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Occurrence of Cancer Pain

Occurrence of Cancer Pain Abstract Occurrence of cancer pain is highly variable and incompletely understood. Surveys are not population-based, are characterized by small heterogeneous samples, and provide sketchy data on etiology of pain, pain syndromes, and clinical or demographic factors. Moreover, the multiple dimensions of pain have not been thoroughly elucidated. Cancer-related pain is caused by the following: 1) direct tumor involvement, 2) diagnostic/therapeutic procedures, and 3) side effects or toxicities of treatment. Individuals may have more than one type of cancer-related pain simultaneously. Occurrence rates range from 14% to 100%, and between 33 and 50% of patients experience pain at some point in the cancer trajectory. Rates are higher (e.g., 70%-100%) in palliative care or pain management settings. Few researchers have focused solely on specific causes of pain in specific patient populations, and only a few included groups at higher risk for pain, such as the elderly or underserved. In general, researchers have not followed pain over time to determine its course, severity, effects on quality of life and functional status, and other related factors. Future researchers should aim to acquire specific information on occurrence of pain in a variety of cancer diagnoses, settings, and groups of people. Longitudinal designs, indepth exploration of dimensions of pain, and delineation of specific issues in groups such as the elderly, children, and vulnerable populations are essential. Addressing these critical areas will improve our understanding of the occurrence and effects of pain and enhance our ability to provide appropriate interventions, thereby increasing patients' quality of life. The experience of pain in people with cancer is highly variable and subjective (1). It consists of several dimensions—physiologic, sensory, affective, cognitive, behavioral, and sociocultural (2)—and is affected by many factors. The multidimensionality of the pain experience poses numerous methodological and clinical challenges for researchers who study the occurrence of pain (defined in this article as incidence or prevalence) in selected cancer patient populations. These challenges also affect other aspects of the occurrence of pain; for example, patterns of pain across the cancer trajectory from diagnosis to survivorship or death and the effect of pain on patient and family. Although numerous researchers have studied the occurrence of cancer pain, their work has been characterized by methodological problems that have ultimately hampered understanding of the pain experience. The most challenging methodological problems are related to research design, sampling, measurement of pain, and other relevant variables. Selected problems are briefly discussed below to illustrate limitations of our current scientific knowledge base and to form a partial basis for recommendations regarding future research. First, most investigators have used cross-sectional designs to examine prevalence of pain in various cancer populations. Common approaches include retrospective chart reviews or prospective questionnaire studies. Retrospective chart reviews, particularly when conducted for broader reasons than just occurrence of pain (3), are limiting because the researchers are reliant on existing records, which may or may not include systematic and complete clinical assessment data. Thus, pain prevalence rates may be relatively accurate, too low, or too high, but certainty about the precision of rates is not possible. In contrast, researchers who conduct prospective studies (4) can control the quality and completeness of pain measurement data; however, they are still limited by obtaining only a “snapshot” of the patient's pain at a particular point in the cancer trajectory. A more optimal research design for avoiding measurement issues and enhancing precision of occurrence rates is a prospective longitudinal approach in which subjects are followed for an extended period through the cancer trajectory. Although such a design can yield the best information about incidence of pain, its use is relatively rare, most likely for reasons of feasibility and expense. As a consequence, the majority of published studies provide prevalence data, but the rates are often imprecise. Second, existing studies are often characterized by small or heterogeneous samples chosen by methods of convenience or study purpose rather than randomly. Even when such samples are census in nature (taking all available patients over a given period) and consecutive (5), conclusions about how well such samples represent the larger population of similar cancer patients are impossible. When samples include patients with a variety of cancer diagnoses (6, 7), knowledge of pain characteristics and effects of pain is necessarily incomplete. Furthermore, studies may have biases introduced by temporal issues such as season and timing, differences in clinical settings, and variability of patient demographic and clinical characteristics (8). For a variety of reasons, these biases are frequently not defined, controlled, or measured. A third methodological challenge is related to the variable dimensions of pain that researchers choose to measure, the instruments they use, and the ability (or lack thereof) of readers to compare data across studies. Some researchers study only the presence and severity of pain, using visual analogue or numerical rating scales (9), whereas others study pain frequency, severity, and interference with functional variables, using broad-based scales such as the Memorial Symptom Assessment Scale (10). Still others use multidimensional instruments such as the McGill Pain Questionnaire or Brief Pain Inventory to describe the dimensions of pain more broadly, including effect on daily function and emotional response (11,12). Finally, many published studies do not provide complete information about etiology of pain, types of pain syndromes, and potentially relevant clinical (e.g., phase of treatment or survivorship) or demographic (e.g., age, gender, ethnicity, or culture) factors. Although many published reports provide information on patients' diagnoses, and sometimes on their stage of disease, it is less common to report treatment status, types of cancer pain and specific pain syndromes (see below), or other relevant factors, and indeed some samples consist of very mixed groups (13,14). Furthermore, when the cause or type of pain (tumor involvement, diagnostic or therapeutic procedures, or side effect of treatment) is not reported, comparisons across studies are difficult to make, and conclusions about occurrence of specific types of pain cannot be easily made, leaving gaps in our knowledge. Despite these many methodological limitations to studying the occurrence of cancer pain, there is a substantial body of knowledge that informs our understanding of cancer-related pain. The purpose of this article is to examine what is known about the occurrence of cancer pain, with a focus on etiology and mechanisms, effects across the lifespan, and relationship to culture. At the conclusion of the article, recommendations are made for future research based on the methodological issues described earlier and on the current state of our knowledge. Etiology and Mechanisms One issue that makes studying the occurrence of cancer pain challenging is the many ways in which it can be categorized (see Table 1) (15). Each of these has merit, depending on the specific situation, rationale, and individuals involved. For instance, severity of pain is extremely useful in clinical management, because clinicians can assess pain in relation to interventions, using it as a marker of the degree to which the interventions are successful. Similarly, categorizing pain by the underlying pathophysiological mechanism is useful, because it can aid in the development of mechanism-specific