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[Note: This Clinical Practice Guideline is posted online by AHCPR at: AHCPR archives. It has been used as a primary source of basic information about management of pain in end-of-life care. - HPA :or.] Management of Cancer Pain Clinical Guideline Number 9
AHCPR Publication No. 94-0592: March 1994
Link to the National Guideline Clearinghouse [Inside Front Cover]The Agency for Health Care Policy and Research (AHCPR) was established in December 1989 under Public Law 101-239 (Omnibus Budget Reconciliation Act of 1989) to enhance the quality, appropriateness, and effectiveness of health care services and access to these services. AHCPR carries out its mission by conducting and supporting general health services research, including medical effectiveness research, facilitating development of clinical practice guidelines, and disseminating research findings and guidelines to health care providers, policymakers, and the public. The legislation also established within AHCPR the Office of the Forum for Quality and Effectiveness in Health Care (the Forum). The Forum has primary responsibility for facilitating the development, periodic review, and updating of clinical practice guidelines. The guidelines will assist practitioners in the prevention, diagnosis, treatment, and management of clinical conditions. Other components of AHCPR include the following. The Center for Medical Effectiveness Research has principal responsibility for patient outcomes research and studies of variations in clinical practice. The Center for General Health Services Extramural Research supports research on primary care, the cost and financing of health care, and access to care for underserved and rural populations. The Center for General Health Services Intramural Research uses large data sets for policy research on national health care expenditures and utilization, hospital studies, and long-term care. The Center for Research Dissemination and Liaison produces and disseminates findings from AHCPR-supported research, including guidelines, and conducts research on dissemination methods. The Office of Health Technology Assessment responds to requests from Federal health programs for assessment of health care technologies. The Office of Science and Data Development develops specialized data bases for patient outcomes research. Guidelines are available in formats suitable for health care practitioners, the scientific community, educators, and consumers. AHCPR invites comments and suggestions from users for consideration in development and updating of future guidelines. Please send written comments to Director, Office of the Forum, AHCPR, Willco Building, Suite 310, 6000 Executive Boulevard, Rockville, MD 20852. Guideline Development and UseGuidelines are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical conditions. This guideline was developed by a multidisciplinary panel of private-sector clinicians and other experts convened by the Agency for Health Care Policy and Research (AHCPR). The panel employed an explicit, science-based methodology and expert clinical judgment to develop specific statements on patient assessment and management for the clinical condition selected. Extensive literature searches were conducted, and critical reviews and syntheses were used to evaluate empirical evidence and significant outcomes. Peer review and field review were undertaken to evaluate the validity, reliability, and utility of the guideline in clinical practice. The panel's recommendations are primarily based on the published scientific literature. When the scientific literature was incomplete or inconsistent in a particular area, the recommendations reflect the professional judgment of panel members and consultants. In some instances, there was not unanimity of opinion. The guideline reflects the state of knowledge, current at the time of publication, on effective and appropriate care. Given the inevitable changes in the state of scientific information and technology, periodic review, updating, and revision will be done. We believe that the AHCPR-assisted clinical guideline development process will make positive contributions to the quality of care in the United States. We encourage practitioners and patients to use the information provided in this clinical practice guideline. The recommendations may not be appropriate for use in all circumstances. Decisions to adopt any particular recommendation must be made by the practitioner in light of available resources and circumstances presented by individual patients. J. Jarrett Clinton, MD Administrator Agency for Health Care Policy and Research Publication of this guideline does not necessarily represent endorsement by the U.S. Department of Health and Human Services. ForewordCancer is increasingly prevalent in the United States, and the pain associated with it is frequently undertreated. Cancer is diagnosed in over one million Americans annually, and one of five deaths in the United States about 1,400 per day results from cancer. Patients with cancer often have multiple pain problems, but in most patients, the pain can be effectively controlled. Nevertheless, undertreatment is common because of a lack of knowledge by clinicians about effective assessment and management, negative attitudes of patients and clinicians toward the use of drugs for pain relief, and a variety of problems related to drug regulations, and the cost of and reimbursement for effective pain management. This guideline was developed by an interdisciplinary panel of clinicians, patients, researchers, and experts in health policy. The guideline provides a synthesis of scientific research and expert judgment to make recommendations on pain assessment and management. Approximately 470 health care professionals and 70 patients were involved either as consultants and peer reviewers or as participants in pilot testing. The Clinical Practice Guideline for the Management of Cancer Pain was commissioned by the Agency for Health Care Policy and Research (AHCPR). It follows and makes reference to an earlier guideline on acute pain management after surgery or trauma, also commissioned by AHCPR. The cancer pain guideline includes a section on the management of HIV positive/AIDS-related pain because of similarities in the sources of pain and the management approaches. This guideline is designed to help clinicians understand the assessment and treatment of cancer pain and associated symptoms. It reflects a multimodal approach to the management of pain, and it emphasizes the need for careful and continuous assessment to match interventions to the sources of pain in individual patients. AbstractCancer is diagnosed in over one million Americans annually, and one of five deaths in the United States about 1,400 per day result from cancer. Despite recent advances in the understanding of pain and pain management approaches, pain control remains a significant problem for patients with cancer. This guideline is designed to help any clinician who works with any oncology patient in any setting to understand the assessment and treatment of pain and associated symptoms. The guideline was developed by an interdisciplinary panel of clinicians, patients, and experts in health policy. The panel used a combination of scientific evidence and expert judgment to make recommendations about pain management in patients with cancer. The guideline makes recommendations about the assessment and management of pain. Interventions described include the use of (1) analgesics and adjuvant drugs; (2) cognitive/behavior strategies; (3) physical modalities; (4) palliative radiation and antineoplastic therapies; (5) nerve blocks; and (6) palliative and ablative surgery. The cost of cancer pain in suffering, disability, and quality of life is high. The guidelines recommend that cancer pain be treated aggressively by pharmacologic and nonpharmacologic approaches. In most instances, pain can be treated effectively with relatively low-cost, noninvasive therapies. Given this evidence, health system barriers that interfere with effective pain management -- such as restrictive legislation regarding the uses of opioid analgesics and third-party payer practices that do not reimburse for less invasive interventions -- should be changed. This document is in the public domain and may be used and reprinted without special permission, except for those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders. AHCPR appreciates citation as to source, and the suggested format is provided below Jacox A, Carr DB, Payne R, et al. Management of Cancer Pain. Clinical Practice Guideline No. 9. AHCPR Publication No. 94-0592. Rockville, MD. Agency for Health Care Policy and Research, U.S. Department of Health and Human Services, Public Health Service, March 1994. DedicationTheClinical Practice Guideline for the Management of Cancer Pain is dedicated to the memory of Jeanne Stover, a member of the panel that developed the guidelines. Jeanne represented the National Coalition for Cancer Survivorship on the panel. A 23-year survivor of breast cancer, she had metastatic disease during the last 9 years of her life and succumbed to this disease during her tenure as a panel member. She was a founding member of Living Through Cancer, a cancer self-help group in Albuquerque, New Mexico. The panel appreciates the insights and wisdom that Jeanne shared with us. Panel Members
AcknowledgmentsThe Cancer Pain Management Panel expresses profound appreciation to the patients who helped us in the development of the consumer version of the guideline and to our numerous colleagues in many disciplines who made valuable contributions during the development of the guideline. The scientific reviewers critiqued sections or complete drafts of the guideline document, and a variety of individuals pilot tested the guideline. A full listing of those involved in this effort appears in the list of contributors at the end of the document. Special recognition goes to Ehud Arbit, MD, Andrew Brown, MB BS, Stuart DuPen, MD, Nora Janjan, MD, Mathew Lefkowitz, MD, Margo McCaffery, RN, MS, Raphael Pollock, MD, PhD, Karen Syjala, PhD, Anna Williams, RN, MN, and Melissa Wolff, RT, MS all of whom provided original text for the document. We also acknowledge the extraordinary review efforts of Charles Cote MD, June Dahl, PhD, Stuart Grossman, MD, Philipp Lippe, MD, Margo McCaffery, RN, MS, Patricia McGrath, PhD, Richard Patt, MD, Vivian Sheidler, RN, MS, Thomas Smith, MD, and Sridhar Vasudevan, MD. These individuals provided major and repeated reviews of various aspects of the guideline, as well as valuable advice to the panel chairs. We acknowledge the critical approach and tireless, energetic efforts to the many aspects of guideline development of Jane Ballantyne, MB, Elon Eisenberg, MD, Donna Mahrenholz, RN, PhD, and particularly Janice Ulmer, RN, PhD, all of whom served as staff to the panel. Dr. Patricia Stephens provided excellent and timely editing for several drafts of the guideline. Research assistants who provided valuable services in reviewing the literature included Dorothy Herron, RN, MSN, Yeonghee Shin, RN, PhD, and Joyce Willens, RN, MSN. Other valuable services in the preparation of various materials were provided by research assistants Leslie Dunham, Stella Seal, Sabreena Woods, and our secretary, Yvonne Deane-Hibbert, at the Johns Hopkins University. Drs. Frederick Mosteller, Thomas Chalmers, and Catherine Berkey of the Technology Assessment Group, Harvard School of Public Health, gave valuable guidance during literature reviews for meta-analyses. Miss Evelyn Hall, at Massachusetts General Hospital, provided expert secretarial assistance in the development of guideline materials. Drs. Richard Kitz and George Battit of the Massachusetts General Hospital provided ongoing support and encouragement for work at that site. Executive SummaryPain control in people with cancer remains a significant problem in health care even though cancer pain can be managed effectively in up to 90 percent of patients. Recognition of the widespread undertreatment of cancer pain has prompted recent corrective efforts from health care disciplines, professional and consumer organizations, and governments throughout the world. The Clinical Practice Guideline for the Management of Cancer Pain was commissioned by the Agency for Health Care Policy and Research (AHCPR). It follows and makes reference to a 1992 guideline on acute pain management after surgery or trauma, also commissioned by AHCPR. This guideline is designed to help clinicians who work with oncology patients to understand the assessment and treatment of pain and associated symptoms. It also discusses briefly the management of pain in patients with human immunodeficiency virus (HIV) and/or acquired immunodeficiency syndrome (AIDS). The guideline has ten goals:
Not all cancer pain or associated symptoms can be entirely eliminated, but available approaches, when appropriately and attentively applied, effectively relieve pain in most patients. The importance of effective pain management extends beyond analgesia to encompass the patient's quality of life and ability to function in the family and society. Because patients vary greatly in their diagnoses and stage of disease progression, their responses to pain and interventions, and their personal preferences, the guideline offers a flexible approach to the management of cancer pain that clinicians can use in daily practice and adapt, as appropriate, to the treatment of painful noncancerous conditions. The guideline emphasizes:
The guideline includes general strategies for pain management, as well as the management of specific pain syndromes, and it addresses issues related to special populations. It also contains a pain management flowchart, analgesic dosage tables, sample pain assessment tools, examples of nondrug interventions, and information about resources for patients and their families. The first chapter is an overview of the prevalence of cancer and cancer pain. A key recommendation is that clinicians should reassure patients and their families that most pain can be relieved safely and effectively. Barriers to effective cancer pain management identified by the panel include problems related to health care professionals, to patients, and to the health care and drug regulatory system. The panel recommends that curricula for health professionals include sufficient content on pain to prepare clinicians to assess and manage pain effectively. The panel acknowledges that clinicians need to educate patients and their families about pain and its management and to encourage patients to be active participants in their care. Clinicians are encouraged to collaborate with patients and families, taking costs of drugs and technologies into account in selecting pain management strategies. The panel noted the need for Federal, State, and local laws and regulatory policies to be developed so as not to hamper the appropriate use of opioid analgesics for cancer pain. The first chapter presents a flowchart that indicates the need to use multiple modalities concurrently in pain management and emphasizes the need to begin with the least invasive methods capable of controlling the pain, titrating the pain treatment to the patient's needs. The process whereby panelists were selected, the methods used in the development of the guideline, and a summary of the scientific evidence for the interventions are presented. Chapter 2 emphasizes the need for health professionals to ask patients about pain and to accept the patient's self-report as the primary source of assessment. The need for comprehensive assessment and careful documentation is discussed, with attention to initial evaluation and appraisal of any new pain that emerges. A mnemonic for the recommended clinical approach is given. A discussion of the assessment of common cancer pain syndromes includes bone metastases, epidural metastases/spinal cord compression, plexopathies, peripheral neuropathies, acute and postherpetic neuralgia, abdominal pain, and mucositis. The pharmacologic management of pain is presented in Chapter 3. The importance of individualizing the regimen to the patient and of using the simplest dosage schedules and least invasive pain management modalities is emphasized. The World Health Organization's analgesic ladder is discussed, with suggestions about how various drugs should be used alone and in combination. The need to make a distinction between opioid tolerance and physical dependence on the one hand and "addiction" on the other is stressed because the pervasive misconception that these three entities are the same hinders effective pain management. Chapter 3 describes the use of nonsteroidal anti-inflammatory drugs and opioids, and discusses how to titrate drugs to effect for individual patients. Various routes of administration and the management of drug side effects are discussed. The panel noted that respiratory depression is infrequently a significant limiting factor in pain management because, with repeated doses, tolerance develops. This tolerance allows adequate pain treatment without much risk of respiratory compromise. The person dying from cancer should not be allowed to live out life with unrelieved pain because of a fear of side effects; rather, appropriate, aggressive, palliative support should be given. The use of adjuvant drugs to increase the analgesic efficacy of opioids, to treat concurrent symptoms that exacerbate pain, and to provide independent analgesia for specific types of pain is described. Careful discharge planning when a patient moves from one setting to another is emphasized. Chapters 4 and 5 discuss the nonpharmacologic management of pain. Chapter 4 includes recommendations for the use of physical modalities, including the use of superficial heat and cold, massage, exercise, transcutaneous electrical nerve stimulation, and acupuncture, and psychosocial interventions, including relaxation and imagery, distraction and reframing, patient education, psychotherapy and structured support, and hypnosis. For each modality, brief explanations are given regarding the mechanisms of operation and practical ways in which they can be applied in the patient care setting. The importance of referring patients to peer support groups and providing pastoral counseling for those who wish it is also emphasized. Chapter 5 discusses more invasive therapies, including palliative radiation, anesthetic techniques including nerve blocks, neurosurgery, and palliative surgery. The panel recommends that, with rare exception, noninvasive treatment should precede invasive palliative approaches. Chapter 6 describes the management of procedure-related pain. It discusses the use of drugs and other approaches for the relief of pain produced by the multiple invasive procedures that patients undergo as part of their treatment. The discussion thus far in the guideline is largely focused on adult patients. Chapter 7 includes a discussion of a number of special populations for whom clinicians should give special attention and considerations, including the very young and very old, the cognitively impaired, known or suspected substance abusers, and non-English-speaking persons. When developing a pain treatment plan, clinicians should be aware of the unique needs and circumstances of patients from various ethnic and cultural backgrounds. The need for assessment methods appropriate for neonates, children, and adolescents is stressed. Elderly patients should be considered at risk for undertreatment of pain. Uncontrolled pain is an important factor contributing to feelings of hopelessness, suicidal ideation, and requests for clinician-assisted suicide or euthanasia; therefore, it should be aggressively assessed and treated. Because patients with current substance abuse disorders are at risk for undertreatment of cancer pain, their care should be managed by clinicians knowledgeable in both pain management and substance abuse. Because patients with HIV positive/AIDS often have pain problems similar to those of patients with cancer, recommendations for pain assessment and management in this guideline generally should be used for pain in these patients. Chapter 8 discusses the need for monitoring the quality of pain management and for developing formal means within each institution to evaluate pain management practices and to obtain patient feedback to gauge the adequacy of pain control. Institutional policy should define who is responsible for pain management, the acceptable level of patient monitoring, and the appropriate roles and limits of practice for health care providers. The nearly 500 consultants, peer reviewers, and site reviewers who contributed to the development of the guideline are listed. The Attachments contain tables showing the strength of evidence for recommendations, pain assessment instruments, and sample relaxation exercises. Explanation of Strength of EvidenceThis guideline contains recommendations at the beginning of each chapter. Recommendations are followed in parentheses by a rating of the strength of evidence. When the strength of evidence is A or B, the panel's recommendations are based primarily on the evidence. When the strength of recommendation is C or D, the panel used the available empirical evidence but based their recommendations primarily on expert judgment. When the recommendation is a statement of panel opinion regarding desirable practice and there is evidence that the practice is not commonly being followed, the term "panel consensus" is used. A more complete explanation of strength of evidence is contained in Attachment A. 1. OverviewRecommendations1. Clinicians should reassure patients and their families that most pain can be relieved safely and effectively. (A) 2. Clinicians should assess patients and, if pain is present, provide optimal relief throughout the course of illness. (Panel Consensus) 3. Curricula for health professionals should include sufficient content on pain to prepare clinicians to assess and manage pain effectively. (Panel Consensus) 4. Clinicians should include patient and family education about pain and its management in the treatment plan and encourage patients to be active participants in pain management. (A) 5. Federal, State, and local laws and regulatory polices should not hamper the appropriate use of opioid analgesics for cancer pain. (Panel Consensus) 6. Clinicians should collaborate with patients and families, taking costs of drugs and technologies into account in selecting pain management strategies. (Panel Consensus) Scope of the ProblemCancer is diagnosed in over 1 million Americans annually. About 8 million Americans now have cancer or a history of cancer; half of these diagnoses were made within the past 5 years. Cancer causes 1 of every 10 deaths worldwide (Stjernsward and Teoh, 1990) and is increasingly prevalent in the United States, where it causes 1 of 5 deaths--about 1,400 per day (American Cancer Society, 1994). Pain associated with cancer is frequently undertreated in adults (Bonica, 1990) and children ( Miser, Dothage, Wesley, et al., 1987). Patients with cancer often have multiple pain problems (Coyle, Adelhardt, Foley, et al., 1990). Cancer pain may be due to (1) tumor progression and related pathology (e.g., nerve damage), (2) operations and other invasive diagnostic or therapeutic procedures, (3) toxicities of chemotherapy and radiation, (4) infection, or (5) muscle aches when patients limit physical activity (Foley, 1979). The incidence of pain in patients with cancer depends on the type and stage of disease. At the time of diagnosis and at intermediate stages, 30 to 45 percent of patients experience moderate to severe pain (Daut and Cleeland, 1982). On average, nearly 75 percent of patients with advanced cancer have pain. Of cancer patients with pain, 40 to 50 percent report it as moderate to severe, and another 25 to 30 percent describe it as very severe (Bonica, 1990). In approximately 90 percent of patients, cancer pain can be controlled through relatively simple means (Goisis, Gorini, Ratti, et al., 1989; Schug, Zech, and Dorr, 1990; Teoh and Stjernsward, 1992; Ventafridda, Caraceni, and Gamba, 1990), yet a consensus statement from the National Cancer Institute Workshop on Cancer Pain indicated that the "undertreatment of pain and other symptoms of cancer is a serious and neglected public health problem" (National Cancer Institute, 1990). The Workshop concluded that "...every patient with cancer should have the expectation of pain control as an integral aspect of his/her care throughout the course of the disease" (National Cancer Institute, 1990). Because cancer pain control is a problem of international scope, the World Health Organization (WHO) has urged that every nation give high priority to establishing a cancer pain relief policy ( Stjernsward and Teoh, 1990). In the United States, many organizations have worked toward this goal (Ad Hoc Committee on Cancer Pain of the American Society of Clinical Oncology, 1992; American Pain Society, 1986; Health and Public Policy Committee, American College of Physicians, 1983; McGivney and Crooks, 1984; Spross, McGuire, and Schmitt, 1990 a, b,c; Weissman, Burchman, Dinndorf, et al., 1988). Importance of Controlling Cancer PainPain control merits high priority for two reasons. First, unrelieved pain causes unnecessary suffering. Because pain diminishes activity, appetite, and sleep, it can further weaken already debilitated patients. The psychological effect of cancer pain can be devastating. Patients with cancer often lose hope when pain emerges, believing that pain heralds the inexorable progress of a feared, destructive, and fatal disease. Chronic unrelieved pain can lead patients to reject active treatment programs, and when their pain is severe or they are depressed, to consider or commit suicide. Besides mitigating suffering, pain control is important because, even when the underlying disease process is stable, uncontrolled pain prevents patients from working productively, enjoying recreation, or taking pleasure in their usual role in the family and society (Moinpour and Chapman, 1991). Pain control therefore merits a high priority not only for those with advanced disease, but also for the patient whose condition is stable and whose life expectancy is long. Suffering, Loss of Control, and Quality of LifeA Patient's Perspective:
Cancer pain may resolve with the patient's cure or continue indefinitely as a complication of otherwise curative therapy. Although cancer pain is often thought of as a crisis that emerges in advanced stages of disease, it may occur for many reasons and cause suffering, loss of control, and impaired quality of life throughout the patient's course of care, even for the patient whose condition is stable and whose life expectancy is long. Suffering denotes an extended sense of threat to self-image and life, a perceived lack of options for coping with symptoms or problems caused by cancer, a sense of personal loss, and a lack of a basis for hope. "Suffering can include physical pain but is by no means limited to it.... Most generally, suffering can be defined as the state of severe distress associated with events that threaten the intactness of the person.... The suffering of patients with terminal cancer can often be relieved by demonstrating that their pain truly can be controlled" (Cassel, 1982). Pain can exacerbate individual suffering by worsening helplessness, anxiety, and depression. Shock and disbelief, followed by symptoms of anxiety and depression (irritability and disruption of appetite and sleep, inability to concentrate or carry out usual activities) are common when people first learn they have cancer or discover that treatment has failed or disease has recurred (Massie and Holland, 1990). These symptoms usually resolve within a few weeks with support from family and caregivers, although medication to promote sleep and reduce anxiety may be necessary in crisis periods. "The relief of suffering and the cure of disease must be seen as twin obligations of a medical profession that is truly dedicated to the care of the sick" (Cassel, 1982).
