment-induced neuropathy, and hepatic capsular distention, among others. However, the incidence of pain in metastatic CRC is unknown. Moreover, many persons diagnosed with CRC have comorbid conditions and may die of another disease, some of which can benefit from palliative pain management. 10,11 A recent U.S. Institute of Medicine report highlights the need to improve pain relief and recommends a population-level prevention and management strategy. 12 This report also emphasizes that better data are needed to address the major gaps in our knowledge of pain and pain management practices in society. Although the management of pain is complex given its diverse etiology or mechanisms, there are effective strategies for managing cancer-related pain. Cancer pain management is based on a three-step analgesic ladder approach, established more than two decades ago by the World Health Organization. 13 Opioids are positioned at the second and third steps, with so-called strong opioids (e.g., morphine and hydromorphone) recommended for moderate-to-severe pain. 13e16 Thus, prescription of opioid analgesics is a key component of pain and symptom management. Despite the reported high prevalence of pain in advanced cancer patients and a systematic approach for the effective management of pain, cancer pain is often undertreated in this population. 9,17e19 However, we have a limited understanding of the demographic, clinical, and health service factors that influence pain management, specifically opioid use, in persons with cancer at the end of life. The objectives of this study were to use a population-based method to assess the use of opioid analgesics within the community among older persons with CRC in the six months before death and determine factors associated with the use of opioid analgesics in this population. Gaining a better understanding of opioid use in this population will help to address barriers to pain management in the community and promote safe and appropriate cancer pain management. In particular, this information will help to identify targeted areas for improving cancer pain management and potential issues, such as subpopulations at increased risk for undertreatment. Methods Study Population Data for this study were derived from an ongoing retrospective study of all persons who were diagnosed with CRC between January 1, 2001 and December 31, 2005 in NS, Canada. For the larger study, personnel from the Nova Scotia Cancer Registry identified all CRC cases diagnosed in NS in the time period and undertook a comprehensive chart review to stage this cohort using the Collaborative Stage Data Collection System. 20 Histologic classification was determined by the International Classification of Diseases for Oncology, Third Edition, codes: 21 C18 (excluding C18.1), C19, and C20. Cases diagnosed in individuals younger than 20 years and those diagnosed based on death certificate or autopsy only were

3 22 Fisher et al. Vol. 46 No. 1 July 2013 excluded. If patients had more than one CRC diagnosis in the time period, only one case per patient was retained. This population-based cohort (n ¼ 3510) was anonymously linked at the patient level to 14 administrative health databases via a unique study identifier. Of these patients, linkage was possible for all. The databases included the Medical Service Insurance Physician Services database (physicians billing data), Canadian Institute for Health Information Discharge Abstract Database (hospital discharge abstracts), Nova Scotia Seniors Pharmacare Program (NSSPP), palliative care program (PCP) databases, and Canadian census data. The linkage provided a comprehensive longitudinal data set to examine health service utilization across the continuum of care. Further details related to this larger study, including descriptions of the various linked databases and a detailed explanation of the data linkage process, are reported elsewhere. 22 Ethical approval was obtained from the Capital District Health Authority s Research Ethics Board. For this study, we examined all persons in the larger cohort who 1) were 66 years and older at the date of diagnosis; 2) died between January 1, 2001 and April 1, 2008; and 3) were residents of two health districts in NS with formal PCPs during the study period (n ¼ 657). The study was restricted to persons 66 years of age and older and who had died by April 2008 to ensure that we had at least six months of drug data before death for all persons in the cohort. This study was restricted to persons who resided in health districts with PCPs because we wished to include enrollment in a PCP as a covariate in the analysis. These two health districts provide health services to approximately 540,000 individuals (57% of the provincial population). Measures Prescriptions that were filled at a community pharmacy were captured from the NSSPP database. The NSSPP provides public-funded prescription drug coverage for 85% of NS residents aged 65 years and older 23 and includes medications prescribed for persons in the community and long-term care facilities (not medications administered in hospitals). We included all prescriptions filled for oral and nonoral forms of opioid analgesics and opioid analgesic compounds, under the NSSPP, in the six months before the date of death. Medications were classified according to the World Health Organization Anatomical Therapeutic Chemical Classification system, Canadian version. 