pain-relieving interventions. Among many experts, cancer-related pain is generally acknowledged to consist of three major etiologic categories (Table 2): pain caused by direct tumor involvement, pain that results from diagnostic or therapeutic procedures, and pain that is caused by side effects or toxicities of cancer treatment (16,17). These categories can be further subdivided into syndromes or subtypes, each of which has specific characteristics with respect to manifestations, temporal nature, and defining qualities. Because it is common for a single individual to have more than one type of cancer-related pain at the same time, and for pain to wax and wane throughout the course of cancer (15), gathering accurate information about occurrence of pain is exceedingly complex. Perhaps in part because of this complexity, it does not appear to be the norm for researchers to report data on the specific categories, syndromes, and subtypes of cancer pain in their samples. Nevertheless, existing data do provide some insight into the occurrence of pain. Overall occurrence rates range from approximately 14% to 100%, and because of the methodological issues discussed above, it is nearly impossible to disentangle specific incidence and prevalence rates from this broad range. Between one-third and one-half of people with cancer will experience pain at some point in their cancer trajectory (18). Careful analysis of existing studies reveals numerous patterns of occurrence, depending on the patient population, study methodology, instruments used to assess pain, and other factors. The majority of incidence or prevalence studies have focused on people with types of cancer most commonly associated with pain, for instance, breast, lung, and prostate cancers, or on those with solid tumors in general. To date, most researchers have focused on the three major etiologies described above. These studies are briefly reviewed in the sections that follow. It is important to note, however, that many of the studies described below were affected by some of the aforementioned methodological problems; thus, their results should be interpreted accordingly. These problems help explain, in part, why the data include widely variable occurrence rates, mixed heterogeneous samples, disparate pain-related variables (e.g., frequency, severity, location, quality, and effect), and inconclusive interpretations regarding pain in specific cancer diagnoses or other subsets of patients. Direct Tumor Involvement Pain caused by direct tumor involvement generally takes one of three forms, or types, of pain (somatic, visceral, and neuropathic; see Table 2). The mechanisms causing somatic, visceral, and neuropathic pain are tumor invasion, distension of a hollow viscus (such as the bowel), edema, tissue inflammation, and necrosis. Some experts call these mechanisms “syndromes” and have described them well over the years (15–17). When cancer pain from any of these three types of pain becomes particularly severe, it is usually because the tumor mass has invaded pain-sensitive anatomic structures. Most researchers who have studied the occurrence of pain reported a variety of cancers in their samples, with little attempt to delineate incidence or prevalence according to the specific type of cancer. Furthermore, although many investigators have not specifically reported whether pain was caused by direct tumor involvement, it can probably be safely assumed that this was the case in the majority of studies. Sample sizes in published occurrence studies have ranged from 63 to 2266 (3–13,19–33). In addition, two extremely large surveys—one of 13 625 cancer patients in U.S. nursing homes (34) and one of 35 683 patients in Japanese hospitals (35)—have also been conducted. Most study samples, however, range from 150 to 300 patients. Settings are variable and include inpatient wards, outpatient clinics or offices, and specialty services such as palliative care or pain management. Occurrence rates are highly variable, but no researchers have reported a rate of less than 14% (13), and a few have reported a rate of 100% (19). Most researchers typically report a range of rates; for example, 43%-80% (24), 38%-60% (14), 54%-92% (28), or 63%-90% (26). In some cases the range is very wide (e.g., 14%-64%, 52%-100%) (13,21), whereas in others it is narrow (30%-39%) (33), depending on patient population, types of pain, and other factors. Interpretation of these data is somewhat difficult because of the tremendous variation in sites and types of cancer, settings, design, instrumentation, and the fact that some patients had cancer pain of more than one etiology. The variability in findings very clearly illustrates the effect of the methodological problems discussed above. Moreover, in reporting on the occurrence of pain, researchers generally report prevalence rates, only rarely report incidence rates, and on occasion report something such as the proportion of patients requiring opioid therapy who are therefore presumed to have pain, causing readers to assume they are addressing prevalence. This variability in reported outcome measures obviously makes it nearly impossible to compare occurrence rates across studies. Two general findings, however, are relatively clear. First, occurrence rates appear to be somewhat higher (e.g., 70%-100%) in settings that focus on palliative care or pain management (8,22), which reflects the progressive disease experienced by patients in those settings. Second, certain cancers, specifically lung, prostate, and breast, are more commonly associated with pain because of their natural history and pattern of growth and metastasis. Diagnostic and Therapeutic Procedures Few researchers have conducted studies that focused solely on pain caused by diagnostic or therapeutic procedures, generally preferring to report statistics on both tumor and diagnostic/treatment pain. Most published information consists of clinical descriptions and the occasional anecdotal report. Authors do not always distinguish between acute pain (generally accepted as being caused by tissue damage, with a definite pattern of onset and a limited duration) and chronic pain (defined as pain without any biological value that persists beyond normal healing time, about 3 months) (1), but both types are relevant in this category. The pain associated with diagnostic procedures results from the typical tests an individual might undergo in a diagnostic work-up for cancer. Examples include invasive examinations (e.g., fine-needle aspiration and radiologic/nuclear medicine studies using contrast medium) and biopsies (e.g., incisional and excisional). The lack of research may reflect health care providers' views that this pain is not significant; however, there is no doubt that it causes distress and anxiety in patients. The pain associated with therapeutic procedures is better described in the literature (16), particularly because some procedures not only cause acute pain immediately after the procedure but can also result in chronic pain (17). For instance, a number of postsurgical pain syndromes have been delineated (e.g., postthoracotomy pain, postmastectomy pain, phantom limb pain). Similarly, there are well-defined postradiation pain syndromes such as myelopathy or osteoradionecrosis. As noted above, there are surprisingly few studies of diagnostic and therapeutic procedural pain, with only a few reported in the past two decades that clearly included this etiology. Sample sizes ranged from 108 to 2266 patients and were mostly adults. Settings included general inpatient, outpatient, and postsurgical care areas. Examples of occurrence rates in individual studies were 7% (9), 17% (33), 20% (11), and 40% (20). In one study (33), only about 20% of the patients had pain related to treatment, whereas 85% had tumor-related pain. A few investigators have reported rates of pain occurrence for specific populations; for example, a 20% rate of postmastectomy pain (11). Although the data are scanty, and the settings and research methods vary widely, it is clear that the range of occurrence of this category of pain is more restricted than pain caused by tumor invasion. Side Effects or Toxicities The third type of pain based on etiology is the pain that occurs as a result of side effects or toxicities of cancer treatment. There are two major categories of pain resulting from treatment. Chemotherapy-related pain includes well-known examples such as acute oral pain secondary to mucositis and peripheral neuropathy. Radiation therapy-related pain includes examples such as myelopathy, brachial or lumbar plexopathy, and discomfort from skin “burns.” With some notable exceptions, few researchers have devoted themselves to obtaining occurrence data on these types of pain. Only a few studies have been identified in the last 15 years or so that clearly included occurrence of pain caused by side effects or toxicities of treatment. Sample sizes ranged from 47 to 2266 patients and were made up of mostly adults. Types of pain included acute oral pain from mucositis, general cancer treatment-related pain, and breakthrough pain. Settings were inpatient and outpatient care areas and included newly diagnosed cancer patients. Reported occurrence rates ranged from 17% on a pain service (33) to 40% in a pediatric population (20) to 100% in patients receiving transplant or experiencing breakthrough pain (19,36). One of the most notable examples is the acute oral pain that is caused by mucositis, a treatment side effect, which is perhaps the most well-known and common cause of pain in selected groups of cancer patients. Miser et al. (20) noted a 40% occurrence rate in children receiving chemotherapy. In some cancer patient populations—for example, adults receiving allogeneic stem cell or bone marrow transplant—occurrence rates can be as high as 100% (36). Pain Across the Life Span The occurrence of cancer pain across the lifespan has received scanty attention from researchers. The majority of the studies above focused on adults, although some included subsets of patients who were elderly (i.e., ≥65 years of age). Two general age groups are important to consider—children and the elderly. Children Children's experience of pain is different from adults. They have a different profile of cancers; specifically, more leukemias and lymphomas than solid tumors. As a result, they have less tumor-related pain and more pain that is the result of diagnostic or therapeutic procedures and treatment toxicities. There are very few studies in this area. Studies done by Miser and colleagues (20,21) at the National Institutes of Health in the 1980s remain classic and definitive, although other studies have added to our knowledge of pain in children with cancer (37). There have been only a very small number of studies in the last 15 years or so, with samples ranging from 77 to 92 patients in both inpatient and outpatient areas. Children have pain that can be classified in the same three categories, described above, as the pain of adults, direct tumor involvement, therapeutic procedures, and side effects or toxicities of treatment (20,21,37). Pain caused by tumor occurs in 25%–46% of patients, often as a result of leukemic infiltration of bones or joints. Procedural pain from lumbar puncture, venipuncture, and bone marrow aspiration occurs in approximately 40% of children. Last, pain caused by treatment toxicities (e.g., mucositis, infection) occurs in 40%–50% of children. The occurrence rate of tumor-related pain is clearly lower than that seen in adults, and very importantly, the rates for procedural and treatment-related pain are significantly higher than for adults. These differences have ramifications for how pain may be anticipated and managed by clinicians in the pediatric cancer setting. Elderly Despite the fact that cancer is primarily a disease of older people, the elderly have been neglected when it comes to studies of the occurrence of cancer pain. A few investigators have reported data on intensity of pain in elder subsets of their studies (7); however, there are very few studies focusing specifically on occurrence of cancer pain in elders, perhaps only four in the past 8 years. Two studies are particularly notable: Bernabei et al. (34) studied 13 625 cancer patients in the nursing home setting, showing an occurrence rate ranging from 25% to 50%. Hiraga et al. (35) investigated the occurrence of pain in 840 elderly patients who were newly diagnosed with cancer. At diagnosis, the occurrence rate was 48%, and later in the cancer trajectory it was 25%. Aside from these scanty data, however, little is known about etiology, syndromes, or stage of cancer as they relate to the occurrence, and even to the overall experience, of pain in elders. However, evidence indicates that pain in elders may be less well managed than pain in younger groups (38). The relationship between comorbid conditions and occurrence of pain is similarly understudied. In one study, there appeared to be a link between comorbid conditions and incidence of pain (39). Other researchers have noted relationships between composite symptom scores (including pain) and comorbid conditions (40,41), but they have not examined any direct relationship between such conditions and occurrence of pain. Recent work indicates that pain and fatigue might be mediating variables in the relationship between medical conditions and physical, role, and social functioning in elders with medical conditions such as arthritis, hypertension, and congestive heart failure (42). Pain in the Context of Culture Another very important area in understanding the occurrence of pain is the relationship between pain and culture, including the patient's cultural group. Published studies focusing on cultural issues and pain have several important characteristics. For instance, although the majority of studies have been conducted in the United States, several large international studies have examined rates of pain, yielding essentially similar results to those in U.S. studies. Countries in which these studies were performed included England, Finland, France, Germany, Ireland, Japan, South Africa, Switzerland, and Taiwan (6,12,23,24,27,29,30,35). As with literature discussed earlier, however, these studies had heterogeneous samples and methods, making direct comparisons very difficult. Another equally important area is the experience of pain in underrepresented and underserved groups of patients. There are hints that these groups are receiving suboptimal pain management; for instance, Cleeland et al. (38) and Anderson et al. (43) have demonstrated that cancer patients who are from minority groups, are elderly, or are female may not receive, but need, thorough and accurate assessment of pain and other symptoms. Lack of adequate assessment can obscure or confound information on the occurrence of pain in these subpopulations of cancer patients. At this point, little is known about how pain varies across gender, ethnic, racial, or cultural groups. Summary and Directions for Future Research Only a few investigators have included minority groups or others at particular risk of pain, such as the elderly or women, in their studies of pain occurrence, let alone focused exclusively on them. Other researchers have focused on patients with specific types of pain, such as transitory or breakthrough pain. Some investigators have carefully followed pain over time to determine its course, severity, effect on quality of life and functional status, and other related factors (22). Despite these efforts, the state of the science remains in its infancy, and the sum of knowledge is still small. Pain occurs relatively frequently in people with cancer, although it is highly variable and dependent on many factors, described above. It is probably safe to say that approximately one-third to one-half or more of people with cancer experience pain at some point in the