Personal control refers to an individual's ability to shape immediate and long-range circumstances through one's own actions (Wallston, Wallston, Smith, et al., 1987), including:
Personal control is undermined when cancer is diagnosed and is further reduced by ongoing pain, invasive or undignified procedures, treatment toxicities, hospitalization, and surgery. When pain reduces patients' options to exercise control, it diminishes psychological well-being and makes them feel helpless and vulnerable. Therefore, clinicians should support active patient involvement in effective and practical methods to manage pain. The quality of life of cancer patients with pain is significantly worse than that of cancer patients without pain ( Ferrell, Rhiner, Cohen, et al., 1991). Table 1 depicts the effect of pain in four quality-of-life domains physical, psychological, spiritual, and social. Family and loved ones of cancer patients share the suffering, loss of control, and impaired quality of life and also experience psychological and social stresses. Family caregivers need sleep and respite from the burdens of caregiving and may have socioeconomic needs and fears related to the costs of providing care. Even in the absence of psychological, emotional, and physical stressors, the family may feel unprepared to deal with the patient's many needs. They often have to assess pain, make decisions about the amount and type of medication, and determine when the dose of medication is to be given. Sophisticated pain management strategies may require them to manage complex medication regimens involving parenteral or epidural infusions in the home. Some family caregivers may hesitate to give adequate doses of pain medicines out of fear that the patient will become addicted or tolerant or develop respiratory depression (Ferrell, Cohen, Rhiner, et al., 1991).Clinicians should reassure patients and families that most pain can be relieved safely and effectively. Family caregivers may feel unprepared to deal with a patient's need for pain relief or may deny that the patient is in pain to avoid facing the possibility that the disease is progressing. These situations require ongoing discussions among patients, family caregivers, and experienced health care providers about pain management goals. Overview of Pain and Pain Management ModalitiesThe anatomy, physiology, and pharmacology of pain and analgesia have been studied extensively. A major advance has been the finding that neural pathways that arise in the brain stem descend to the spinal cord and modulate activity in spinal nociceptive pathways (Fields and Basbaum, 1978). These descending pathways, as well as related pain pathways within and above the spinal cord, respond to opioids and other analgesic drugs as well as physiologic and experimental stimuli, including stress (Mayer and Liebeskind, 1974), to produce analgesia. It has been speculated that the activation of this descending control system by the action of endogenous opioids such as b-endorphin and enkephalins may account for the phenomenon of placebo analgesia and the apparent analgesic effect of acupuncture in some clinical circumstances. Pain may be defined as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (International Association for the Study of Pain, Subcommittee on Taxonomy, 1979). Although the mechanisms of pain and pain pathways are becoming better understood, it should be emphasized that an individual's perception of pain and appreciation of its meaning are complex phenomena that involve psychological and emotional processes in addition to activation of nociceptive pathways (McGrath, 1990a). Pain intensity is not proportional to the type or extent of tissue damage but may be influenced at many sites within the nervous system. The perception of pain depends on the complex interactions between nociceptive and non-nociceptive impulses in ascending pathways, in relation to the activation of descending pain-inhibitory systems. This framework provides the basis for a comprehensive, multimodal approach to the assessment and treatment of patients with pain and fits with the clinical observation that there is no single approach to effective pain management. Instead, individualized pain management should take into account the stage of disease, concurrent medical conditions, characteristics of pain, and psychological and cultural characteristics of the patient. It also requires ongoing reassessment of the pain and treatment effectiveness. Figure 1 is a flowchart depicting cancer pain management from the initial assessment of pain and its cause to the various treatment modalities, including the WHO analgesic ladder and numerous other drug and non-drug modalities (World Health Organization, 1990). The best choice of modality often changes as the patient's condition and the characteristics of the pain change. It is important that the effectiveness of analgesic modalities used separately or in combination be carefully assessed. The flowchart indicates the complexity of both the sources of pain and the types of modalities available for managing it. This guideline elaborates on the modalities, making recommendations about their appropriate use.Whenever pain is present, clinicians should provide optimal pain relief by routinely assessing pain and treating it with one or more of the modalities described here. The WHO ladder (Figure 2) portrays a progression in the doses and types of analgesic drugs for effective pain management. When this noninvasive approach is ineffective, alternative modalities include other routes of drug administration, nerve blocks, and ablative neurosurgery (Figure 3). As Figure 3 indicates, patients receiving treatments of varying degrees of invasiveness may also benefit from other modalities; the number of patients receiving these modalities either separately or in combination has not been well documented. The estimates presented in Figure 3 reflect various clinical populations and may not represent all settings and populations; furthermore, they do not necessarily reflect what is optimal, but only a range of current opinions. There is a need for research to determine the effectiveness of many of these modalities used alone or in combination for different patient populations in various settings. Barriers To Effective Pain ManagementPain management is often needlessly suboptimal (Table 2). Health care professionals are seldom trained in pain management, may not realize the importance of pain management or recognize that a patient is in pain, and may fear prescribing opioid medications. Like some clinicians, patients and families may shun the use of opioids and, because of their fears of addiction and worries about tolerance, may not complain about pain or about poor pain relief. Therefore, the panel recommends that clinicians include patient and family education about pain and its management in the treatment plan. Another barrier is that pain management has not traditionally been a priority of the health care system. Pain treatment may not be reimbursed or readily accessible, and institutions may be more concerned about a patient's possible opioid addiction or the diversion of controlled substances than about optimizing pain relief. Clinicians should reassure patients who are reluctant to report pain and who fear addiction and unmanageable side effects that there are many ways to relieve pain safely and effectively. Talking with clinicians knowledgeable about pain management and reading the consumer versions of this guideline (Jacox, Carr, Payne, et al., in press) should help patients and their families to overcome fears and concerns that hinder effective pain relief. Problems related to the health care system and suggestions for resolving these are addressed extensively elsewhere ( Angarola and Wray, 1989; Cain and Hammes, in press; Cleeland, Cleeland, Dar et al., 1986; Cleeland, 1987; Ferrell and Griffith, in press; Hammes and Cain, in press; Hill, 1993; Joranson, in press; Kolassa, in press; Shapiro, in press, a, Shapiro, in press, b). Two of the problems restrictive regulation of controlled substances and reimbursement policies are discussed briefly here. Legal Regulation of OpioidsThe Federal government attempts to ensure the availability of opioid analgesics for legitimate medical and scientific purposes while controlling the abuse and illegal diversion of such substances (Shapiro, in press, a). The Controlled Substances Act (CSA) is one of the principal Federal laws that affects the use and availability of controlled substances, including opioid analgesics. The CSA provides for the registration of all handlers of controlled substances, as well as for the labeling, order forms, recordkeeping, and reporting of substances or their use. These activities enable enforcement agencies to identify manufacturers, distributors, clinicians, and pharmacists who divert controlled substances for illicit uses. The CSA also includes provisions that explicitly aim to avoid interference with the availability of U.S. Food and Drug Administration (FDA)-approved drugs for legitimate purposes. The CSA does not restrict a clinician's medical decision about which drug to prescribe, in what amounts, or for what duration, although it does prohibit physicians from prescribing opioids to maintain narcotic addiction unless the physician is separately registered to treat addiction. "Addict" is defined in the CSA as one who habitually uses an opioid drug so as to endanger public health or safety or one who has lost control over opioid use ( Controlled Substances Act, 21 U.S.C., sec. 802). This definition rarely applies to a patient being treated with opioids for cancer pain (Kanner and Foley, 1981). Furthermore, Federal controlled substances regulations clarify that the Federal law is not intended to impose limitations on a physician's ability to prescribe opioid analgesics to persons with intractable pain in situations where no relief or cure is possible or none has been found after reasonable efforts (21 CFR 1306.07(c)). State laws vary greatly, and many restrict or regulate the prescribing of opioids in the treatment of pain in ways that Federal law does not. For example, many State drug diversion laws contain ill-defined terms that in effect restrict opioid prescribing (Joranson, 1990). Other State laws also regulate pain treatment by restricting medication prescriptions to a specific number of dosage units or to a 1-month supply, or by monitoring the prescription of controlled substances through multiple-copy prescription programs. WHO has observed that although multiple-copy prescription programs are intended to reduce careless prescribing, "Health care workers may be reluctant to prescribe, stock or dispense opioids as they feel that there is a possibility of their professional licenses being suspended or revoked by the governing authority in cases where large quantities of opioids are provided to an individual, even though the medical need for such drugs can be proved" (World Health Organization, 1990). In States with formal cancer pain initiatives, health professionals have worked with State agencies to identify and remove legal impediments to the use of controlled substances for cancer pain (Dahl, Joranson, Engber, et al., 1988). A 1990 revision of the Uniform Controlled Substances Act addresses the legitimate use of controlled substances by recognizing that the prescribing, administering, and dispensing of opioid analgesics for intractable pain is part of professional medical treatment. It states that if terms such as addict, habitual user, and drug-dependent person are used in States' statutes, definitions of these terms should clearly indicate that they do not apply to patients receiving controlled substances pursuant to a practitioner's order (Uniform Controlled Substances Act, 1990). Each State legislature has received the revision from the Uniform Law Commissioners. The panel recommends that laws and regulatory policies aimed at diversion control not hamper the appropriate use of opioid analgesics for cancer pain. Clinicians are responsible for knowing how controlled substances are regulated in their States. Such information can be obtained from State medical, nursing, and pharmacy licensing boards (see Angarola, 1990; Joranson, 1990; Shapiro, in press, a, for additional information on the regulation of analgesic drugs). Cost and Reimbursement for Pain ManagementDetermining the overall cost of pain management is difficult because it generally is not separated from other treatment costs, but rather is included as part of the patient's stay in the hospital or an outpatient visit. Components of pain management costs and a comparison of analgesic drug costs are discussed by Ferrell and Griffith (in press) and Kolassa (in press). Access to professional services, prescription drugs, and medical equipment is usually necessary for effective pain care (Joranson, in press). Reimbursement or lack of it influences the way in which pain is treated, where it is treated, and the supportive care that is available (Yasco and Verfurth, 1992). Reimbursement policies of third-party payers for pain management differ substantially, and many people with cancer are uninsured or underinsured. According to one report ( American Cancer Society, 1989), low-income people experience greater pain and suffering from cancer than do other Americans, and a disproportionate share of people with little or no insurance are minorities. For those who are insured, reimbursement policies may favor the use of more expensive pain management modalities over less expensive ones. Medicare, for example, does not reimburse for outpatient oral analgesics but will reimburse for pain management in an inpatient facility. Thus, "a person may well have reimbursement for the $4,000.00 cost of patient controlled analgesia (PCA) morphine but will have no coverage for $100.00 of oral morphine solution" ( Ferrell and Griffith, in press). Joranson (in press) has reported on the variation in the policies of private payers and health maintenance organizations, in which policies are often unclear about or offer minimal coverage for pain management. Reimbursement policies on pain management should be studied to enable further