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Pain (PDQ®)

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Purpose of This PDQ Summary
Overview
Pain Assessment
Pharmacologic Management
Physical and Psychosocial Interventions
Antineoplastic Interventions
Invasive Interventions
Discharge Planning
Treating Elderly Patients
Current Clinical Trials
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Changes to This Summary (10/02/2009)
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Purpose of This PDQ Summary

This PDQ cancer information summary provides comprehensive, peer-reviewed information for health professionals about the pathophysiology and treatment of pain. This information is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board.

Information about the following is included in this summary:

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients during and after cancer treatment. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

Overview

The International Association for the Study of Pain defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Cancer pain can be managed effectively through relatively simple means in up to 90% of the eight million Americans who have cancer or a history of cancer. Unfortunately, pain associated with cancer is frequently undertreated. [1]

Although cancer pain or associated symptoms cannot always be entirely eliminated, appropriate use of available therapies can effectively relieve pain in most patients. Pain management improves the patient’s quality of life throughout all stages of the disease. Patients with advanced cancer experience multiple concurrent symptoms with pain; therefore, optimal pain management necessitates a systematic symptom assessment and appropriate management for optimal quality of life. [2] Despite the wide range of available pain management therapies, data are insufficient to guide their use in children, adolescents, older adults, and special populations. [3]

State and local laws often restrict the medical use of opioids to relieve cancer pain, and third-party payers may not reimburse for noninvasive pain control treatments. Thus, clinicians should work with regulators, state cancer pain initiatives, or other groups to eliminate these health care system barriers to effective pain management. (These and other barriers to effective pain management are listed below.) Changes in health care delivery may create additional disincentives for clinicians to practice effective pain management.

Flexibility is the key to managing cancer pain. As patients vary in diagnosis, stage of disease, responses to pain and interventions, and personal preferences, so must pain management. The recommended clinical approach outlined below emphasizes a focus on patient involvement.

  1. Ask about pain regularly. Assess pain and associated symptoms systematically using brief assessment tools. Assessment should include discussion about common symptoms experienced by cancer patients and how each symptom will be treated. [2] [3] Asking a patient to identify his or her most troublesome symptom is also of clinical value because the most troublesome symptom is not always the most severe, as demonstrated in a survey of 146 patients in the palliative phase of treatment for lung, gastrointestinal, or breast cancer. [7]

  2. Believe patient and family reports of pain and what relieves the pain. (Caveats include patients with significant psychological/existential distress and patients with cognitive impairment.) [8] [9]

  3. Choose pain-control options appropriate for the patient, family, and setting.

  4. Deliver interventions in a timely, logical, coordinated fashion.

  5. Empower patients and their families. Enable patients to control their course as much as possible.

Highlights of Patient Management

Effective pain management is best achieved by a team approach involving patients, their families, and health care providers. The clinician should:

References:

  1. Weiss SC, Emanuel LL, Fairclough DL, et al.: Understanding the experience of pain in terminally ill patients. Lancet 357 (9265): 1311-5, 2001.
  2. Meuser T, Pietruck C, Radbruch L, et al.: Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93 (3): 247-57, 2001.
  3. Patrick DL, Ferketich SL, Frame PS, et al.: National Institutes of Health State-of-the-Science Conference Statement: Symptom Management in Cancer: Pain, Depression, and Fatigue, July 15-17, 2002. J Natl Cancer Inst 95 (15): 1110-7, 2003.
  4. Bruera E, Willey JS, Ewert-Flannagan PA, et al.: Pain intensity assessment by bedside nurses and palliative care consultants: a retrospective study. Support Care Cancer 13 (4): 228-31, 2005.
  5. Anderson KO, Richman SP, Hurley J, et al.: Cancer pain management among underserved minority outpatients: perceived needs and barriers to optimal control. Cancer 94 (8): 2295-304, 2002.
  6. Miaskowski C, Dodd MJ, West C, et al.: Lack of adherence with the analgesic regimen: a significant barrier to effective cancer pain management. J Clin Oncol 19 (23): 4275-9, 2001.
  7. Hoekstra J, Vernooij-Dassen MJ, de Vos R, et al.: The added value of assessing the 'most troublesome' symptom among patients with cancer in the palliative phase. Patient Educ Couns 65 (2): 223-9, 2007.
  8. Allen RS, Haley WE, Small BJ, et al.: Pain reports by older hospice cancer patients and family caregivers: the role of cognitive functioning. Gerontologist 42 (4): 507-14, 2002.
  9. Bruera E, Sweeney C, Willey J, et al.: Perception of discomfort by relatives and nurses in unresponsive terminally ill patients with cancer: a prospective study. J Pain Symptom Manage 26 (3): 818-26, 2003.