cancer trajectory. Tumor-related pain is more often associated with certain kinds of cancer, specifically those solid tumors in adults that metastasize to bone and other pain-sensitive structures. Most of the existing research on occurrence of pain has addressed the intensity of pain, with some modicum of attention paid to its effect on quality of life across physical, emotional, functional, and social domains. Only occasionally have researchers attempted to correlate occurrence of pain with other symptoms, although the notion of symptom constellations or clusters (see other articles in this issue) is rapidly gaining attention. And although a few investigators have begun to address pain among groups of cancer survivors, for example, postmastectomy breast cancer patients (11), almost none have systematically investigated the occurrence of pain in either short- or long-term cancer survivors. Little is known about many aspects of the occurrence of cancer pain. For instance, what happens to pain over time, and how does it manifest itself in relation to type, stage, and extent of disease? What are the details of procedural or treatment-related pain, and how do they change over time? How do people experience pain from a multidimensional perspective—physiological, sensory, emotional, cognitive, behavioral, and sociocultural—in relation to its occurrence? What is the occurrence of pain in children, the elderly, and a wide variety of underserved/underrepresented individuals? What is the occurrence of pain in cancer survivors and what factors contribute to the experience? Recommendations for future research address at least four major areas of inquiry (Table 3). First, more precise estimates of incidence and prevalence of cancer pain by etiology, mechanism of action, or other clinically meaningful classification systems are needed. Second, occurrence data need to be longitudinal rather than cross-sectional to better understand, assess, and treat patients as they progress through the cancer trajectory. Third, the experience of pain needs to be more clearly elucidated, going beyond the usual approach of intensity or severity to correlate occurrence with effects across all dimensions of pain. Finally, information on occurrence of cancer pain in specific groups of individuals (certain cancer diagnoses, the young, the elderly, the underserved, and survivors) is desperately needed to better understand the scope and effect of pain and to develop successful ways of managing it. Future investigators can enhance the state of the science by working to acquire specific information on the occurrence of pain in a variety of cancer diagnoses, settings, and groups of people. These studies will serve to increase our understanding of the scope and nature of the occurrence of pain. It has been difficult in the past to determine the precise characteristics of cancer-related pain in the literature because of aggregate reporting; lack of specific information broken down by type of cancer, stage, type of cancer pain; and other factors such as the methodological challenges discussed above. There are multiple pathways to increasing our knowledge about the occurrence of cancer pain. When investigators design studies, they need to keep several things in mind. First, the objectives of the research should be clear in terms of what type or types of pain are being studied, in what types of patients, and how the data will be used. Second, the design, size, and nature of the sample and analysis must match the study's objectives. Third, instruments should be valid and reliable, providing useful and relevant data that can be compared with results of other studies. Findings need to be clinically meaningful and useful, and the accrued knowledge must be acquired with the goal of ultimately improving outcomes for people with cancer pain. Investigators who make a conscious effort to conduct rigorous and relevant research will improve our understanding of the occurrence of cancer pain and enhance our ability to fashion appropriate and clinically salient interventions, thereby increasing patients' quality of life. Table 1. Etiology, classification systems, and syndromes of pain Etiology: tumor, procedures, toxicities Pathophysiology/mechanism: nociceptive (somatic and visceral) neuropathic, idiopathic Patient type and stage of disease Chronicity: acute or chronic symptoms Pattern: constant, breakthrough, incident, intermittent Severity: intensity Syndrome: osseous, neural, muscle, abdominal, other  Etiology: tumor, procedures, toxicities Pathophysiology/mechanism: nociceptive (somatic and visceral) neuropathic, idiopathic Patient type and stage of disease Chronicity: acute or chronic symptoms Pattern: constant, breakthrough, incident, intermittent Severity: intensity Syndrome: osseous, neural, muscle, abdominal, other  View Large Table 2. Major categories of cancer pain based on etiology* Direct tumor involvement: Types and examples  • Somatic-activation of nociceptors in cutaneous and deep tissues      Bone metastases; osseous invasion  • Visceral-injury to sympathetically innervated organs      Intestinal obstruction; inflammation  • Neuropathic-aberrant somatosensory processes caused by injury to nervous system      Spinal cord compression; brachial plexopathy  Therapeutic procedures: Types and examples  • Invasive examinations      Fine needle aspiration      Radiologic or nuclear medicine tests with contrast      Venipuncture, lumbar puncture, spinal tap  • Biopsies-incisional and excisional      Bone and bone marrow      Lymph node, skin      Breast  Side effects or toxicities: Types and examples  • Chemotherapy-related      Acute oral pain due to mucositis      Peripheral neuropathy      Post-herpetic neuralgia      Pseudo-rheumatism  • Radiation-related      Myelopathy      Brachial plexopathy      Lumbar plexopathy      Skin “burns”  Direct tumor involvement: Types and examples  • Somatic-activation of nociceptors in cutaneous and deep tissues      Bone metastases; osseous invasion  • Visceral-injury to sympathetically innervated organs      Intestinal obstruction; inflammation  • Neuropathic-aberrant somatosensory processes caused by injury to nervous system      Spinal cord compression; brachial plexopathy  Therapeutic procedures: Types and examples  • Invasive examinations      Fine needle aspiration      Radiologic or nuclear medicine tests with contrast      Venipuncture, lumbar puncture, spinal tap  • Biopsies-incisional and excisional      Bone and bone marrow      Lymph node, skin      Breast  Side effects or toxicities: Types and examples  • Chemotherapy-related      Acute oral pain due to mucositis      Peripheral neuropathy      Post-herpetic neuralgia      Pseudo-rheumatism  • Radiation-related      Myelopathy      Brachial plexopathy      Lumbar plexopathy      Skin “burns”  * Many patients have more than one category. View Large Table 3. Directions for future research More precise estimates of incidence and prevalence by etiology or other classification More cancer site-specific longitudinal data across diagnostic, treatment, post-treatment, and survivorship phases Clearer characterization of the pain experience (impact on dimensions, and outcomes) over the cancer trajectory More information on pain in different groups such as children, elderly, minorities, and others  More precise estimates of incidence and prevalence by etiology or other classification More cancer site-specific longitudinal data across diagnostic, treatment, post-treatment, and survivorship phases Clearer characterization of the pain experience (impact on dimensions, and outcomes) over the cancer trajectory More information on pain in different groups such as children, elderly, minorities, and others  View Large References 1 International Association for the Study of Pain. Subcommittee on Taxonomy. Classification of chronic pain. 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Occurrence of Cancer Pain

McGuire, Deborah B.