24 For analyses, medications were categorized into strong opioids (morphine, hydromorphone, oxycodone, and fentanyl), codeine/meperidine, and opioid compounds (acetylsalicylic acid/opioid combinations and acetaminophen/opioid combinations). There were no prescriptions for meperidine or codeine (as single entity) identified in the data. All strong opioids and all opioid compounds, with the exception of the nonprescription combination of opioid analgesic codeine 8 mg with acetaminophen or acetylsalicylic acid (e.g., Tylenol No. 1Ô), are benefits under the NSSPP. The dependent measure was filling at least one prescription for a strong opioid analgesic in the community in the six months before death. The independent measures for this study were sex, age (at death as continuous variable, in years), location of residence (urban/rural, using the metropolitan influence zone classification 25 ), comorbidity count (0/1/2þ, using the Elixhauser 26 list of comorbidities), presence of specific comorbid conditions (yes/ no, for cardiovascular disease, diabetes, and chronic pulmonary disease), material and social deprivation indices, 27 CRC site (colon/ rectal), Stage IV at diagnosis (yes/no), CRC diagnosis less than six months before death (yes/no), cause of death (CRC/non-CRC, as identified on the death certificate), residence in a long-term care facility (yes/no), enrollment in a PCP (yes/no), number of days in hospital during the six months before death (continuous variable), and location of death (in hospital/out of hospital). The presence of specific comorbid conditions (cardiovascular disease, diabetes, and chronic pulmonary disease) was included as an independent measure because these conditions may cause physicians to be reluctant to prescribe opioids and thus negatively impact filling an opioid prescription. The PCPs include inpatient units, in-hospital consultation services, outpatient clinics for ambulatory patients, and home consultation services. Enrollment in a PCP is defined by contact or consultation with a member of the interdisciplinary palliative care

4 Vol. 46 No. 1 July 2013 Opioid Use in Persons With Colorectal Cancer 23 team, which may occur in any one of the settings identified previously. The comorbidity count was calculated by computing the sum of all recorded comorbid conditions, 26 excluding cancer, in the two years before the date of diagnosis and 30 days after diagnosis (score range 0e28 days). Comorbid conditions were retrieved as diagnoses codes from hospital discharge abstracts; these codes include all diagnoses recorded as the cause(s) of the hospital admission and all diagnoses that affected the resource consumption or length of stay of the patient. Computing a comorbidity count in this way may have underestimated the actual number of comorbid conditions but was performed to identify comorbid conditions that would be likely to influence health service utilization and clinical outcomes. To determine social and material deprivation indices, we linked postal codes at diagnosis to 2001 census data using the Postal Code Conversion File Plus. Three indicators of material deprivation (proportion of persons with a high school diploma, employment/population ratio, and average income) and three indicators of social deprivation (proportions of persons living alone; single parent families; and separated, divorced, and widowed persons) were extracted from census data and used to generate social and material deprivation indices using the method described by Pampalon and Raymond. 