Pain Assessment

Failure to assess pain is a critical factor leading to undertreatment. Assessment involves both the clinician and the patient. Assessment should occur:

Identifying the etiology of pain is important to its management. Clinicians treating patients with cancer should recognize the common cancer pain syndromes (see lists below). Prompt diagnosis and treatment of these syndromes can reduce morbidity associated with unrelieved pain. Distinct cultural components may need to be incorporated into a multidimensional assessment of pain. [1] [2] [3] [4] A comprehensive review of cancer pain with a focus on neuropathic pain provides an overview of pain pathophysiologies and an extensive review of available and investigational pharmacotherapies. [5]

Initial Assessment

The goal of the initial assessment of pain is to characterize the pathophysiology of the pain and to determine the intensity of the pain and its impact on the patient’s ability to function. For example, one study evaluated the association between psychological distress and pain in 120 patients with advanced cancer. Pain intensity and pain that interfered with walking ability, normal work, and relations with other people as measured by the Brief Pain Inventory (Greek version) were found to be significant predictors of anxiety as measured by the Hospital Anxiety and Depression Scale on multivariate analysis. Using the same tools, the authors also found pain that interfered with enjoyment of life was a predictor of depression. [6] Factors that may influence analgesic response and result in persistent pain include changing nociception due to disease progression, intractable side effects, tolerance, neuropathic pain, and opioid metabolites. [7] The following are essential to the initial assessment:

The experience of cancer pain is complex and includes physical, psychosocial, and spiritual dimensions. There is no universally accepted pain classification measure that would assist with predicting the complexity of pain management, particularly for cancer pain patients, who may be more difficult to treat. Clinicians and researchers lack a common language to discuss and compare outcomes of cancer pain assessment and management. Oncologists use the tumor, nodes, metastases (TNM) system to provide a universal language to describe a variety of cancers. The need for a similar classification system for cancer pain resulted in the development of the Edmonton Staging System. [9] [10] This system has been further refined in two reports that have gathered construct validity evidence using an international panel of content experts [11] and a multicenter study to determine interrater reliability and predictive value. [12] The development of an internationally recognized classification system for cancer pain could play a significant role in improving the assessment of cancer pain, allow a more meaningful assessment of clinical prognosis and treatment, and better enable researchers to compare results with regard to cancer pain management. [13]

Patient Self-Report

The mainstay of pain assessment is the patient self-report; however, family caregivers are often used as proxies for patient reports, especially in situations in which communication barriers exist, such as cognitive impairment or language difficulties. Family members who act as proxies typically, as a group, report higher levels of pain than patient self-reports, but there is individual variation. [14] Differences in clinician assessment of pain intensity are also significant. A retrospective review of 41 patient charts using pain ratings of palliative care consultants as the gold standard found high agreement with assessments performed by bedside nurses (registered nurses [RNs] and clinical nurse assistants [CNAs]) when pain was not present or was mild but poor agreement for moderate or severe pain (sensitivity: RNs, 45%; CNAs, 30%). [15]