JNCI Monographs , Volume 2004 (32) – Jul 1, 2004
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Oxford University Press
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© Oxford University Press
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1052-6773
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1745-6614
DOI
10.1093/jncimonographs/lgh015
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15263041
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Abstract

Abstract Occurrence of cancer pain is highly variable and incompletely understood. Surveys are not population-based, are characterized by small heterogeneous samples, and provide sketchy data on etiology of pain, pain syndromes, and clinical or demographic factors. Moreover, the multiple dimensions of pain have not been thoroughly elucidated. Cancer-related pain is caused by the following: 1) direct tumor involvement, 2) diagnostic/therapeutic procedures, and 3) side effects or toxicities of treatment. Individuals may have more than one type of cancer-related pain simultaneously. Occurrence rates range from 14% to 100%, and between 33 and 50% of patients experience pain at some point in the cancer trajectory. Rates are higher (e.g., 70%-100%) in palliative care or pain management settings. Few researchers have focused solely on specific causes of pain in specific patient populations, and only a few included groups at higher risk for pain, such as the elderly or underserved. In general, researchers have not followed pain over time to determine its course, severity, effects on quality of life and functional status, and other related factors. Future researchers should aim to acquire specific information on occurrence of pain in a variety of cancer diagnoses, settings, and groups of people. Longitudinal designs, indepth exploration of dimensions of pain, and delineation of specific issues in groups such as the elderly, children, and vulnerable populations are essential. Addressing these critical areas will improve our understanding of the occurrence and effects of pain and enhance our ability to provide appropriate interventions, thereby increasing patients' quality of life. The experience of pain in people with cancer is highly variable and subjective (1). It consists of several dimensions—physiologic, sensory, affective, cognitive, behavioral, and sociocultural (2)—and is affected by many factors. The multidimensionality of the pain experience poses numerous methodological and clinical challenges for researchers who study the occurrence of pain (defined in this article as incidence or prevalence) in selected cancer patient populations. These challenges also affect other aspects of the occurrence of pain; for example, patterns of pain across the cancer trajectory from diagnosis to survivorship or death and the effect of pain on patient and family. Although numerous researchers have studied the occurrence of cancer pain, their work has been characterized by methodological problems that have ultimately hampered understanding of the pain experience. The most challenging methodological problems are related to research design, sampling, measurement of pain, and other relevant variables. Selected problems are briefly discussed below to illustrate limitations of our current scientific knowledge base and to form a partial basis for recommendations regarding future research. First, most investigators have used cross-sectional designs to examine prevalence of pain in various cancer populations. Common approaches include retrospective chart reviews or prospective questionnaire studies. Retrospective chart reviews, particularly when conducted for broader reasons than just occurrence of pain (3), are limiting because the researchers are reliant on existing records, which may or may not include systematic and complete clinical assessment data. Thus, pain prevalence rates may be relatively accurate, too low, or too high, but certainty about the precision of rates is not possible. In contrast, researchers who conduct prospective studies (4) can control the quality and completeness of pain measurement data; however, they are still limited by obtaining only a “snapshot” of the patient's pain at a particular point in the cancer trajectory. A more optimal research design for avoiding measurement issues and enhancing precision of occurrence rates is a prospective longitudinal approach in which subjects are followed for an extended period through the cancer trajectory. Although such a design can yield the best information about incidence of pain, its use is relatively rare, most likely for reasons of feasibility and expense. As a consequence, the majority of published studies provide prevalence data, but the rates are often imprecise. Second, existing studies are often characterized by small or heterogeneous samples chosen by methods of convenience or study purpose rather than randomly. Even when such samples are census in nature (taking all available patients over a given period) and consecutive (5), conclusions about how well such samples represent the larger population of similar cancer patients are impossible. When samples include patients with a variety of cancer diagnoses (6, 7), knowledge of pain characteristics and effects of pain is necessarily incomplete. Furthermore, studies may have biases introduced by temporal issues such as season and timing, differences in clinical settings, and variability of patient demographic and clinical characteristics (8). For a variety of reasons, these biases are frequently not defined, controlled, or measured. A third methodological challenge is related to the variable dimensions of pain that researchers choose to measure, the instruments they use, and the ability (or lack thereof) of readers to compare data across studies. Some researchers study only the presence and severity of pain, using visual analogue or numerical rating scales (9), whereas others study pain frequency, severity, and interference with functional variables, using broad-based scales such as the Memorial Symptom Assessment Scale (10). Still others use multidimensional instruments such as the McGill Pain Questionnaire or Brief Pain Inventory to describe the dimensions of pain more broadly, including effect on daily function and emotional response (11,12). Finally, many published studies do not provide complete information about etiology of pain, types of pain syndromes, and potentially relevant clinical (e.g., phase of treatment or survivorship) or demographic (e.g., age, gender, ethnicity, or culture) factors. Although many published reports provide information on patients' diagnoses, and sometimes on their stage of disease, it is less common to report treatment status, types of cancer pain and specific pain syndromes (see below), or other relevant factors, and indeed some samples consist of very mixed groups (13,14). Furthermore, when the cause or type of pain (tumor involvement, diagnostic or therapeutic procedures, or side effect of treatment) is not reported, comparisons across studies are difficult to make, and conclusions about occurrence of specific types of pain cannot be easily made, leaving gaps in our knowledge. Despite these many methodological limitations to studying the occurrence of cancer pain, there is a substantial body of knowledge that informs our understanding of cancer-related pain. The purpose of this article is to examine what is known about the occurrence of cancer pain, with a focus on etiology and mechanisms, effects across the lifespan, and relationship to culture. At the conclusion of the article, recommendations are made for future research based on the methodological issues described earlier and on the current state of our knowledge. Etiology and Mechanisms One issue that makes studying the occurrence of cancer pain challenging is the many ways in which it can be categorized (see Table 1) (15). Each of these has merit, depending on the specific situation, rationale, and individuals involved. For instance, severity of pain is extremely useful in clinical management, because clinicians