understanding of those that promote the most cost effective pain management. Clinicians should consider a patient's ability to pay for treatment. The costs of medication and other treatments may overburden a patient with limited financial resources and result in compromises between adherence to the prescribed regimen and other financial responsibilities (Brand, Smith, and Grand, 1977). Costs of analgesic drugs, for example, including many that are equally effective for pain management, vary dramatically (Kolassa, in press). For example, an analysis of the costs of NSAIDs included in the drug tables of this guideline showed that the retail price of NSAIDs (excluding acetaminophen and aspirin) in 1992 ranged from $10.50 to $127.80 for a 30-day supply (Kolassa, in press). Although the primary concern of the clinician is to manage pain effectively, the ability to do this may be influenced by the patient's economic status. Therefore, clinicians should collaborate with patients and families, taking cost of drugs and technologies into account when selecting pain management strategies. Methods Used To Develop the GuidelineThis guideline was developed by an interdisciplinary, expert panel, commissioned by AHCPR, that comprises practitioners in nursing, medicine, pharmacy, psychology, and physical therapy; health care consumers; and an ethicist. The panel used four processes to develop the guidelines. First, it undertook an extensive and interdisciplinary clinical review of current needs, therapeutic practices and principles, and emerging technologies for cancer pain control. This process included a review of all pertinent guidelines and standards, the solicitation of information and opinions from external consultants, and an open forum (announced in the Federal Register and held in Washington, DC, on September 5, 1991) to receive the broadest possible input from concerned parties. Second, the panel performed a comprehensive scientific review of the field to define the existing knowledge base and evaluate critically the assumptions and common wisdom in the field. Although the primary focus of the review was on cancer pain, the panel also reviewed the pain literature on HIV positive/AIDS. When there were few studies available that tested the use of interventions with various populations of cancer patients, studies conducted on other clinical populations were used as supplementary scientific evidence. The panel examined studies on patients of all ages. It performed a best-evidence synthesis of the scientific evidence, including a meta-analysis when sufficient numbers of experimental studies were found in the literature. Nineteen data bases were searched, and approximately 9,600 citations were screened. Six hundred twenty-five research studies were critiqued for scientific merit, and 550 were included in tables of evidence for the various interventions. Attachment A gives ratings of strength of the scientific evidence for interventions, along with the types and ratings for evidence of the specific interventions included in the guidelines. Briefly, the strength and consistency of evidence for recommendations describes the evidence and notes whether it is generally consistent or inconsistent. Strength of evidence ranges from A (strongest) to D (little or no systematic empirical evidence). When the strength of evidence is A or B, the panel's recommendations are based primarily on the evidence. When the strength of recommendation is C or D, the panel used the available empirical evidence but based their recommendations primarily on expert judgment. When the recommendation is a statement of panel opinion regarding desirable practice and there is evidence that the practice is not commonly being followed, the term "panel consensus" is used. Third, guideline drafts were developed by members of the panel, consultants, and panel staff. In all, 17 drafts were written. Fourth, the panel initiated peer review of two drafts of the guideline and field tested a draft with intended users in clinical sites. Comments were reviewed and incorporated into the final guideline. The patient brochure was developed by panel members and field tested with 69 patients and six clinicians. Four hundred sixty-eight consultants, peer reviewers, and site testers reviewed and contributed to the development of the guideline. The entire process was anchored by the panel, which met six times over a period of 2 years. Organization of GuidelineUsers of this guideline can easily refer to sections of immediate interest. It begins with a discussion of pain assessment and then presents methods of pain control. These methods appear in separate sections dealing with the pharmacologic management of pain, the use of psychosocial and physical modalities, and the use of anesthetic and surgical interventions and radiation therapy. One chapter discusses procedure-related pain in adults and children. Another addresses pain in special populations, including infants and children, the elderly, known or suspected substance abusers, minorities, HIV positive/AIDS patients, and people with psychiatric problems. The final section discusses institutional responsibility for effective pain management. Attachment A contains tables of scientific evidence for the interventions. Attachment B contains pain assessment instruments for adults and children. Attachment C includes sample relaxation exercises. A glossary, as well as lists of consultants, peer reviewers, and site testers of the guideline are also provided. To derive maximal benefit, clinicians should read the entire guideline. 2. Assessment of Pain in the Patient With CancerRecommendations7. Health professionals should ask about pain, and the patient's self-report should be the primary source of assessment. (B) 8. Clinicians should assess pain with easily administered rating scales and should document the efficacy of pain relief at regular intervals after starting or changing treatment. Documentation forms should be readily accessible to all clinicians involved in the patient's care. (Panel Consensus) 9. Clinicians should teach patients and their families to use assessment tools in their homes in order to promote continuity of effective pain management across all settings. (Panel Consensus) 10. The initial evaluation of pain should include:
11. Clinicians should be aware of common pain syndromes: this prompt recognition may hasten therapy and minimize the morbidity of unrelieved pain. (B) 12. Changes in pain patterns or the development of new pain should trigger a diagnostic evaluation and modification of the treatment plan. (Panel Consensus) Assessment of pain in the cancer patient is imperative for all health care professionals because failure to assess pain can lead to its undertreatment. The critical role of the assessment of cancer pain was highlighted in a 1993 study of 897 oncologists who, collectively in the previous 6 months, had managed more than 70,000 cancer patients. According to these physicians, poor pain assessment was the greatest barrier to effective cancer pain management in their own practices (Von Roenn, Cleeland, Gonin, et al., 1993). Because of the multiple possible causes of pain, careful evaluation of pain is required. Initial Pain AssessmentThe initial assessment should occur with each new report of pain and should focus on identifying the cause of the pain and developing a pain management plan. Subsequent assessments should evaluate the effectiveness of the plan and, if pain is unrelieved, determine whether the cause is related to the progression of disease, a new cause of pain, or the cancer treatment. The initial evaluation of pain should include:
Attention to detail is important: a delayed or incorrect diagnosis, particularly with a syndrome such as spinal cord compression, can result in increased morbidity, needless pain and suffering, or both. The initial assessment should provide a detailed description of each type of pain (Table 3). Health professionals should ask about pain, and the patient's self-report should be the primary source of assessment. The self-report should include a description of the pain; its location, intensity/severity, and aggravating and relieving factors; and the patient's cognitive response to pain. Neither behavior nor vital signs should be used in lieu of a self-report (Beyer, McGrath, and Berde, 1990). It is best to use brief, easy-to-use assessment tools that reliably document pain intensity and pain relief and to relate these to other dimensions of pain such as mood. (Examples of both brief and comprehensive pain inventories are included in Attachment B.) One routine clinical approach to pain assessment and management is summarized by the mnemonic "ABCDE":
In the initial assessment, document the onset and temporal pattern of the pain. Ask patients to point to the exact location of the pain on themselves or the clinician (The Brief Pain Inventory and the Initial Pain Assessment Tool in Attachment B). Determine whether the pain radiates or spreads to other parts of the body. Ask patients to describe their pain: the descriptive words they use can provide valuable clues as to the cause. For example, patients who describe back pain that radiates like a tight band around their chest and worsens with coughing or defecation should be evaluated for potential spinal cord compression, a complication of vertebral body metastasis. Patients who describe their pain as "burning" or "tingling" are likely to have a neuropathic cause of pain particularly when it is associated with subjective numbness, loss of sensation, and weakness (Elliott and Foley, 1989). Three commonly used self-report assessment tools ( Figure 4) are:
If the patient understands the scale and is capable of answering and if end points and adjective descriptors are carefully selected, each of these instruments can be valid and reliable (Gracely and Wolskee, 1983; Houde, 1982; Sriwatanakul, Kelvie, and Lasagna, 1982). An assessment of pain intensity should include an evaluation of not only the present pain intensity but also pain at its least and worst. Knowing factors that aggravate or relieve pain helps clinicians to design a pain treatment plan. The initial pain assessment should elicit information about changes in activities of daily living, including work and recreational activities, sleep patterns, mobility, appetite, sexual functioning, and mood. A psychosocial assessment should emphasize the effect of pain on patients and their families, as well as patients' preferences among pain management methods. Patients who are able to answer should be asked about the effectiveness of past and present pain treatments, such as antineoplastic therapy or specific pharmacologic and nonpharmacologic therapies. The clinician should perform a physical and neurologic examination related to the pain report (see below, Assessment of Common Cancer Pain Syndromes). The painful area should be carefully examined to determine if palpation or manipulation of the site exacerbates the pain. Common sites of pain referral should be evaluated (e.g., shoulder pain may emanate from subdiaphragmatic abdominal sources; knee and hip pain may be referred from lumbar spine lesions). In addition, the patient should be observed for cues that indicate pain, e.g., distorted posture, impaired mobility, guarding the painful area, restricted movement of a limb, anxiety, attention seeking, or depression. However, absence of these behaviors should not be interpreted to mean that the patient has no pain. Neurologic examination should be focused. For example, pain in the head and neck region requires careful cranial nerve examination to exclude intracranial pathology and lesions at the base of the skull, that may require definition by specialized magnetic resonance imaging (MRI) or computed tomography (CT). Neck or back pain require careful motor, sensory, and reflex examination of the arms and legs, as well as evaluation of rectal and urinary sphincter function to exclude plexopathy and spinal cord lesions. Appropriate diagnostic tests should be performed to determine the cause of the pain and the extent of disease, and patients should be offered analgesia to facilitate these evaluations (e.g., to allow the patient to lie flat for CT or MRI scans). It is important to correlate the results of these studies with physical and neurologic findings to assure that appropriate areas of the body have been imaged and that identified abnormalities do in fact explain the patient's pain. Pain may be the first sign of tumor recurrence or progression and may appear or increase before changes are evident in imaging studies; therefore, imaging studies may have to be repeated. Ongoing Pain AssessmentThe assessment of the patient's pain and the efficacy of the treatment plan should be ongoing, and the pain reports should be documented. Simply to record a patient's responses to the question "How is your pain?" invites misunderstanding and hinders quantification. Pain should be assessed and documented:
Occasionally, discrepancies between behaviors and a patient's self-report of pain may occur. For example, patients may describe pain as an 8, on a scale of 0 to 10, while smiling and walking freely, or conversely, as a 2 while experiencing tachycardia, splinting, and sweating, although this is less usual. These discrepancies may result from several factors, including the effectiveness of the patient's coping skills (see Chapter 4). The patient who uses distraction and relaxation techniques may engage in diversionary activities while still experiencing severe pain; in fact, this is a goal of many behavioral pain therapies. Patients may deny severe pain for a variety of reasons, including a perception that stoicism is expected or rewarded or a fear that the pain symbolizes disease progression. Similarly, patients managed with as-needed analgesia may perceive that medication will be given only if the pain score is very high. When discussing pain assessment and control with patients, members of the health care team should emphasize the importance of a factual report, thereby avoiding both stoicism and exaggeration. If anxiety or other concerns are significant, patients should be asked to rate their emotional distress separately from their pain, using similar scales (see Pain Distress Scales in Attachment B). They also may be asked to rate their mood or the effectiveness of analgesic therapies (see the Memorial Pain Assessment Card in Attachment B). When discrepancies between behaviors and self-reports of pain occur, these differences should be discussed with the patient, and the pain management plan should then be revised. Most cancer patients are treated for pain in outpatient and home care settings. Plans should be made to ensure ongoing assessment of the pain and the effectiveness of treatments in these settings. Patients can keep a log of their pain intensity scores and report these scores during followup visits or through telephone followup. In addition, patients should be taught to report changes in their pain or any new pain so that appropriate reassessment and changes in the treatment plan can be initiated. Patients unable to communicate effectively with staff require special consideration (see Chapter 7). Even patients previously able to communicate may be unable to do so as their disease progresses. Aggressive efforts should be made to find a translator for the non-English-speaking patient to determine a convenient way to assess pain. Many of the pain assessment tools have already been translated (Beyer and Wells, 1993; Cleeland and Syrjala, 1992). When developing a treatment plan, members of the health care team should pay particular attention to the preferences and needs of patients whose education or cultural traditions may impede effective communication (see Chapter 7 for additional discussion). Certain cultures have strong beliefs about pain and its management, and members of these cultures may hesitate to report unrelieved pain or may have specific preferences for pain-relieving measures. When developing a treatment plan, clinicians should be aware of the unique needs and circumstances of patients from different age groups or various ethnic and cultural backgrounds. Assessment of Common Cancer Pain SyndromesPatients can experience acute or chronic pain from their cancer, diagnostic procedures, treatment, or preexisting conditions. Thus, patients should be carefully assessed to ensure that the cause of pain is established whenever possible and treated appropriately. Some causes of cancer pain are relatively easy to diagnose and treat (e.g., pathologic fractures). However, clinicians treating patients with cancer should also be able to recognize readily the common pain syndromes that may cause intractable pain and that may signal disease recurrence in order to optimize therapy and minimize the morbidity of unrelieved pain. Furthermore, because many intractable pain problems involve neurologic structures (e.g., epidural spinal cord compression; metastatic brachial and lumbosacral plexopathy), prompt recognition and treatment of these syndromes may also minimize neurologic impairment (Elliott and Foley, 1989). Bone MetastasesMultiple myeloma and cancers of the breast, prostate, and lung account for a large majority of bone metastases. The most common sites of bone metastasis include the vertebrae, pelvis, femur, and skull. Distal extremity metastases are uncommon (Malawer and Delaney, 1989). The most frequent symptom is pain, although 25 percent of patients with bone metastases have no symptoms (Wagner, 1984). Pain may result from direct tumor involvement of bone with activation of local nociceptors, or compression of adjacent nerves, vascular structures, and soft tissue. Because patients often have multiple sites of bone metastases, multiple areas of pain are common. Pain is usually described as dull and aching, is usually localized to the area of metastasis, and is increased by movement. However, spine metastases may impinge upon nerve roots and result in radicular pain. Patients with metastases to the base of the skull may complain of headache; pain on head movement; and face, neck, or shoulder pain (Greenberg, Deck, Vikram, et al., 1981). Besides pain and immobility, complications of bone metastases include fractures, hypercalcemia, and spinal cord compression. Pathologic fractures occur most commonly in cancers of the breast, lung, kidney, and thyroid and in multiple myeloma, usually in the proximal femur or humerus (Oda and Schurman, 1983). Hypercalcemia is most often observed in cancers of the breast, lung, and kidney and in multiple myeloma. The diagnosis of bone metastasis is established by radiographic confirmation and, rarely, biopsy. Radionuclide scintigraphy and magnetic resonance imaging are the most sensitive means of detecting bone metastases, often demonstrating abnormalities before those seen on plain radiographs. Plain radiographs showing typical lytic, blastic, or mixed lesions are usually diagnostic and easily distinguished from lesions resulting from nonmetastatic causes (Wilner, 1982). However, plain radiographs and bone scintigraphy may be negative early in the course of myeloma, in some osseous metastases, and at sites of previously radiated bone (Kelly and Payne, 1991). Magnetic resonance imaging may be helpful in such cases when bone involvement is suspected. Epidural Metastases/Spinal Cord CompressionEpidural metastasis is the most ominous complication of bone metastasis to the vertebral spine and is a medical emergency. Failure to diagnose and treat this condition will lead to permanent neurologic deficits due to spinal cord dysfunction. Early diagnosis, before overt neurologic deficits, should result in improved outcome (Byrne, 1992). Epidural metastasis is a common complication in patients with breast, prostate, or lung cancer; multiple myeloma; renal cell carcinoma; or melanoma. The tumor enters the epidural space by contiguous spread from adjacent vertebral metastases in the vast majority of cases (Rodriguez and Dinapoli, 1980). The remaining cases arise from the direct invasion of retroperitoneal tumor or tumor located in the posterior thorax through adjacent intervertebral foramina or, rarely, from bloodborne seeding of the epidural space. The pain is usually midline, but patients whose tumor involves nerve roots have sharp or shooting pain in a radicular distribution. Untreated, the pain slowly intensifies with a mean duration of 7 weeks from the onset of pain to the onset of neurologic deficits due to spinal cord compression (Gilbert, Kim, and Posner, 1978). Signs of spinal cord compression include motor, sensory, and autonomic (e.g., bladder and bowel) dysfunction. More than 70 percent of patients with spinal cord compression have an abnormal plain radiograph in the region of pain (compression fracture, blastic, or lytic metastases) (Portenoy, Lipton, and Foley, 1987). Because pain is such a reliable early sign, epidural metastases can often be diagnosed and treated before neurologic deficits develop. Patients with persistent back pain in the region of abnormality on plain spine radiograph, with or without neurologic deficits, should undergo evaluation with MRI. Patients with progressive back or neck pain whose plain radiograph is normal should also undergo an imaging study of the epidural space, even if their neurologic examination is normal. Administration of analgesics and corticosteroids constitutes the mainstay of pharmacologic therapy. Radiation therapy or surgical excision followed by radiation therapy are the two standard treatments. Metastases to the SkullTable 4 lists common metastases to the skull, which often cause pain in patients with cancer. PlexopathiesCervical, brachial, and lumbosacral plexi can be sources of intractable pain in cancer patients (Elliott and Foley, 1989). Pain is produced when these structures are infiltrated by tumor or compressed by fibrosis after radiation therapy to adjacent structures. Pain tends to be less prominent in radiation-induced plexopathies than in tumor-related ones. Traction injury related to the positioning of a patient during a prolonged operation may also produce brachial plexopathy. Pain originating in the cervical plexus often occurs as an aching discomfort that may radiate into the neck and occiput. It is most commonly caused by metastases to the cervical lymph nodes or the local extension of primary head and neck tumors. Brachial plexopathy is a common complication of breast and lung cancer and lymphoma, but it can also be caused by metastasis to the brachial plexus from a remote primary tumor (Kori, Foley, and Posner, 1981). Pain occurs in up to 85 percent of patients with brachial plexus involvement and may precede weakness or sensory loss by months (Foley, 1987). When the upper plexus is damaged by tumor, pain usually begins in the shoulder and is associated with shooting or electrical sensations in the thumb and index finger. When the lower plexus is involved, as is more common, pain begins in the shoulder and radiates into the elbow, arm, and medial forearm, and into the fourth and fifth digits. In about 25 percent of patients, both upper and lower divisions are involved. Compared with tumor-related plexopathy, radiation damage to the brachial plexus causes less severe pain, distributed initially in the upper division. Epidural extension may occur in up to 50 percent of patients with superior pulmonary sulcus ("Pancoast") tumors (Kanner and Foley, 1981). Epidural disease is more likely to occur when the entire plexus is involved and Horner's syndrome is present, which indicates medial and paraspinal spread of tumor. Lymphoma may produce brachial plexopathy and spinal cord compression in the absence of vertebral body erosion. CT and MRI of the brachial plexus and epidural spaces are the diagnostic procedures of choice, and are essential to define the extent of disease and to determine the appropriate radiation ports. The lumbosacral plexus, embedded in the psoas muscle, may be invaded by tumors of the abdomen and pelvis. Colorectal, endometrial, and renal cancers, as well as sarcomas and lymphomas, may invade this plexus by direct spread. However, 25 percent of lumbosacral plexopathies are metastatic (Jaeckle, Young, and Foley, 1985). Pain is usually felt in the lower abdomen, buttock, and leg. Infiltration of the sacral plexus may produce perineal and perirectal pain, which is exacerbated by sitting and lying prone. Pain typically precedes, by weeks or even months, the neurologic signs of weakness, sensory loss, or urinary incontinence. Abdominal and pelvic CT or MRI may provide the diagnosis and allow definition of radiation portals. Similar to patients with brachial plexopathy, patients with diffuse or bilateral lumbosacral plexus involvement may have an epidural extension of tumor, in which case, MRI of the epidural space is also required. Epidural disease of the cauda equina or leptomeningeal tumor may produce a clinical syndrome similar to lumbosacral plexopathy (Elliott and Foley, 1989). Pain may precede overt neurologic signs in spinal cord compression, plexopathies, and spinal metastasis. Prompt recognition of these syndromes and institution of appropriate treatment can avoid paralysis and incontinence. Peripheral NeuropathiesPeripheral nerves can be compressed or infiltrated by tumor or constricted by fibrosis, which in rare instances is a complication of radiation treatment. They may also be damaged by neurotoxic chemotherapy or by cutaneous incisions and the retraction of tissues during surgery (Table 5). Myeloma may cause a progressive painful neuropathy in about 15 percent of patients. In as many as 8 of 10 such patients, neuropathy precedes the onset of other symptoms (Davis and Drachman, 1972). This sensorimotor neuropathy is characterized by distal paraesthesias, sensory loss, weakness, and muscle wasting, and it may occasionally ascend upward in a manner similar to Guillain-Barr syndrome. Vincristine, cisplatin, and taxol produce dose-related peripheral neuropathies, usually manifested as dysesthesia in the feet and later (as the neuropathy progresses) in the hands; continuous burning pain is rarely a problem. Vincristine neuropathy may also give rise to cranial neuralgias, including jaw claudication. Treatment of chemotherapy-related neuropathy involves decreasing or stopping the offending agent (when possible) and the use of analgesics. In the absence of recurrent tumor, persistent pain following surgery may result from intraoperative injury to cutaneous or deeper nerves. Postsurgical pain syndromes are characterized by either persistent pain after the surgical procedure or recurrent pain after the initial surgical pain has resolved. The clinical characteristics relate to the location and extent of nerve injury (Kelly and Payne, 1991). Treatment of these syndromes involves the use of analgesics and, occasionally, regional nerve blocks. Acute and Postherpetic NeuralgiaVaricella-zoster virus infection or reactivation ("shingles") is more likely to occur in patients with cancer than in the general population because of the higher incidence of immunosuppression in the former. Zoster neuralgia may cause acute and chronic pain ( Rusthoven, Ahlgren, Elhakim, et al., 1988). Disseminated zoster is twice as likely to occur in patients with progressive tumor than those in remission (Rusthoven, Ahlgren, Elhakim, et al., 1988). Thoracic and cranial dermatomes are most commonly affected, and the incidence of postherpetic neuralgia (pain after healing of rash) increases with age (Watson, Evans, Reed, et al., 1982). Varicella-zoster virus infection is characterized by a burning, aching pain. Lancinating or shocklike pain may be superimposed in the area of the crusted (or healed) herpetic skin lesions, in which there is usually sensory loss. Hyperpathia may be profound. For acute zoster, antiviral therapies in combination with analgesics are recommended. For postherpetic neuralgia, antiviral therapies are of limited use, and therapies for neuropathic pain are used (see Chapter 3). Empiric observations suggest that nerve blocks during acute herpes zoster infection reduce pain, shorten the acute episode, and prevent the emergence of postherpetic neuralgia ( Bonica, 1990B). Treatment approaches for neuropathic pain are discussed later (see also Figure 1). Abdominal PainAbdominal tumors are frequently characterized by pain that is colicky, worse after eating, and associated