Pain assessment tools may be unidimensional or multidimensional. Multiple assessment tools exist. Among the more commonly used bedside tools are numeric rating scales, verbal rating scales, visual analog scales, and picture scales. [16] [17] Pain intensity at initial assessment has been demonstrated to be a significant predictor of subsequent pain management complexity (i.e., the need for more pharmacological and multidimensional approaches) and length of time to achieve stable pain control. [18] To enhance pain management across all settings, clinicians should teach families to use pain assessment tools in their homes. The clinician should help the patient to describe:

Physical Examination

A thorough physical examination is required to determine the pathophysiology of pain. Specific features of the neurologic examination such as altered sensation (hypoesthesia, hyperesthesia, hyperpathia, allodynia) in a painful area are suggestive of neuropathic pain. Physical findings of tumor growth and metastasis are also important to identify.

Assessment of the Outcomes of Pain Management

Pain-related outcomes: Clinicians should document and be aware of outcomes of pain therapy. It is helpful to think of pain-related outcomes as primarily measured in two ways: decreased pain intensity and improvement in psychosocial functioning. Using rating scales of pain intensity at its worst and on average and using pain interference scales can help clinicians monitor outcomes. Measurement of the percentage of pain relief is also useful, though measuring patient satisfaction is less useful because of the low expectations patients sometimes hold for pain control. [24] [25]

Drug-taking outcomes: Clinicians prescribing chronic opioids should also monitor and document patients’ drug-taking behaviors. Outcomes related to addiction in cancer patients are rare but nonetheless should be periodically assessed; these assessments can be reassuring to patients. Tolerance and dependence are not addiction related. Documentation of patients’ compliance with regard to changes in dosing and duration of prescriptions is essential in all pain practice.

The clinical assessment of drug-taking behaviors in medically ill patients with pain is complex. Aberrant drug-taking behavior from cancer pain management is related to premorbid history of drug addiction and the likelihood of other pain treatment. A pilot questionnaire was used to characterize drug-related behaviors and attitudes in cancer and AIDS patients. Despite limitations, this study highlights wide potential variation among different palliative care populations in patterns of past and present aberrant drug-taking behaviors and the need for a clinically useful screening approach. The implications for psychosocial and pharmacological management of symptoms such as pain, as well as any aberrant behavior, remains unclear. [26] [27] [28]

Previous drug abuse is likely to lead to specific needs for appropriate dosing during cancer pain therapy. A prospective open-label study compared morphine dosage and effectiveness in AIDS patients with and without previous substance abuse. Results demonstrated that both groups benefited, but patients with a history of drug use require and will tolerate substantially higher morphine doses to achieve stable pain control. [29] This study should increase confidence in providing appropriate pain management to patients who have a history of drug use. [30]

References:

  1. Chung JW, Wong TK, Yang JC: The lens model: assessment of cancer pain in a Chinese context. Cancer Nurs 23 (6): 454-61, 2000.
  2. Cleeland CS, Nakamura Y, Mendoza TR, et al.: Dimensions of the impact of cancer pain in a four country sample: new information from multidimensional scaling. Pain 67 (2-3): 267-73, 1996.
  3. Greenwald HP: Interethnic differences in pain perception. Pain 44 (2): 157-63, 1991.
  4. Bates MS, Edwards WT, Anderson KO: Ethnocultural influences on variation in chronic pain perception. Pain 52 (1): 101-12, 1993.
  5. Fine PG, Miaskowski C, Paice JA: Meeting the challenges in cancer pain management. J Support Oncol 2 (6 Suppl 4): 5-22; quiz 23-4, 2004 Nov-Dec.
  6. Mystakidou K, Tsilika E, Parpa E, et al.: Psychological distress of patients with advanced cancer: influence and contribution of pain severity and pain interference. Cancer Nurs 29 (5): 400-5, 2006 Sep-Oct.
  7. Mercadante S, Portenoy RK: Opioid poorly-responsive cancer pain. Part 1: clinical considerations. J Pain Symptom Manage 21 (2): 144-50, 2001.
  8. Otis-Green S, Sherman R, Perez M, et al.: An integrated psychosocial-spiritual model for cancer pain management. Cancer Pract 10 (Suppl 1): S58-65, 2002 May-Jun.
  9. Bruera E, MacMillan K, Hanson J, et al.: The Edmonton staging system for cancer pain: preliminary report. Pain 37 (2): 203-9, 1989.
  10. Bruera E, Schoeller T, Wenk R, et al.: A prospective multicenter assessment of the Edmonton staging system for cancer pain. J Pain Symptom Manage 10 (5): 348-55, 1995.
  11. Nekolaichuk CL, Fainsinger RL, Lawlor PG: A validation study of a pain classification system for advanced cancer patients using content experts: the Edmonton Classification System for Cancer Pain. Palliat Med 19 (6): 466-76, 2005.
  12. Fainsinger RL, Nekolaichuk CL, Lawlor PG, et al.: A multicenter study of the revised Edmonton Staging System for classifying cancer pain in advanced cancer patients. J Pain Symptom Manage 29 (3): 224-37, 2005.
  13. Fainsinger RL, Nekolaichuk CL: A "TNM" classification system for cancer pain: the Edmonton Classification System for Cancer Pain (ECS-CP). Support Care Cancer 16 (6): 547-55, 2008.
  14. Allen RS, Haley WE, Small BJ, et al.: Pain reports by older hospice cancer patients and family caregivers: the role of cognitive functioning. Gerontologist 42 (4): 507-14, 2002.
  15. Bruera E, Willey JS, Ewert-Flannagan PA, et al.: Pain intensity assessment by bedside nurses and palliative care consultants: a retrospective study. Support Care Cancer 13 (4): 228-31, 2005.
  16. Jensen MP, Karoly P: Measurement of cancer pain via patient self-report. In: Chapman CR, Foley KM, eds.: Current and Emerging Issues in Cancer Pain: Research and Practice. New York, NY: Raven Press, 1993, pp 193-218.
  17. Hølen JC, Hjermstad MJ, Loge JH, et al.: Pain assessment tools: is the content appropriate for use in palliative care? J Pain Symptom Manage 32 (6): 567-80, 2006.
  18. Fainsinger RL, Fairchild A, Nekolaichuk C, et al.: Is pain intensity a predictor of the complexity of cancer pain management? J Clin Oncol 27 (4): 585-90, 2009.
  19. Mercadante S, Radbruch L, Caraceni A, et al.: Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer 94 (3): 832-9, 2002.
  20. Mystakidou K, Tsilika E, Parpa E, et al.: Exploring the relationships between depression, hopelessness, cognitive status, pain, and spirituality in patients with advanced cancer. Arch Psychiatr Nurs 21 (3): 150-61, 2007.
  21. Spiegel D, Bloom JR: Pain in metastatic breast cancer. Cancer 52 (2): 341-5, 1983.
  22. Daut RL, Cleeland CS: The prevalence and severity of pain in cancer. Cancer 50 (9): 1913-8, 1982.
  23. Schumacher KL, Koresawa S, West C, et al.: The usefulness of a daily pain management diary for outpatients with cancer-related pain. Oncol Nurs Forum 29 (9): 1304-13, 2002.
  24. Rhodes DJ, Koshy RC, Waterfield WC, et al.: Feasibility of quantitative pain assessment in outpatient oncology practice. J Clin Oncol 19 (2): 501-8, 2001.
  25. Hwang SS, Chang VT, Kasimis B: Dynamic cancer pain management outcomes: the relationship between pain severity, pain relief, functional interference, satisfaction and global quality of life over time. J Pain Symptom Manage 23 (3): 190-200, 2002.
  26. Passik SD, Kirsh KL, McDonald MV, et al.: A pilot survey of aberrant drug-taking attitudes and behaviors in samples of cancer and AIDS patients. J Pain Symptom Manage 19 (4): 274-86, 2000.
  27. Kirsh KL, Whitcomb LA, Donaghy K, et al.: Abuse and addiction issues in medically ill patients with pain: attempts at clarification of terms and empirical study. Clin J Pain 18 (4 Suppl): S52-60, 2002 Jul-Aug.
  28. Passik SD, Kirsh KL, Whitcomb L, et al.: A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther 26 (4): 552-61, 2004.
  29. Kaplan R, Slywka J, Slagle S, et al.: A titrated morphine analgesic regimen comparing substance users and non-users with AIDS-related pain. J Pain Symptom Manage 19 (4): 265-73, 2000.
  30. Whitcomb LA, Kirsh KL, Passik SD: Substance abuse issues in cancer pain. Curr Pain Headache Rep 6 (3): 183-90, 2002.