can assess pain in relation to interventions, using it as a marker of the degree to which the interventions are successful. Similarly, categorizing pain by the underlying pathophysiological mechanism is useful, because it can aid in the development of mechanism-specific pain-relieving interventions. Among many experts, cancer-related pain is generally acknowledged to consist of three major etiologic categories (Table 2): pain caused by direct tumor involvement, pain that results from diagnostic or therapeutic procedures, and pain that is caused by side effects or toxicities of cancer treatment (16,17). These categories can be further subdivided into syndromes or subtypes, each of which has specific characteristics with respect to manifestations, temporal nature, and defining qualities. Because it is common for a single individual to have more than one type of cancer-related pain at the same time, and for pain to wax and wane throughout the course of cancer (15), gathering accurate information about occurrence of pain is exceedingly complex. Perhaps in part because of this complexity, it does not appear to be the norm for researchers to report data on the specific categories, syndromes, and subtypes of cancer pain in their samples. Nevertheless, existing data do provide some insight into the occurrence of pain. Overall occurrence rates range from approximately 14% to 100%, and because of the methodological issues discussed above, it is nearly impossible to disentangle specific incidence and prevalence rates from this broad range. Between one-third and one-half of people with cancer will experience pain at some point in their cancer trajectory (18). Careful analysis of existing studies reveals numerous patterns of occurrence, depending on the patient population, study methodology, instruments used to assess pain, and other factors. The majority of incidence or prevalence studies have focused on people with types of cancer most commonly associated with pain, for instance, breast, lung, and prostate cancers, or on those with solid tumors in general. To date, most researchers have focused on the three major etiologies described above. These studies are briefly reviewed in the sections that follow. It is important to note, however, that many of the studies described below were affected by some of the aforementioned methodological problems; thus, their results should be interpreted accordingly. These problems help explain, in part, why the data include widely variable occurrence rates, mixed heterogeneous samples, disparate pain-related variables (e.g., frequency, severity, location, quality, and effect), and inconclusive interpretations regarding pain in specific cancer diagnoses or other subsets of patients. Direct Tumor Involvement Pain caused by direct tumor involvement generally takes one of three forms, or types, of pain (somatic, visceral, and neuropathic; see Table 2). The mechanisms causing somatic, visceral, and neuropathic pain are tumor invasion, distension of a hollow viscus (such as the bowel), edema, tissue inflammation, and necrosis. Some experts call these mechanisms “syndromes” and have described them well over the years (15–17). When cancer pain from any of these three types of pain becomes particularly severe, it is usually because the tumor mass has invaded pain-sensitive anatomic structures. Most researchers who have studied the occurrence of pain reported a variety of cancers in their samples, with little attempt to delineate incidence or prevalence according to the specific type of cancer. Furthermore, although many investigators have not specifically reported whether pain was caused by direct tumor involvement, it can probably be safely assumed that this was the case in the majority of studies. Sample sizes in published occurrence studies have ranged from 63 to 2266 (3–13,19–33). In addition, two extremely large surveys—one of 13 625 cancer patients in U.S. nursing homes (34) and one of 35 683 patients in Japanese hospitals (35)—have also been conducted. Most study samples, however, range from 150 to 300 patients. Settings are variable and include inpatient wards, outpatient clinics or offices, and specialty services such as palliative care or pain management. Occurrence rates are highly variable, but no researchers have reported a rate of less than 14% (13), and a few have reported a rate of 100% (19). Most researchers typically report a range of rates; for example, 43%-80% (24), 38%-60% (14), 54%-92% (28), or 63%-90% (26). In some cases the range is very wide (e.g., 14%-64%, 52%-100%) (13,21), whereas in others it is narrow (30%-39%) (33), depending on patient population, types of pain, and other factors. Interpretation of these data is somewhat difficult because of the tremendous variation in sites and types of cancer, settings, design, instrumentation, and the fact that some patients had cancer pain of more than one etiology. The variability in findings very clearly illustrates the effect of the methodological problems discussed above. Moreover, in reporting on the occurrence of pain, researchers generally report prevalence rates, only rarely report incidence rates, and on occasion report something such as the proportion of patients requiring opioid therapy who are therefore presumed to have pain, causing readers to assume they are addressing prevalence. This variability in reported outcome measures obviously makes it nearly impossible to compare occurrence rates across studies. Two general findings, however, are relatively clear. First, occurrence rates appear to be somewhat higher (e.g., 70%-100%) in settings that focus on palliative care or pain management (8,22), which reflects the progressive disease experienced by patients in those settings. Second, certain cancers, specifically lung, prostate, and breast, are more commonly associated with pain because of their natural history and pattern of growth and metastasis. Diagnostic and Therapeutic Procedures Few researchers have conducted studies that focused solely on pain caused by diagnostic or therapeutic procedures, generally preferring to report statistics on both tumor and diagnostic/treatment pain. Most published information consists of clinical descriptions and the occasional anecdotal report. Authors do not always distinguish between acute pain (generally accepted as being caused by tissue damage, with a definite pattern of onset and a limited duration) and chronic pain (defined as pain without any biological value that persists beyond normal healing time, about 3 months) (1), but both types are relevant in this category. The pain associated with diagnostic procedures results from the typical tests an individual might undergo in a diagnostic work-up for cancer. Examples include invasive examinations (e.g., fine-needle aspiration and radiologic/nuclear medicine studies using contrast medium) and biopsies (e.g., incisional and excisional). The lack of research may reflect health care providers' views that this pain is not significant; however, there is no doubt that it causes distress and anxiety in patients. The pain associated with therapeutic procedures is better described in the literature (16), particularly because some procedures not only cause acute pain immediately after the procedure but can also result in chronic pain (17). For instance, a number of postsurgical pain syndromes have been delineated (e.g., postthoracotomy pain, postmastectomy pain, phantom limb pain). Similarly, there are well-defined postradiation pain syndromes such as myelopathy or osteoradionecrosis. As noted above, there are surprisingly few studies of diagnostic and therapeutic procedural pain, with only a few reported in the past two decades that clearly included this etiology. Sample sizes ranged from 108 to 2266 patients and were mostly adults. Settings included general inpatient, outpatient, and postsurgical care areas. Examples of occurrence rates in individual studies were 7% (9), 17% (33), 20% (11), and 40% (20). In one study (33), only about 20% of the patients had pain related to treatment, whereas 85% had