with nausea. Pain may be referred widely throughout the abdomen to distant cutaneous sites (e.g., shoulder, neck, and back). Patients with tumors of the small or large intestine occasionally have a combination of obstruction, pain, and hematemesis or rectal bleeding. Common causes of abdominal pain for these patients are listed in Table 6. Patients with cancer are vulnerable to developing the same nonmalignant medical and surgical causes of abdominal pain, such as appendicitis, cholecystitis, and pancreatitis, as are individuals without cancer. Opioid analgesic therapy is often constrained in this group of patients by nausea, constipation, and ileus related to tumor-related bowel obstruction. Treatment of abdominal pain with nerve blocks is discussed in Chapter 5. MucositisMucositis can occur in any patient receiving cytotoxic chemotherapy or radiation to the head and neck. In patients receiving chemotherapy, the incidence and severity of mucosal toxicity is influenced by the individual drugs, their dosages, and the schedule of their administration. Preexisting poor oral hygiene may also contribute to mucositis. Pain is often intense and interferes with oral intake. Chemotherapy-induced mucositis usually begins 3 to 5 days after therapy is started, reaches its peak at 7 to 10 days, and slowly resolves over the next 5 to 7 days unless complicated by infection or hemorrhage (Dreizen, 1990). Clinical signs of mucositis include diminished mucosal thickness and keratinization, superficial sloughing, and ulceration. Radiation of the oropharyngeal and esophageal mucosa results in predictable inflammatory effects, usually appearing at the end of the second week of treatment, plateauing during the fourth week of radiation, and sometimes persisting for 2 to 3 weeks after the completion of treatment (Baker, 1982). Initially, the mucosa in the path of radiation appears reddened and swollen; as treatment continues, the mucosa can be covered with a fibrous exudate. In both chemotherapy- and radiation-associated mucositis pain, intensity is related to the extent of tissue damage and the degree of local inflammation. Typically, the patient describes a burning sensation, often accompanied by erythema. Because clinical signs and symptoms may change, patients with mucositis should be assessed frequently (Table 7). Management involves the aggressive use of analgesics (such as systemic patient-controlled analgesia) and agent-specific antimicrobial agents ( Epstein, 1990; Janjan, Weissman, and Pahule, 1992). Assessment of New PainPain assessment is an ongoing process requiring constant attention to new pain (see Figure 1). Changes in pain patterns or the development of new pain should not be attributed to preexisting causes but should instead trigger diagnostic evaluation. New pain may signal treatable problems such as infection or fracture. A change in pain often signals advancing disease, and because pain management relies on the treatment of the underlying disease, establishing a medical diagnosis with the criteria discussed earlier is critical. A 1992 report showed that a comprehensive pain assessment revealed new causes of pain in 64 percent of 270 oncology patients with new pain complaints; most of the new diagnoses were neurologic (Gonzales, Payne, Foley, et al., 1992). Thus, the need to reassess persistent pain to identify new causes cannot be overemphasized. 3. Pharmacologic ManagementRecommendations13. An essential principle in using medications to manage cancer pain is to individualize the regimen to the patient. (A) 14. The simplest dosage schedules and least invasive pain management modalities should be used first. (Panel Consensus) 15. Pharmacologic management of mild to moderate cancer pain should include an NSAID or acetaminophen, unless there is a contraindication. (A) 16. When pain persists or increases, an opioid should be added. (A) 17. Treatment of persistent or moderate to severe pain should be based on increasing the opioid potency or dose. (A) 18. Medications for persistent cancer-related pain should be administered on an around-the-clock basis with additional "as-needed" doses, because regularly scheduled dosing maintains a constant level of drug in the body and helps to prevent a recurrence of pain. (A) 19. Patients receiving opioid agonists should not be given a mixed agonist-antagonist because doing so may precipitate a withdrawal syndrome and increase pain. (B) 20. Meperidine should not be used if continued opioid use is anticipated. (B) 21. Opioid tolerance and physical dependence are expected with long-term opioid treatment and should not be confused with addiction. (Panel Consensus) 22. The oral route is the preferred route of analgesic administration because it is the most convenient and cost-effective method of administration. When patients cannot take medications orally, rectal and transdermal routes should be considered because they are also relatively noninvasive. (Panel Consensus) 23. Intramuscular administration of drugs should be avoided because this route can be painful and inconvenient, and absorption is not reliable. (B) 24. Failure of maximal systemic doses of opioids and coanalgesics should precede the consideration of intraspinal analgesic systems. (Panel Consensus) 25. Because there is great interindividual variation in susceptibility to opioid-induced side effects, clinicians should monitor for these potential side effects. (B) 26. Constipation is a common problem associated with long-term opioid administration and should be anticipated, treated prophylactically, and monitored constantly. (B) 27. Naloxone, when indicated for reversal of opioid-induced respiratory depression, should be titrated in doses that improve respiratory function but do not reverse analgesia. (B) 28. Placebos should not be used in the management of cancer pain. (Panel Consensus) 29. Patients should be given a written pain management plan. (A) 30. Communication about pain management should occur when a patient is transferred from one setting to another. (B) Drug therapy is the cornerstone of the many modalities available to manage cancer pain because it is effective, relatively low risk, inexpensive, and usually of rapid onset. An essential principle in using medications to manage cancer pain is to individualize the regimen to the patient (Foley, 1985a). Three major classes of drugs are used alone or, more commonly, in combination to manage pain in the cancer patient:
Before choosing drugs to manage pain or other symptoms, identify the specific cause(s) of the pain, evaluate its intensity and quality, and then match the drug to the pain intensity and other characteristics.The simplest dosage schedules and least invasive pain management modalities should be used first. After drug therapy has been started, pain should be assessed to determine the ongoing effectiveness of the analgesic therapy. For opioid analgesics, if pain relief is inadequate, the dose should be increased until pain relief is achieved or unacceptable side effects occur. In the case of NSAIDs and adjuvant analgesic drugs, which have ceiling effects to their analgesic efficacy, if the upper limit of the recommended dose is reached and pain relief is not achieved, then that particular drug should be discontinued and a second drug in that class should be used. Most cancer pain can be managed by oral administration of drugs; however, difficulty in swallowing, gastrointestinal (GI) disturbances that render drug absorption unreliable, the amount of drug required, and many other factors may require alternative routes of administration (Coyle, Adelhardt, Foley, et al., 1990; Grond, Zech, Schug, et al., 1991). Table 8 summarizes some of the advantages and disadvantages of cancer pain therapies. The WHO LadderA simple, well-validated, and effective method for assuring the rational titration of therapy for cancer pain has been devised by WHO (World Health Organization, 1990). It has been shown to be effective in relieving pain for approximately 90 percent of patients with cancer (Ventafridda, Caraceni, and Gamba, 1990) and over 75 percent of cancer patients who are terminally ill (Grond, Zech, Schug, et al., 1991). This approach is based on the concept of an analgesic ladder (Figure 2). The five essential concepts in the WHO approach to drug therapy of cancer pain are:
The first step in this approach is the use of acetaminophen, aspirin, or another NSAID for mild to moderate pain. Adjuvant drugs to enhance analgesic efficacy, treat concurrent symptoms that exacerbate pain, and provide independent analgesic activity for specific types of pain may be used at any step. When pain persists or increases, an opioid such as codeine or hydrocodone should be added (not substituted) to the NSAID. Opioids at this step are often administered in fixed dose combinations with acetaminophen or aspirin because this combination provides additive analgesia (Weingart, Sorkness, and Earhart, 1985). Fixed-combination products may be limited by the content of acetaminophen or NSAID, which may produce dose-related toxicity. When higher doses of opioid are necessary, the third step is used. At this step separate dosage forms of the opioid and nonopioid analgesic should be used to avoid exceeding maximally recommended doses of acetaminophen or NSAID. Pain that is persistent, or moderate to severe at the outset, should be treated by increasing opioid potency or using higher dosages. Drugs such as codeine or hydrocodone are replaced with more potent opioids (usually morphine, hydromorphone, methadone, fentanyl, or levorphanol), as described below. Medications for persistent cancer-related pain should be administered on an around-the-clock basis, with additional "as-needed" doses, because regularly scheduled dosing maintains a constant level of drug in the body and helps to prevent a recurrence of pain. Patients who have moderate to severe pain when first seen by the clinician should be started at the second or third step of the ladder. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)NSAIDs are used as initial therapy in mild pain because they are effective, are often available over the counter, and can be used effectively in combination with opioids and adjuvant analgesics if pain intensity increases. Acetaminophen is included with this group, even though its anti-inflammatory effects are less potent, because it has similar analgesic potency and pharmacologic characteristics. A major advantage of acetaminophen in comparison to other NSAIDs is its lack of effect on platelet function, which makes it less risky to use in thrombocytopenic patients. It is also relatively inexpensive. NSAIDs decrease levels of inflammatory mediators generated at the site of tissue injury by inhibiting the enzyme cyclooxygenase, which catalyzes the conversion of arachidonic acid to prostaglandins and leukotrienes (Sunshine and Olson, 1989). These mediators sensitize nerves to painful stimuli. Although NSAIDs may also affect the central nervous system, these drugs do not activate opioid receptors and therefore produce analgesia by a different mechanism than opioids. Hence:
In contrast to opioids, NSAIDs do not produce tolerance, physical, or psychological dependence, are antipyretic, and have a different spectrum of toxicity. Used as single agents, NSAIDs have a ceiling effect on their analgesic potential, so the use of doses higher than those specified in the package insert is not recommended. The nonacetylated salicylates such as salsalate, sodium salicylate, and choline magnesium trisalicylate do not affect platelet aggregation profoundly and do not alter bleeding time (Danesh, Saniabadi, Russell, et al., 1987; Day, Furst, Graham, et al., 1987; Estes and Kaplan, 1980; Morris, Sherman, McQuain, et al., 1985; Stuart and Pisko, 1981; Zucker and Rothwell, 1978). Aspirin, the prototype of the acetylated salicylate, produces an irreversible inhibition of platelet aggregation, which may prolong bleeding time for up to several days after ingestion (Stuart, Murphy, Oski, et al., 1972; Sutor, Bowie, and Owen, 1971; Weiss, Aledont, and Kochwa, 1968). The nonacetylated salicylates, such as sodium salicylate and choline magnesium trisalicylate, have minimal effects on platelet aggregation and do not appear to alter bleeding time clinically (Day, Furst, Graham, et al., 1987; Morris, Sherman, McQuain, et al., 1985; Stuart and Pisko, 1981; Zucker and Rothwell, 1978). Other NSAIDs produce a reversible inhibition of platelet aggregation, which persists while the drug is in the systemic circulation (Schlegel, 1987). Therefore, with the exception of the nonacetylated salicylates noted above, NSAIDs should be avoided if possible in patients who are thrombocytopenic or who have a clotting impairment. NSAIDs bind extensively to plasma proteins and therefore may be displaced by or may displace other protein-bound drugs such as coumadin, methotrexate, digoxin, cyclosporine, oral antidiabetic agents, and sulfa drugs. Such interactions may enhance therapeutic or toxic effects of either drug. The use of NSAIDs has been associated with both minor (dyspepsia, heartburn, nausea, vomiting, anorexia, diarrhea, constipation, flatulence, bloating, epigastric pain, and abdominal pain) and major (bleeding, ulceration, and perforation) GI toxicities. Serious effects are not always preceded by minor GI effects; patients should be advised to report any GI disturbances. Hepatic and renal dysfunction or toxicity, which can occur at any time in the course of NSAID therapy, are of particular concern during long-term use (Sunshine and Olson, 1989). The risk of renal dysfunction is greatest in patients with advanced age, preexisting renal impairment, heart failure, hepatic dysfunction, hypovolemia, concomitant therapy with other nephrotoxic drugs such as diuretics, or elevated levels of angiotensin II or catecholamines. Antipyretic and anti-inflammatory effects of NSAIDs may mask the usual signs and symptoms of infections. Adverse effects of NSAIDs that may appear at any time include:
Even though NSAIDs are effective in relieving mild pain and are opioid sparing for moderate to severe pain, patients who take them, especially if elderly, should be monitored carefully for adverse effects. Most NSAIDs are available as oral tablets, caplets, or capsules, and several are available as oral liquids. Rectal suppositories of aspirin, acetaminophen, and other NSAIDs are commercially available or can be compounded easily by pharmacists. Ketorolac tromethamine is the only NSAID that is currently available for short-term parenteral administration. Table 9 provides dosing data for acetaminophen and NSAIDs. It is impossible to predict which NSAID will be best tolerated by a particular patient; no particular NSAID has demonstrated superiority over others for pain relief. Once an NSAID has been selected, the dose should be increased until pain has been relieved or the maximal recommended dose has been achieved. The duration of analgesia does not always correlate with the serum half-life of the NSAID. Therefore, the response of the patient should guide the clinician in selecting dosing intervals of these agents. Because NSAIDs and adjuvant analgesics have ceiling effects to their efficacy, if a patient does not respond to the maximal dose of one NSAID, another should be tried before discontinuation of NSAID therapy. The initial choice of NSAID should be based on the efficacy, safety, and relative expense; generally, the least expensive NSAID should be chosen. OpioidsOpioids are the major class of analgesics used in the management of moderate to severe pain because of their effectiveness, ease of titration, and favorable risk-to-benefit ratio. Opioids produce analgesia by binding to specific receptors both within and outside the CNS (Stein, 1993; Hargreaves and Joris, 1993). Opioid analgesics are classified as full agonists, partial agonists, or mixed agonist-antagonists, depending on the specific receptors to which they bind and their intrinsic activity at that receptor. Commonly used full agonists include morphine, hydromorphone, codeine, oxycodone, hydrocodone, methadone, levorphanol, and fentanyl. These opioids are classified as full agonists because they do not have a ceiling to their analgesic efficacy and will not reverse or antagonize the effects of other opioids within this class given simultaneously. Side effects include constipation, nausea, urinary retention, confusion, sedation, and respiratory depression. Buprenorphine is a partial agonist. It has a relatively low intrinsic efficacy at the opioid receptor in comparison to full opioid agonists and displays a ceiling effect to analgesia. Mixed agonist-antagonists in clinical use include pentazocine, butorphanol tartrate, dezocine, and nalbuphine hydrochloride. These drugs have an analgesic ceiling. In contrast to full agonists, these drugs block opioid analgesia at one type of opioid receptor (mu) or are neutral at this receptor while simultaneously activating a different opioid receptor (kappa). Patients receiving full opioid agonists should not be given a mixed agonist-antagonist because doing so may precipitate a withdrawal syndrome and increase pain. Morphine is the most commonly used opioid for moderate to severe pain because of its availability in a wide variety of dosage forms, its well-characterized pharmacokinetics and pharmacodynamics, and its relatively low cost. Meperidine may be useful for brief courses (e.g., a few days) to treat acute pain and to manage rigors (shivering) induced by medication, but it generally should be avoided in patients with cancer because of its short duration of action (2.5 to 3.5 hours) and its toxic metabolite, normeperidine. This metabolite accumulates, particularly when renal function is impaired, and causes CNS stimulation, which may lead to dysphoria, agitation, and seizures (Kaiko, Foley, Grabinski, et al., 1983). Therefore, meperidine should not be used if continued opioid use is anticipated. Equianalgesic doses of commonly used opioids and starting doses for those drugs are listed in Tables 10 and 11. Tolerance and Physical DependenceOpioid tolerance and physical dependence are expected with long-term opioid treatment and should not be confused with psychological dependence ("addiction"), manifested as drug abuse behavior. The misunderstanding of these terms in relation to opioid use leads to ineffective practices in prescribing, administering, and dispensing opioids for cancer pain and contributes to the problem of undertreatment. The presence of opioid tolerance and physical dependence does not equate with "addiction." Physical dependence on opioids is revealed when the opioid is abruptly discontinued or when naloxone is administered and is typically manifested as anxiety, irritability, chills and hot flashes, joint pain, lacrimation, rhinorrhea, diaphoresis, nausea, vomiting, and abdominal cramps and diarrhea. The mildest form of the opioid abstinence syndrome may be confused with viral "flu-like" syndromes. For opioids with short half-lives (i.e., codeine, hydrocodone, morphine, hydromorphone), the onset of withdrawal symptoms can occur within 6 to 12 hours and peak at 24 to 72 hours after discontinuation. For opioids with long half-lives (i.e., methadone, levorphanol, transdermal fentanyl), the onset of the abstinence syndrome may be delayed for 24 hours or more after drug discontinuation and may be of milder intensity. The appearance of the abstinence syndrome defines physical dependence on opioids, which may occur after just 2 weeks of opioid therapy, but does not imply psychological dependence or addiction. Most patients with cancer take opioids for more than 2 weeks, and only very rarely do they exhibit the drug abuse behaviors and psychological dependence that characterize addiction (Portenoy and Payne, 1992). Patients with cancer occasionally require discontinuation or rapid decreases in doses of opioids when the cause of pain is effectively eliminated by antineoplastic treatments or pain perception is modified by neuroablative or neurolytic procedures. In such circumstances, the opioid abstinence syndrome can be avoided by withdrawal of the opioid on a schedule that provides half the prior daily dose for each of the first 2 days and then reduces the daily dose by 25 percent every 2 days thereafter until the total dose (in morphine equivalents) is 30 mg/day. The drug may be discontinued after 2 days on the 30 mg/day dose (American Pain Society, 1992). Transdermal clonidine (0.1 to 0.2 mg/day) may reduce anxiety, tachycardia, and other autonomic symptoms associated with opioid withdrawal. Tolerance to opioids is defined as the need to increase dose requirements over time to maintain pain relief. For most cancer patients, the first indication of tolerance is a decrease in the duration of analgesia for a given dose. Increasing dose requirements are most consistently correlated with progressive disease, which produces increased pain intensity (Foley, 1985a). Patients with stable disease do not usually require increasing doses (Foley, 1993; Levy, 1989). Dosage TitrationOpioid doses should be adjusted in each patient to achieve pain relief with an acceptable level of adverse effects. Dosage typically requires adjustment over time. With the exception of fentanyl delivered by the transdermal route, there is no ceiling or maximal recommended dose for full opioid agonists, and in fact, very large doses of morphine, e.g., several hundred milligrams every 4 hours, may be needed for severe pain (Foley, 1985a). Effective pain relief can be accomplished by the anticipation and prevention of pain. Because many patients have persistent or daily pain, it is important to use opioids on a regular schedule rather than only "as needed." Around-the-clock administration of analgesics allows each dose to become effective before the previous dose has lost its effectiveness. A patient should be given "as-needed" doses for the first 24 to 48 hours when a new drug is started to define the best daily dosing requirements for that individual patient. In addition to the titration of individual drugs, the modalities for pain management are titrated when the pain is persistent and is moderate to severe in intensity (see Figure 3). Pain management for moderate to severe pain should begin with oral opioids in combination with an NSAID or acetaminophen. The optimal dose will control pain with the fewest side effects, such as sedation, mental clouding, nausea, or constipation. Adjuvant drugs (see below) may be used to counteract the predictable side effects of opioids. For example, hydroxyzine may be added to opioids and NSAIDs to manage anxiety and nausea, especially when they occur simultaneously and are not intense. Dietary caffeine supplementation may provide additive analgesia and counteract opioid induced sedation. Antiemetic drugs such as phenothiazines and metoclopramide may be added to manage opioid-induced nausea. It is usually advisable to observe the patient's response to several different opioids, sequentially, before switching routes of administration or trying an anesthetic, neurosurgical, or other invasive approach to relieve persistent pain (Galer, Coyle, Pasternak, et al., 1992). For example, patients who experience dose-limiting sedation, nausea, or mental clouding on oral morphine should be switched to an equianalgesic dose of hydromorphone or fentanyl. The dose of the second opioid should then be adjusted. Sequential analgesic trials should be based on regular assessments of pain, with continuous attention to antineoplastic and noninvasive nonpharmacologic therapies (see Figure 1). Administration MethodsThe speed of onset and duration of action for any opioid depend on the specific drug chosen and its formulation (tablet, elixir, etc.). Most are well absorbed after oral or rectal administration, yet absorption may not be complete. Further, drugs absorbed from the gut are subject to first-pass metabolism in the liver and, hence, should be given at higher doses than when given parenterally. Although dosage requirements for different parenteral routes (intravenous, subcutaneous, and intramuscular) are comparable or equivalent, the onset of drug action is typically most rapid after intravenous dosing because there is no delay in absorption. Therefore, drug dose and frequency should be titrated to the individual patient's response and analgesic needs when changing the route of administration or the type of formulation. Oral.The oral route is the preferred route of analgesic administration because it is the most convenient and cost-effective. Oral opioids are available in tablet, capsule, and liquid forms and in immediate and controlled-release formulations; morphine is available in immediate and controlled-release forms. Controlled-release tablets become immediately released when crushed and are therefore not appropriate for patients who are unable to swallow whole tablets. A small percentage may require alternate routes during their illness and when they are unable to swallow, such as during mucositis or in the terminal phase. Coyle, Adelhardt, Foley, et al. (1990) found that many patients required more than one route of administration to maintain pain control in the last 4 weeks of life.When patients cannot take medications orally, other less invasive routes such as rectal or transdermal routes should be tried. During intravenous and subcutaneous administration, local irritation of the skin or vein may occur. Therefore, parenteral routes should be used only when simpler, less demanding, and less costly methods are inappropriate or ineffective. Rectal.The rectal route may be used when patients have nausea or vomiting or are fasting either preoperatively or postoperatively. The rectal route is contraindicated if there are lesions of the anus or rectum because placement of the suppository will cause pain. This route is also not useful if there is diarrhea or in elderly or infirm patients who are physically unable to place the suppository. There are commercially available suppositories of morphine, hydromorphone, and oxymorphone. Medications can also be placed in a colostomy or similar stoma, provided that the flow of effluent is slow enough to allow the drug to be absorbed via the mucosa (McCaffery, Martin, and Ferrell, 1992). When converting from the oral to the rectal route, start with the same amount as the oral dose and titrate as needed. Transdermal.Transdermal administration bypasses GI absorption. Fentanyl is currently the only opioid commercially available in a transdermal form (TDS-Fentanyl). Four patch sizes are available and provide delivery of fentanyl at 25, 50, 75, or 100 mg/hour; therefore, there is flexibility in drug dosing. The maximal recommended daily dose is 300 mg/hour. Patients requiring larger doses should be switched to an equianalgesic dose of an oral or subcutaneously administered opioid. Each patch contains a 72-hour supply of fentanyl, which is passively absorbed through the skin over this period. Levels in plasma rise slowly over 12 to 18 hours after patch placement, and the dosage form has an elimination half-life of 21 hours. Therefore, unlike intravenous fentanyl, the transdermal administration of fentanyl is not suitable for rapid dose titration (Payne, 1992; Portenoy, Southam, Gupta, et al., 1993). Transdermal fentanyl should be considered when patients already on opioid therapy have relatively constant pain and infrequent episodes of breakthrough pain such that rapid increases or decreases in pain intensity are not anticipated. As with other long acting analgesics, all patients should be provided with oral or parenteral rapidly acting short duration opioids to manage breakthrough pain (Portenoy and Hagen, 1990). The most commonly reported side effects of transdermal fentanyl administration are nausea, mental clouding, and skin irritation. Nasal.The transnasal route is an alternative delivery method that may be useful when patients are no longer able to tolerate the oral route. Although several agents are currently being studied, the only commercially available formulation is the mixed agonist-antagonist drug butorphanol, which is rapidly taken up by the vascular nasal mucosa. The major indication for its use is acute headache. Although this formulation has general appeal by virtue of its potential for rapid action because it is a mixed agonist-antagonist, this drug is not recommended for routine use in cancer pain treatment.