Pharmacologic Management

Basic Principles of Cancer Pain Management

The World Health Organization (WHO) has described a three-step analgesic ladder as a framework for pain management. [1] It involves a stepped approach based on the severity of the pain. If the pain is mild, one may begin by prescribing a Step 1 analgesic such as acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). Potential adverse effects should be noted, particularly the renal and gastrointestinal adverse effects of the NSAIDs. If pain persists or worsens despite appropriate dose increases, a change to a Step 2 or Step 3 analgesic is indicated. Most patients with cancer pain will require a Step 2 or Step 3 analgesic. Step 1 can be skipped in those patients presenting at the onset with moderate-to-severe pain in favor of Step 2 or Step 3. At each step, an adjuvant drug or modality such as radiation therapy may be considered in selected patients. WHO recommendations are based on worldwide availability of drugs and not strictly on pharmacology.

Analgesics should be given “by mouth, by the clock, by the ladder, and for the individual.” [1] This requires regular scheduling of the analgesic, not just as needed. In addition, rescue-doses for breakthrough pain need to be added. The oral route is preferred as long as a patient is able to swallow. Each analgesic regimen should be adjusted for each patient’s individual circumstances and physical condition.

Acetaminophen and Nonsteroidal Anti-inflammatory Drugs

NSAIDs are effective for relief of mild pain and may have an opioid dose–sparing effect that helps reduce side effects when given with opioids for moderate-to-severe pain. Acetaminophen is included with aspirin and other NSAIDs because it has similar analgesic potency, though it lacks peripheral anti-inflammatory activity. [2] Side effects can occur at any time, and patients who take acetaminophen or NSAIDs, especially elderly patients, should be followed carefully. [3] [4] [5] There is growing debate about whether NSAIDs are useful and have significant opioid-sparing effects. One meta-analysis [6] suggests that the usefulness of NSAIDs is limited and that they do not significantly spare opioid doses. Another study suggests that NSAIDs are useful and reduce the need for opioid dose increases; however, only patients with pain progression after 1 week of opioid stabilization were selected for the study. [7]

The coxibs are a subclass of NSAIDs designed to selectively inhibit cyclooxygenase-2 (COX-2). [8] Development of these drugs was based on the hypothesis that COX-2 was the source of prostaglandins E2 and I2, which mediate inflammation, and COX-1 was the source of the same prostaglandins in gastric epithelium, with the potential advantage over traditional NSAIDs of less gastrointestinal ulceration and bleeding and the absence of platelet inhibition. Direct comparisons between COX-2 inhibitors are few. A systematic meta-analysis of COX-2 inhibitors compared with traditional NSAIDs or different COX-2 inhibitors for postoperative pain suggests that rofecoxib, 50 mg, and parecoxib, 40 mg, are equipotent to traditional NSAIDs for postoperative pain after minor and major surgical procedures and have a longer duration of action after dental surgery. Rofecoxib was found to provide superior analgesic effect compared with celecoxib, 200 mg. There were insufficient data to comment on toxicity. [9]