27 All variables were extracted from, or computed using variables extracted from, the following administrative databases: Nova Scotia Cancer Registry, physicians billings, hospital discharge abstracts, PCP databases, and national census data. Table 1 identifies the specific databases from which the variables were extracted. Statistical Analysis Descriptive statistics (frequencies and relative proportions) were calculated for sociodemographic and clinical characteristics, health service use, and opioid use during the six months before death. Opioid use was defined as filling at least one prescription for a singleentity opioid analgesic or opioid compound during this time period. Univariate regression models, using all the independent variables presented previously, were constructed to examine the factors associated with having filled at least one prescription in the six months Table 1 List of Administrative Health Databases and the Variables Extracted for This Study Databases Variables Nova Scotia Cancer Registry Medical Service Insurance Physician Services Discharge Abstract Database Canadian 2001 census data Nova Scotia Seniors Pharmacare Program Palliative care programs Patient demographics (sex and age at diagnosis) Stage at diagnosis and date of diagnosis Tumor site (colon and rectum) Date and cause of death Residence in a long-term care facility (identified by physician visits in the longterm care facility) Number of days in hospital Comorbid conditions (to compute comorbidity count and identify specific comorbid conditions) Location of death Neighborhood- or communitylevel measures: Socioeconomic variables to compute social and material deprivation indices Location of residence (rural/urban) Filled opioid prescriptions Date of enrollment before death for any opioid, any strong opioid analgesic, and any opioid compound. A series of multivariate logistic regression models were subsequently constructed to examine the factors associated with the prescription of opioids. Covariates were included in the models if they demonstrated a significant association with opioid use in the unadjusted models (P < 0.05) or if there were substantive reasons for inclusion in the models. For example, the variable location of residence (urban and rural) was included in the final model, despite demonstrating a nonsignificant relationship with opioid use in the unadjusted models because differential access to care based on geographic location has been noted in the literature for persons nearing the end of life in NS. 28e30 Variables were entered into the multivariate models in hierarchical blocks, beginning with the sociodemographic variables. The final model included the following independent variables: sex, age, CRC diagnosis less than six months before death, cause of death, residence in a long-term care facility, enrollment in a PCP, number of days in hospital during the six months before death, and

5 24 Fisher et al. Vol. 46 No. 1 July 2013 location of death. Previous models included the comorbidity count, presence of specific comorbid conditions, material and social deprivation indices, and number of emergency department visits. None of these covariates demonstrated a significant relationship with opioid use or changed the effect of the other covariates; therefore, they were not included in the final model. The focus of the multivariate analysis was strong opioids because these opioids are the recommended pain management strategy for moderate-to-severe pain, 13 in particular for advanced cancer-related pain. However, the final multivariate model also was run for any opioid (i.e., including opioid combinations) and no substantive differences were found (data not shown). For all analyses, P < 0.05 was considered statistically significant. Statistical analysis was performed using SAS version 9.1 (SAS Institute, Inc., Cary, NC). Results Table 2 presents the characteristics of the study population. Related to health service use, 55.9% of the cohort was enrolled in a PCP and 62.7% died in hospital. The median number of days spent in hospital in the six months (182 days) before death was 15.0 days; in other words, half of the study subjects spent 8.2% or less of their last six months of life in hospital. More than half of the cohort (59.2%) had at least one comorbid condition, and 65.1% had CRC listed as a cause of their death. Table 3 presents the number and percentage of individuals who filled at least one prescription for strong opioids or opioid compounds in the six months before death. More than one-third of individuals (n ¼ 242, 36.7%) filled at least one prescription for any type of opioid analgesic (i.e., strong opioid or opioid compound). Slightly less than one-third of individuals (n ¼ 204, 31.1%) filled at least one prescription for a strong opioid, with the most common being hydromorphone, and 13.4% (n ¼ 88) for opioid compounds. Table 4 presents the results of the multivariate logistic regression analysis examining the factors associated with the use of any strong opioid during the six months before death. Table 2 Characteristics of the Study Population (n ¼ 657) Characteristic n (%) Male 334 (50.8) Age (years) At diagnosis, mean SD 78.6 (7.3) At death, mean SD 80.5 (7.3) Urban residence, n (%) 589 (89.7) Long-term care resident, n (%) 93 (14.3) Colon cancer diagnosis, n (%) 471 (71.7) Stage IV at diagnosis, n (%) 