tumor-related pain. A few investigators have reported rates of pain occurrence for specific populations; for example, a 20% rate of postmastectomy pain (11). Although the data are scanty, and the settings and research methods vary widely, it is clear that the range of occurrence of this category of pain is more restricted than pain caused by tumor invasion. Side Effects or Toxicities The third type of pain based on etiology is the pain that occurs as a result of side effects or toxicities of cancer treatment. There are two major categories of pain resulting from treatment. Chemotherapy-related pain includes well-known examples such as acute oral pain secondary to mucositis and peripheral neuropathy. Radiation therapy-related pain includes examples such as myelopathy, brachial or lumbar plexopathy, and discomfort from skin “burns.” With some notable exceptions, few researchers have devoted themselves to obtaining occurrence data on these types of pain. Only a few studies have been identified in the last 15 years or so that clearly included occurrence of pain caused by side effects or toxicities of treatment. Sample sizes ranged from 47 to 2266 patients and were made up of mostly adults. Types of pain included acute oral pain from mucositis, general cancer treatment-related pain, and breakthrough pain. Settings were inpatient and outpatient care areas and included newly diagnosed cancer patients. Reported occurrence rates ranged from 17% on a pain service (33) to 40% in a pediatric population (20) to 100% in patients receiving transplant or experiencing breakthrough pain (19,36). One of the most notable examples is the acute oral pain that is caused by mucositis, a treatment side effect, which is perhaps the most well-known and common cause of pain in selected groups of cancer patients. Miser et al. (20) noted a 40% occurrence rate in children receiving chemotherapy. In some cancer patient populations—for example, adults receiving allogeneic stem cell or bone marrow transplant—occurrence rates can be as high as 100% (36). Pain Across the Life Span The occurrence of cancer pain across the lifespan has received scanty attention from researchers. The majority of the studies above focused on adults, although some included subsets of patients who were elderly (i.e., ≥65 years of age). Two general age groups are important to consider—children and the elderly. Children Children's experience of pain is different from adults. They have a different profile of cancers; specifically, more leukemias and lymphomas than solid tumors. As a result, they have less tumor-related pain and more pain that is the result of diagnostic or therapeutic procedures and treatment toxicities. There are very few studies in this area. Studies done by Miser and colleagues (20,21) at the National Institutes of Health in the 1980s remain classic and definitive, although other studies have added to our knowledge of pain in children with cancer (37). There have been only a very small number of studies in the last 15 years or so, with samples ranging from 77 to 92 patients in both inpatient and outpatient areas. Children have pain that can be classified in the same three categories, described above, as the pain of adults, direct tumor involvement, therapeutic procedures, and side effects or toxicities of treatment (20,21,37). Pain caused by tumor occurs in 25%–46% of patients, often as a result of leukemic infiltration of bones or joints. Procedural pain from lumbar puncture, venipuncture, and bone marrow aspiration occurs in approximately 40% of children. Last, pain caused by treatment toxicities (e.g., mucositis, infection) occurs in 40%–50% of children. The occurrence rate of tumor-related pain is clearly lower than that seen in adults, and very importantly, the rates for procedural and treatment-related pain are significantly higher than for adults. These differences have ramifications for how pain may be anticipated and managed by clinicians in the pediatric cancer setting. Elderly Despite the fact that cancer is primarily a disease of older people, the elderly have been neglected when it comes to studies of the occurrence of cancer pain. A few investigators have reported data on intensity of pain in elder subsets of their studies (7); however, there are very few studies focusing specifically on occurrence of cancer pain in elders, perhaps only four in the past 8 years. Two studies are particularly notable: Bernabei et al. (34) studied 13 625 cancer patients in the nursing home setting, showing an occurrence rate ranging from 25% to 50%. Hiraga et al. (35) investigated the occurrence of pain in 840 elderly patients who were newly diagnosed with cancer. At diagnosis, the occurrence rate was 48%, and later in the cancer trajectory it was 25%. Aside from these scanty data, however, little is known about etiology, syndromes, or stage of cancer as they relate to the occurrence, and even to the overall experience, of pain in elders. However, evidence indicates that pain in elders may be less well managed than pain in younger groups (38). The relationship between comorbid conditions and occurrence of pain is similarly understudied. In one study, there appeared to be a link between comorbid conditions and incidence of pain (39). Other researchers have noted relationships between composite symptom scores (including pain) and comorbid conditions (40,41), but they have not examined any direct relationship between such conditions and occurrence of pain. Recent work indicates that pain and fatigue might be mediating variables in the relationship between medical conditions and physical, role, and social functioning in elders with medical conditions such as arthritis, hypertension, and congestive heart failure (42). Pain in the Context of Culture Another very important area in understanding the occurrence of pain is the relationship between pain and culture, including the patient's cultural group. Published studies focusing on cultural issues and pain have several important characteristics. For instance, although the majority of studies have been conducted in the United States, several large international studies have examined rates of pain, yielding essentially similar results to those in U.S. studies. Countries in which these studies were performed included England, Finland, France, Germany, Ireland, Japan, South Africa, Switzerland, and Taiwan (6,12,23,24,27,29,30,35). As with literature discussed earlier, however, these studies had heterogeneous samples and methods, making direct comparisons very difficult. Another equally important area is the experience of pain in underrepresented and underserved groups of patients. There are hints that these groups are receiving suboptimal pain management; for instance, Cleeland et al. (38) and Anderson et al. (43) have demonstrated that cancer patients who are from minority groups, are elderly, or are female may not receive, but need, thorough and accurate assessment of pain and other symptoms. Lack of adequate assessment can obscure or confound information on the occurrence of pain in these subpopulations of cancer patients. At this point, little is known about how pain varies across gender, ethnic, racial, or cultural groups. Summary and Directions for Future Research Only a few investigators have included minority groups or others at particular risk of pain, such as the elderly or women, in their studies of pain occurrence, let alone focused exclusively on them. Other researchers have focused on patients with specific types of pain, such as transitory or breakthrough pain. Some investigators have carefully followed pain over time to determine its course, severity, effect on quality of life and functional status, and other related factors (22). Despite these efforts, the state of the science remains in its infancy, and the sum of knowledge is still small. Pain occurs relatively frequently in people with cancer, although it is highly variable and dependent on many factors, described above. It is probably safe to say that approximately one-third to one-half or more of people with cancer