There are three coxibs that were approved by the U.S. Food and Drug Administration (FDA): celecoxib, rofecoxib, and valdecoxib. On September 30, 2004, rofecoxib was withdrawn from the market after a study demonstrated that subjects in a colon cancer prevention trial taking the drug at higher-than-typical doses on a long-term basis had a significant increase in the incidence of serious thromboembolic complications. The question that remains unanswered is whether the increased risk applies to all COX-2 inhibitors, with the caution that the burden of proof rests with those who might claim that this is a problem for rofecoxib alone and does not extend to other coxibs. [8] [10] On April 7, 2005, valdecoxib was withdrawn from the market. FDA is also asking manufacturers of all marketed prescription NSAIDs, including celecoxib (Celebrex) to revise the labeling (package insert) for their products to include a boxed warning, highlighting the potential for increased risk of cardiovascular events and/or the serious, potentially life-threatening gastrointestinal bleeding associated with use of these drugs.

Table 1. Dosing Recommendations for Acetaminophen and NSAIDsa

DrugUsual Dose for Adults and Children ≥50 kg Body WeightUsual Dose for Adults and Childrenb <50 kg Body Weight
Orally Administered Acetaminophen and Over-the-counter NSAIDs
acetaminophenc650 mg q 4 h10–15 mg/kg q 4 h
975 mg q 6 h 15–20 mg/kg q 4 h (rectal) 
aspirind 650 mg q 4 h 10–15 mg/kg q 4 h
975 mg q 6 h 15–20 mg/kg q 4 h (rectal) 
ibuprofen (Motrin, Advil) 400–600 mg q 6 h5–10 mg/kg q 4–6 h
magnesium salicylate (Doan’s, Magan, Mobidin, others)650 mg q 4 h 
naproxen (Naprosyn, Aleve)250–275 mg q 6–8 h5 mg/kg q 8 h
naproxen sodium (Anaprox)275 mg q 6–8 h 
Prescription NSAIDs
carprofen (Rimadyl) 100 mg tid 
choline magnesium trisalicylatee (Trilisate) 1,000–1,500 mg q 6–8 h 25 mg/kg q 6–8 h
choline salicylatee (Arthropan)870 mg q 3–4 h 
diflunisalf (Dolobid) 500 mg q 12 h 
etodolac (Lodine) 200–400 mg q 6–8 h 
fenoprofen calcium (Nalfon)300–600 mg q 6 h 
ketoprofen (Orudis)25–60 mg q 6–8 h 
ketorolac tromethamineg (Toradol) 10 mg q 4–6 h to a maximum of 40 mg/day 
IV administration should not exceed 5 days  
meclofenamate sodiumh (Meclomen) 50–100 mg q 6 h 
mefenamic acid (Ponstel) 250 mg q 6 h 
sodium salicylate (Anacin, Bufferin) 325–650 mg q 3–4 h 
Parenteral NSAIDs
ketorolac tromethamineg, i (Toradol) 60 mg initially, then 30 mg q 6 h  
IV administration should not exceed 5 days  
IV = intravenous; q = every; tid = three times a day.
aOnly the NSAIDs listed here have FDA approval for use as simple analgesics, but clinical experience has also been gained with other drugs.
bAcetaminophen and NSAID dosages for adults weighing less than 50 kg should be adjusted for weight.
cAcetaminophen lacks the peripheral anti-inflammatory and antiplatelet activities of the other NSAIDs.
dThe standard against which other NSAIDs are compared. May inhibit platelet aggregation for longer than 1 week and may cause bleeding. Aspirin is not recommended for pain in children.
eMay have minimal antiplatelet activity.
fAdministration with antacids may decrease absorption.
gUse limited to 5 days or fewer.
hCoombs-positive autoimmune hemolytic anemia has been associated with prolonged use.
iHas the same gastrointestinal toxic effects as oral NSAIDs.

Opioids

Opioids, the major class of analgesics used in management of moderate-to-severe pain, are effective, are easily titrated, and have a favorable benefit-to-risk ratio.