214 (32.6) Elixhauser comorbidity count, a n (%) (40.8) (23.3) 2þ 236 (35.9) Specific chronic conditions, n (%) Cardiovascular disease 212 (32.3) Diabetes 85 (12.9) Chronic pulmonary disease 70 (10.7) Weeks from diagnosis to death Mean SD 74.5 (7.3) Median 49.0 Death within six weeks, n (%) 107 (16.3) Days in hospital in the six months before death Mean SD 26.6 (33.3) Median 15.0 Enrollment in PCP, n (%) 367 (55.9) CRC identified as a cause of death, n (%) 428 (65.1) Died in hospital, n (%) 212 (62.7) PCP ¼ palliative care program; CRC ¼ colorectal cancer. a Represents the sum of all recorded comorbid conditions, 26 excluding cancer, in-hospital discharge abstract data in the two years before the date of diagnosis and 30 days after diagnosis (score range 0e28 days). Adjusting for all covariates, enrollment in a PCP, residence in a long-term care facility, and a CRC cause of death were all associated with increased odds of filling a prescription for a strong opioid. Individuals who were enrolled in a PCP had three times the odds of filling an out-of-hospital prescription for a strong opioid compared with those who were not referred. Long-term care residents had two times the odds of filling a prescription for a strong opioid in the community during the six months before death compared with nonresidents, and Table 3 Number and Percentage of Patients Who Filled at Least One Prescription for Opioid Analgesics During the Six Months Before Death Opioid Analgesics n (%) Any opioid 242 (36.7) Strong opioids 204 (31.1) Hydromorphone 129 (19.6) Morphine 91 (13.9) Fentanyl 20 (3.0) Oxycodone (not in combination) 13 (2.0) Opioid compounds, for example, 88 (13.4) codeine þ acetaminophen

6 Vol. 46 No. 1 July 2013 Opioid Use in Persons With Colorectal Cancer 25 Table 4 Results of the Multivariate Logistic Regression Examining the Factors Associated With Filling at Least One Out-of-Hospital Prescription for a Strong Opioid Analgesic During the Six Months Before Death Factors Estimate Odds Ratio 95% CI Intercept 1.6 Sex (reference ¼ female) a e0.86 Age (years) b e0.99 Long-term care residence (reference ¼ not a long-term care resident) a e3.89 CRC identified as a cause of death (reference ¼ other cause of death) a e2.68 Enrollment in PCP (reference ¼ no enrollment) c e4.94 Diagnosis less than six months before death (reference ¼ diagnosis more b e0.93 than six months before death) Location of death (reference ¼ out of hospital) c e0.51 Number of days in hospital during the six months before death (days) e1.00 CRC ¼ colorectal cancer; PCP ¼ palliative care program. a P < b P < c P < persons whose cause of death was identified as CRC had nearly two times the odds compared with those whose death was attributed to other causes. Conversely, older age, male sex, receiving the CRC diagnosis less than six months before death, and dying in hospital were all associated with lower odds of filling an out-ofhospital prescription for a strong opioid. Fig. 1 presents the predicted odds of filling a prescription for a strong opioid in a community pharmacy during the six months before death by age, location of death, and enrollment in a PCP. Discussion Opioids are the mainstay of treatment for cancer pain because of their relative safety and Fig. 1. Predicted odds of filling an out-of-hospital prescription for a strong opioid (morphine, hydromorphone, fentanyl, or oxycodone) during the six months before death by age, location of death, and enrollment in a PCP (adjusted for all covariates with covariates other than age, death location, and PCP enrollment held at mean values). PCP ¼ palliative care program. reliability, range of administration routes, and efficacy in managing different types of pain. 31 This study revealed that about one-third of a cohort of persons diagnosed with CRC accessed opioid analgesics within the community during the last six months of life. However, more than 60% of our study population did not fill a prescription for any opioid and more than twothirds did not fill a prescription for strong opioids (recommended for moderate-to-severe pain) in their last six months of life. Overall, these findings may reflect insufficient provider knowledge about pain assessment and treatment 32 or provider 33e36 and/or patient 37 fears about prescribing or using opioids ( opiophobia ). Indeed, a common misconception is that opioid use will hasten death through respiratory depression, 38 although there is little evidence to support this belief when the drugs are appropriately titrated. 11,39,40 Reid et al. 37 found that some cancer patients perceived opioids as a last resort for pain control and thus interpreted their physicians offer of morphine for pain relief as a signal that death was near, rejecting the opioid as a consequence. Persons dying of CRC were more likely to fill a prescription for a strong opioid during our study period. This finding suggests that individuals most in need access these medications. Certainly, some people likely accessed opioids and/or other analgesics on hospital admission; the strong negative relationship between inhospital death and community-acquired opioid prescription is consistent with this interpretation. Without measures of pain severity, however, we cannot determine potential unmet need before a hospital admission nor can we