experience pain at some point in the cancer trajectory. Tumor-related pain is more often associated with certain kinds of cancer, specifically those solid tumors in adults that metastasize to bone and other pain-sensitive structures. Most of the existing research on occurrence of pain has addressed the intensity of pain, with some modicum of attention paid to its effect on quality of life across physical, emotional, functional, and social domains. Only occasionally have researchers attempted to correlate occurrence of pain with other symptoms, although the notion of symptom constellations or clusters (see other articles in this issue) is rapidly gaining attention. And although a few investigators have begun to address pain among groups of cancer survivors, for example, postmastectomy breast cancer patients (11), almost none have systematically investigated the occurrence of pain in either short- or long-term cancer survivors. Little is known about many aspects of the occurrence of cancer pain. For instance, what happens to pain over time, and how does it manifest itself in relation to type, stage, and extent of disease? What are the details of procedural or treatment-related pain, and how do they change over time? How do people experience pain from a multidimensional perspective—physiological, sensory, emotional, cognitive, behavioral, and sociocultural—in relation to its occurrence? What is the occurrence of pain in children, the elderly, and a wide variety of underserved/underrepresented individuals? What is the occurrence of pain in cancer survivors and what factors contribute to the experience? Recommendations for future research address at least four major areas of inquiry (Table 3). First, more precise estimates of incidence and prevalence of cancer pain by etiology, mechanism of action, or other clinically meaningful classification systems are needed. Second, occurrence data need to be longitudinal rather than cross-sectional to better understand, assess, and treat patients as they progress through the cancer trajectory. Third, the experience of pain needs to be more clearly elucidated, going beyond the usual approach of intensity or severity to correlate occurrence with effects across all dimensions of pain. Finally, information on occurrence of cancer pain in specific groups of individuals (certain cancer diagnoses, the young, the elderly, the underserved, and survivors) is desperately needed to better understand the scope and effect of pain and to develop successful ways of managing it. Future investigators can enhance the state of the science by working to acquire specific information on the occurrence of pain in a variety of cancer diagnoses, settings, and groups of people. These studies will serve to increase our understanding of the scope and nature of the occurrence of pain. It has been difficult in the past to determine the precise characteristics of cancer-related pain in the literature because of aggregate reporting; lack of specific information broken down by type of cancer, stage, type of cancer pain; and other factors such as the methodological challenges discussed above. There are multiple pathways to increasing our knowledge about the occurrence of cancer pain. When investigators design studies, they need to keep several things in mind. First, the objectives of the research should be clear in terms of what type or types of pain are being studied, in what types of patients, and how the data will be used. Second, the design, size, and nature of the sample and analysis must match the study's objectives. Third, instruments should be valid and reliable, providing useful and relevant data that can be compared with results of other studies. Findings need to be clinically meaningful and useful, and the accrued knowledge must be acquired with the goal of ultimately improving outcomes for people with cancer pain. Investigators who make a conscious effort to conduct rigorous and relevant research will improve our understanding of the occurrence of cancer pain and enhance our ability to fashion appropriate and clinically salient interventions, thereby increasing patients' quality of life. Table 1. Etiology, classification systems, and syndromes of pain Etiology: tumor, procedures, toxicities Pathophysiology/mechanism: nociceptive (somatic and visceral) neuropathic, idiopathic Patient type and stage of disease Chronicity: acute or chronic symptoms Pattern: constant, breakthrough, incident, intermittent Severity: intensity Syndrome: osseous, neural, muscle, abdominal, other  Etiology: tumor, procedures, toxicities Pathophysiology/mechanism: nociceptive (somatic and visceral) neuropathic, idiopathic Patient type and stage of disease Chronicity: acute or chronic symptoms Pattern: constant, breakthrough, incident, intermittent Severity: intensity Syndrome: osseous, neural, muscle, abdominal, other  View Large Table 2. Major categories of cancer pain based on etiology* Direct tumor involvement: Types and examples  • Somatic-activation of nociceptors in cutaneous and deep tissues      Bone metastases; osseous invasion  • Visceral-injury to sympathetically innervated organs      Intestinal obstruction; inflammation  • Neuropathic-aberrant somatosensory processes caused by injury to nervous system      Spinal cord compression; brachial plexopathy  Therapeutic procedures: Types and examples  • Invasive examinations      Fine needle aspiration      Radiologic or nuclear medicine tests with contrast      Venipuncture, lumbar puncture, spinal tap  • Biopsies-incisional and excisional      Bone and bone marrow      Lymph node, skin      Breast  Side effects or toxicities: Types and examples  • Chemotherapy-related      Acute oral pain due to mucositis      Peripheral neuropathy      Post-herpetic neuralgia      Pseudo-rheumatism  • Radiation-related      Myelopathy      Brachial plexopathy      Lumbar plexopathy      Skin “burns”  Direct tumor involvement: Types and examples  • Somatic-activation of nociceptors in cutaneous and deep tissues      Bone metastases; osseous invasion  • Visceral-injury to sympathetically innervated organs      Intestinal obstruction; inflammation  • Neuropathic-aberrant somatosensory processes caused by injury to nervous system      Spinal cord compression; brachial plexopathy  Therapeutic procedures: Types and examples  • Invasive examinations      Fine needle aspiration      Radiologic or nuclear medicine tests with contrast      Venipuncture, lumbar puncture, spinal tap  • Biopsies-incisional and excisional      Bone and bone marrow      Lymph node, skin      Breast  Side effects or toxicities: Types and examples  • Chemotherapy-related      Acute oral pain due to mucositis      Peripheral neuropathy      Post-herpetic neuralgia      Pseudo-rheumatism  • Radiation-related      Myelopathy      Brachial plexopathy      Lumbar plexopathy      Skin “burns”  * Many patients have more than one category. View Large Table 3. Directions for future research More precise estimates of incidence and prevalence by etiology or other classification More cancer site-specific longitudinal data across diagnostic, treatment, post-treatment, and survivorship phases Clearer characterization of the pain experience (impact on dimensions, and outcomes) over the cancer trajectory More information on pain in different groups such as children, elderly, minorities, and others  More precise estimates of incidence and prevalence by etiology or other classification More cancer site-specific longitudinal data across diagnostic, treatment, post-treatment, and survivorship phases Clearer characterization of the pain experience (impact on dimensions, and outcomes) over the cancer trajectory More information on pain in different groups such as children, elderly, minorities, and others  View Large References 1 International Association for the Study of Pain. Subcommittee on Taxonomy. Classification of chronic pain. 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JNCI Monographs – Oxford University Press

Published: Jul 1, 2004

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