The predictable consequences of long-term opioid administration—tolerance and physical dependence—are often confused with psychological dependence (addiction) that manifests as drug abuse. This misunderstanding can lead to ineffective prescribing, administering, or dispensing of opioids for cancer pain. The result is undertreatment of pain. [11]

Clinicians may be reluctant to give high doses of opioids to patients with advanced disease because of a fear of respiratory depression. Many patients with cancer pain become opioid tolerant during long-term opioid therapy. Therefore, the clinician’s fear of shortening life by increasing opioid doses is usually unfounded.

Opioid types

Opioids are classified as full morphine-like agonists, partial agonists, or mixed agonist-antagonists, depending on the specific receptors to which they bind and their activity at these receptors. The benefits of using opioids and the risks associated with their use vary among individuals.

Morphine is the most commonly used opioid in cancer pain management, largely for reasons of availability and familiarity; [12] however, it is useful to be familiar with more than one type of opioid. Wide interindividual variability in response to both the analgesic and adverse effects of opioids is recognized. [13] Some patients may not experience adequate pain control despite appropriate dose adjustments, while others may develop intolerable adverse effects to one particular opioid (see below). Alternative opioids include hydromorphone, oxycodone, methadone, and fentanyl. Knowledge of several medications and formulations give the caregiver much more flexibility in tailoring a regime to a particular patient’s needs.

Short-acting opioids are generally recommended when opioid therapy is being initiated for the first time or when patients are medically unstable or the pain intensity is highly variable. Once stable, patients can be switched to a controlled-release or slow-release formulation. This is more convenient and promotes compliance. (Refer to Table 3 in the Principles of Opioid Administration section of this summary.)

Principles of opioid administration

Most patients with cancer pain require fixed-schedule dosing to manage the constant pain and prevent the pain from worsening. [53] An Italian study of patients whose baseline pain was well controlled on morphine when admitted to a palliative care unit found that most episodes of breakthrough pain were rapidly controlled with IV morphine equivalent to 20% of the calculated equianalgesic total daily dose. Adverse effects were uncommon. [54] An as-needed rescue dose (breakthrough dose) should be combined with the regular fixed-schedule opioid to control the episodic exacerbation of pain, often referred to as breakthrough pain. When this pain is elicited by an action such as weight-bearing, breathing, or defecation, it is termed incident pain. Rescue or breakthrough doses can be given hourly or more frequently as needed, depending on route of administration, pharmacokinetic properties of the drug, and presence or absence of side effects. The breakthrough dose is generally calculated to be 10% to 20% of the total dose of the fixed schedule. [55] Adherence rates are improved when patients are prescribed around-the-clock opioids compared with as-needed prescribing. [56] Preliminary data suggest that the intensity of incident pain related to bone metastases may be diminished by increasing the dose of the scheduled opioid above that needed for control of baseline pain, while maintaining it below that associated with the development of limiting side effects. [57]

Opioid switching

A series of case reports have demonstrated the clinical problem of inadequate pain control with escalating opioid doses in the presence of dose-limiting toxic effects, including hallucinations, confusion, hyperalgesia, myoclonus, sedation, and nausea. [17] [23] [69] [70] [71] It was suggested that these problems could be managed by switching to an alternative opioid, with the result being improved pain management and decreased toxic effects. The improvement with opioid switching, although predominantly demonstrated initially with morphine, has also been reported with other opioids. [72] [73] [74] [75] A retrospective review over a 1-year period in a pediatric oncology center supports efficacy of this technique in children, with resolution of adverse opioid effects, largely pruritus, achieved in 90% of patients, while maintaining pain control. [76]

Note: The values that appear in Table 3 are NOT recommended starting doses. Opioid doses are highly variable and should be based on the individual’s previous responses and overall condition. Important cautions are contained in the footnotes.