7 26 Fisher et al. Vol. 46 No. 1 July 2013 determine whether an in-hospital death could have been avoided if the patient had accessed opioids in the community. Adequate pain control and dying in the preferred location are characteristics of quality palliative care 41,42 and of a good death. 43,44 We found that enrollment in a PCP was associated with filling an opioid prescription in the community. Although those with highest need (e.g., severe and uncontrolled pain) may be referred to a PCP, our findings confirm the role of these programs in enabling access to end-of-life care. Enrollment in PCPs may increase a person s likelihood of dying at home, 45 which is often reported as the preferred location of death by persons with cancer. 46,47 Access to strong opioids in long-term care also may enable residents to die in place at the care facility, rather than be transferred to acute hospital settings. The observed negative association with in-hospital death is consistent with the interpretation that accessing opioids in the community facilitates dying in place. Some subpopulations may be at risk for inadequate pain management. In particular, the finding that the odds of filling a prescription for a strong opioid decreased by 3% for each additional year of age suggests that elderly patients may not be receiving needed opioid therapy. There is evidence in the literature of undertreatment of pain in the elderly 48e50 and, specifically, underuse of opioids. 51 Potential barriers to opioid use in elderly populations may include patient underreporting of pain, 11,52 patient apprehension (e.g., fear of addiction, worry over side effects, and fear that increasing dose indicates worsening condition), 48 and/or provider concerns related to age-related changes in physiology and altered pharmacology. 11 Furthermore, prescribers may be concerned about the potential for drug-disease and drug-drug interactions among patients with comorbid conditions. 53 In this study, however, neither a comorbidity count (measuring the level of comorbidity) nor the presence of specific potentially serious conditions (cardiovascular disease, diabetes, and pulmonary disease) was significantly associated with opioid use. This finding suggests that, in this study population, such concerns did not prevent physicians from prescribing opioid analgesics. Certainly, whereas providers must exercise caution regarding dosage and choice of opioid, these concerns should not preclude appropriate opioid use in the elderly. 11,54 Other subpopulations potentially at risk for unmet need include males and those diagnosed with CRC within six months of death. Our finding that males are less likely to fill an opioid prescription near the end of life is consistent with prior literature showing lower rates of medication use among males vs. females. 55,56 This study has several limitations. First, we did not have measures of pain severity and thus did not have an estimate of the need for opioids in our study population. Without these measures or other indications of need, it is difficult to determine the degree of appropriateness of specific opioid use (or nonuse) for persons in this study. Assessing the appropriateness of medications as death approaches is important to improving our understanding of medication use in this population. 57 Second, the NSSPP only covers persons older than 65 years and does not include medications administered in hospital or prescriptions paid through other insurance (e.g., Veterans Affairs Canada and other insurance programs) or out of pocket. Nevertheless, 85% of all NS residents aged 65 years and older are covered by the NSSPP, 23 and all prescribed opioids (with the exception of oral meperidine, which is not indicated for the management of chronic pain) are benefits under this program. Therefore, we are confident that this data set captures most opioid prescriptions filled in the community by the study population. Despite these limitations, this study helps to address the need for population-based pain medication data 12 and demonstrates the potential for using a population-based study design with linked administrative databases to begin to better understand pain management in our communities. In contrast, studies examining only those individuals enrolled in a PCP and studies using interviewbased methods may not adequately describe the needs of the entire population. 58 In conclusion, this study found that about one-third of persons diagnosed with CRC filled a prescription for a strong opioid analgesic, the recommended pain management strategy for moderate-to-severe pain, while living in the community during their last six months of life. The positive relationship between filling a prescription for a strong opioid and enrollment in a PCP demonstrates the role that palliative care services play in end-of-life care within the