Intravenous or Subcutaneous.Intramuscular administration of drugs should be avoided because this route can be painful and inconvenient, and absorption is not reliable. Intravenous or subcutaneous administration are effective alternatives. Patients who may benefit from continuous infusions of opioids include:
The benefits of opioid infusions, compared with those of intermittent "as-needed" doses by intramuscular or subcutaneous injection, include less pain on injection, fewer delays awaiting preparation and administration of medication, and improved effectiveness (Bruera, Brenneis, and MacDonald, 1987; Portenoy, 1986, Portenoy, 1987). The intravenous route provides the most rapid onset of analgesia, but the duration of analgesia after a bolus dose is shorter than with other routes.
A continuous intravenous infusion provides the most consistent level of analgesia and is easily accomplished for patients who have permanent intravenous access for other purposes such as hydration, alimentation, chemotherapy, or antibiotic administration. If intravenous access is not available or desirable, continuous subcutaneous opioid infusion offers a practical alternative in the hospital and home. The subcutaneous administration of opioids provides levels in blood comparable to those with intravenous doses; therefore, the intravenous dose recommendations can be used (Tables 10 and 11) (Moulin, Kreeft, Murray-Parsons, et al., 1991).
Intraspinal.Analgesics may be administered intraspinally when pain cannot be controlled by oral, transdermal, subcutaneous, or intravenous routes because side effects such as confusion and nausea limit further dose escalation. Documentation of the failure of maximal doses of opioids and coanalgesics administered through other routes should precede consideration of intraspinal analgesia. Furthermore, this route requires experience, meticulous technique, significant family and professional support systems, and sophisticated followup, which are not available in all settings. Before implantation of a permanent device, screening should be conducted to ensure adequate response to spinal therapy. A trial of graded opioid doses administered percutaneously through an epidural catheter generally will indicate whether intraspinal therapy is warranted.
As with systemic opioid administration, the dose range for intraspinal opioid therapy varies widely, depending on the level of pain and tolerance (Du Pen and Williams, 1992). Any agent delivered into the epidural or intrathecal space should be free of preservatives because some preservatives and antioxidants can produce neurotoxicity when used intraspinally (Du Pen, Ramsey, and Chin, 1987; Wang, Hillman, Spielholz, et al., 1984). All patients treated with intraspinal drugs should have access to rescue medications (oral or parenteral) for periods of breakthrough pain or in the case of catheter or drug delivery system malfunction. The coadministration of systemic opioids (which generally is not recommended for postoperative pain management) is safe in most cancer patients because they are tolerant to the respiratory-depressant effects of the drugs.
Morphine is the most commonly used intraspinal drug. Alternative opioids such as hydromorphone, fentanyl, or sufentanil have been used intraspinally to manage cancer pain and may be useful substitutes when the patient experiences side effects from morphine. Intraspinal morphine may produce the same side effects of nausea, mental clouding, and sedation as in oral, rectal, or parenteral dosing, because epidural or subarachnoid morphine is absorbed into the circulation by way of the rich epidural vascular plexus and is also carried in the normal flow of cerebrospinal fluid (CSF) from spinal levels to the brain (Bromage, Camporesi, Durant, et al., 1982; Chauvin, Samii, Schermann, et al., 1982; Cousins, 1988; Max, Inturrisi, Kaiko, et al., 1985). Single-dose epidural administration of 10 mg of morphine produces levels in blood comparable to an intramuscular injection of the same dose (Max, Inturrisi, Kaiko, et al., 1985). Very lipophilic opioids such as fentanyl and sufentanil have a more limited CSF distribution, but these drugs also gain access to the blood and are delivered to the brain via the systemic circulation.
In some patients, it is possible to give relatively small doses of opioid spinally and produce pain relief while avoiding the side effects that can limit prior oral or parenteral dosing. However, patients with a high degree of tolerance to systemic opioids may require large doses of spinal opioids (Cousins and Bridenbaugh, 1987), which may negate the advantages of this targeted approach because side effects may still be prominent at high dosage levels.
The main indication for the long-term administration of intraspinal opioids is intractable pain in the lower part of the body, particularly when pain is bilateral or midline (Du Pen and Williams, 1992). With proper selection and screening, good to excellent pain relief can be expected in up to 90 percent of patients (Krames, Gershow, Glassberg, et al., 1985; Onofrio and Yaksh, 1990). Opioids (sometimes coadministered with other agents such as dilute local anesthetic) (Akerman, Arwestrom, and Post, 1988; Fraser, Chapman, and Dickenson, 1992; Maves and Gebhart, 1992; Tejwani, Rattan, and McDonald, 1992) are delivered to the epidural or subarachnoid space via percutaneously placed catheters connected to ports, reservoirs, or infusion pumps (Table 12). For short-term treatment of weeks to a few months, externalized catheters (tunneled or untunneled) can be used. For more prolonged treatment, the delivery system (catheter plus port or pump) can be internalized. Adverse sequelae include the development of tolerance, urinary retention, constipation, pruritus, device failure, and infection (Du Pen, Peterson, Williams, et al., 1990; Hogan, Haddox, Abram, et al., 1991).
Intraventricular.Experience with intraventricular morphine administration is steadily increasing, and results with this route compare favorably with those with intraspinal administration, with over 90 percent of patients in published series benefitting significantly (Choi, Ha, Ahn, et al., 1989). Most important, intraventricular morphine is beneficial for recalcitrant pain due to head and neck malignancies and tumors (e.g., superior sulcus tumors, breast carcinoma) that affect the brachial plexus. Small maintenance doses of morphine (less than 5 mg daily) are needed to achieve maximal comfort. Complications are rare, the most important being infection; as with intraspinal drug delivery, tolerance and respiratory depression do not appear to be major issues (Acute Pain Management Guideline Panel, 1992). Intraventricular morphine requires the placement of a ventricular catheter connected to a subcutaneous (e.g., Ommaya) reservoir for intermittent administration or an infusion pump for continuous infusion (Lazorthes, Verdie, Bastide, et al., 1985; Obbens, Hill, Leavens, et al., 1987).
Patient-Controlled Analgesia (PCA).PCA allows patients to control the amount of analgesia they receive (Ferrante, Ostheimer, and Covino, 1990). PCA can be accomplished by mouth or by the use of a special pump set to prescribed parameters to administer the drug intravenously, subcutaneously, or epidurally. In contrast to the use of PCA in postoperative pain management, the majority of the opioid dose is usually delivered via continuous systemic infusion. Patient-administered boluses are required to treat breakthrough pain and to provide a basis for more accurate and rapid upward titration of the continuous infusion rate.
Intravenous or subcutaneous PCA allows patients to accommodate transient changes in analgesic requirements (such as during dressing changes or positioning) and to tailor analgesic doses according to their own requirements. PCA is also useful in controlling pain quickly in the patient admitted to the hospital specifically for analgesia, and in determining the opioid dosage requirements for conversion to an oral regimen once a steady level of satisfactory analgesia is attained (Baumann, Batenhorst, Graves, et al., 1986). Intravenous and subcutaneous PCA is safe for both home and hospitalized patients (Baumann, Batenhorst, Graves, et al., 1986; Citron, Johnston-Early, Boyer, et al., 1986; Kerr, Sone, Deangelis, et al., 1988; Swanson, Smith, Bulich, et al., 1989) but is contraindicated for sedated and confused patients (Ferrell, Cronin Nash, and Warfield, 1992). Management of Side EffectsConstipation and sedation are the most common side effects associated with opioids; others include confusion, nausea and vomiting, respiratory depression, dry mouth, urinary retention, pruritus, myoclonus, altered cognitive function, dysphoria, euphoria, sleep disturbances, sexual dysfunction, physiologic dependence, tolerance, and inappropriate secretion of antidiuretic hormone [Edit:info added] (Table 13).Because there is great individual variation in the development of opioid-induced side effects, clinicians should monitor for them and prophylactically treat some inevitable ones.
Constipation.Constipation is a common problem associated with opioid administration. Tolerance to the constipating effects of opioids either does not occur or occurs very slowly during chronic therapy. Constipation may worsen with time because of the disease process (e.g., intestinal obstruction, paralytic ileus due to spinal cord compression, decreased food and fluid intake due to anorexia); therefore a careful search for other causes should be performed (Glar |