8 Vol. 46 No. 1 July 2013 Opioid Use in Persons With Colorectal Cancer 27 community. A substantial proportion of the study population did not fill a prescription for opioids, however, possibly reflecting low need or provider and/or patient factors that impede access to quality pain management at the end of life. Some subpopulations, such as patients of advanced age, may be at increased risk for undermanagement. Disclosures and Acknowledgments Judith Fisher received postdoctoral funding through the Network for End of Life Studies Interdisciplinary Capacity Enhancement, funded by the Canadian Institutes for Health Research through a strategic initiative grant (#HOA ), 2006e2011, the Canadian Health Services Research Foundation, and the Nova Scotia Health Research Foundation. This work was undertaken during her postdoctoral work at Dalhousie University. The study was supported by a Team Grant from the Canadian Institutes for Health Research (grant no. AQC ) and local funding partners (Cancer Care Nova Scotia, Nova Scotia Department of Health, Capital District Health Authority, Dalhousie Medical Research Foundation, and Dalhousie University s Faculty of Medicine). The funding sources had no role in study design or in the collection, analysis, interpretation, or presentation of data. The authors have no potential conflicts of interest to declare with regard to this study. The authors gratefully acknowledge Martha Cox for her assistance with data extraction. References 1. Canadian Cancer Society s Steering Committee. Canadian cancer statistics Toronto: Canadian Cancer Society, Available from cancer.ca/w/media/ccs/canada%20wide/files %20List/English%20files%20heading/PDF%20-% 20Policy%20-%20Canadian%20Cancer%20Statistics %20-%20English/Canadian%20Cancer%20Statistics %202011%20-%20English.ashx. Accessed July 4, Bu J, Urquhart R, Dewar R, Grunfeld E. Factors associated with the late-stage diagnosis of colorectal cancer in Nova Scotia. [poster]. Health Statistics Data Users Conference, Ottawa, September Available from conferences/health-sante2009/poster-affiche2-eng. htm#a1. Accessed September 18, Cancer Care Manitoba. Cancer in Manitoba: 2008 annual statistical report. Winnipeg: Cancer Care Manitoba, Espey DK, Wu XC, Swan J, et al. Annual report to the nation on the status of cancer, , featuring cancer in American Indians and Alaska Natives. Cancer 2007;110:2119e Breivik H, Cherny N, Collett B, et al. Cancerrelated pain: a pan-european survey of prevalence, treatment, and patient attitudes. Ann Oncol 2009; 20:1420e Teunissen SC, Wesker W, Kruitwagen C, et al. Symptom prevalence in patients with incurable cancer: a systematic review. J Pain Symptom Manage 2007;34:94e van den Beuken-van Everdingen MHJ, de Rijke JM, Kessels AG, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007;18:1437e Goudas LC, Bloch R, Gialeli-Goudas M, Lau J, Carr DB. The epidemiology of cancer pain. Cancer Invest 2005;23:182e Larue F, Colleau SM, Brasseur L, Cleeland CS. Multicentre study of cancer pain and its treatment in France. BMJ 1995;310:1034e Murtagh FE, Chai MO, Donohoe P, Edmonds PM, Higginson IJ. The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice. J Pain Palliat Care Pharmacother 2007;21:5e Pergolizzi J, Boger RH, Budd K, et al. Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract 2008;8:287e Committee on Advancing Pain Research, Care, and Education, Institute of Medicine. Relieving pain in America: A blueprint for transforming prevention, care, education, and research. Washington, DC: National Academy Press, World Health Organization. Cancer pain relief: With a guide to opioid availability, 2nd ed. Geneva: World Health Organization, Available from pdf. Accessed January 20, Hanks GW, Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001;84:587e Krakowski I, Theobald S, Balp L, et al. Summary version of the standards, options and recommendations for the use of analgesia for the treatment of nociceptive pain in adults with cancer (update 2002). Br J Cancer 2003;89(Suppl 1):S67eS Scottish Intercollegiate Guidelines Network. Control of pain in adults with cancer: a national

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