Table 3. Approximate Dose Equivalents for Opioid Analgesicsa

DrugOral Dose (mg)Parenteral Doseb
Morphinec3010 mg
Codeined200100 mg
Fentanyle, fNA100 μg
Hydrocodone (Vicodin)30–45NA
Hydromorphone (Dilaudid)c82 mg
Levorphanol (Levo-Dromoran)42 mg
Methadoneg, hThe conversion ratio of methadone is variable. Please refer to the Opioid Types section and Opioid switching section.
Oxycodone (OxyContin)d20–3010–15 mg
Oxymorphone
 (Opana, Opana ER, and Opana IVc)101 mg
IV = intravenous; NA = not available.
aPublished tables vary in the suggested doses that are equianalgesic to morphine. Many of these doses are based on clinical consensus rather than well-controlled trials. Clinical response is the criterion that must be applied for each patient; titration to clinical response is necessary. Because there is not complete cross-tolerance among these drugs, it is usually necessary to use a lower-than-equianalgesic dose when changing drugs and retitrate according to response.
bParenteral dosing includes IV and subcutaneous administration. Onset and duration may vary slightly between these routes; however, doses remain approximately equal. The intramuscular route is not recommended because of variability in uptake of the drug and painful injection.
cCaution: For morphine, hydromorphone, and oxymorphone, rectal administration is an alternate route for patients unable to take oral medications. Equianalgesic doses may differ from oral to parenteral doses because of pharmacokinetic differences. Note: A short-acting opioid should normally be used for initial therapy of moderate-to-severe pain.
dCaution: Doses of aspirin and acetaminophen in combination opioid/NSAID preparations must be adjusted to the patient’s body weight.
eTransdermal fentanyl is an alternative. Transdermal fentanyl dosage is not calculated as equianalgesic to a single morphine dosage but is calculated based on a 24-hour opioid dose. See package insert for dosing calculations. Transdermal fentanyl should not be used in opioid-naive patients.
fTransmucosal and buccal fentanyl are also available and indicated for breakthrough pain, although they are not bioequivalent. Titration of either should be conducted gradually; neither should be used in opioid-naive patients.
gCaution: Methadone is much more potent than indicated in older published literature. On average, it is ten times more potent than morphine. However, its potency relative to morphine is not linear. When morphine at lower doses (e.g., 30–60 mg/d orally) is switched to methadone, the potency may be 3 to 5 times; when switched from high doses (e.g., >300 mg/d orally), the potency may be 12 times or even higher.
hCaution: The oral to IV dose ratio of methadone is not well established. The IV route is very seldom used, except in cancer centers with pain service familiar with parenteral methadone. Intravenous use of methadone in combination with chlorobutanol is associated with QTc wave prolongation. [37] Subcutaneous administration may cause irritation.

It has been suggested that a less complicated approach than opioid switching would be reassessment of the clinical situation and use of adjuvant analgesics, decreasing the opioid dose if possible, use of medical management for opioid-related side effects, and correction of any contributing metabolic abnormalities. [82] [83] Nevertheless, there does appear to be an emerging consensus that opioid switching does have a useful role when pain control remains inadequate with escalating opioid doses and opioid use results in unacceptable opioid-related side effects. [82] [83] [84]

Morphine, as the strong opioid of choice for the management of cancer pain, was used increasingly during the 1970s and 1980s. [85] Associated with this increasing experience was the clinical observation of the risk of accumulation of morphine metabolites, particularly in the presence of renal impairment. Morphine-6-glucuronide, an analgesic metabolite, was recognized as having a useful role in enhancing analgesia. A number of reports, however, have described seizures, cognitive impairment, nausea, and problems of myoclonus that were associated with accumulation of morphine-6-glucuronide. [85] [86] [87] [88] [89] [90] [91] [92]

The potential role of morphine metabolites, in particular the ratio of 3-glucuronide to 6-glucuronide in the development of opioid-related toxicity, has been reported. The literature on this issue has been somewhat controversial. There is no disagreement that morphine metabolites increase in the presence of deteriorating renal function; however, there has been conflicting evidence regarding the role and ratios of the metabolites in patients exhibiting both a poor response to increasing morphine doses and associated toxicity. [93] [94] [95] [96] [97]

Switching from one opioid to another requires familiarity with a range of opioids and the use of opioid dose-conversion tables. [13] [77] When using these ratios, it must be understood that the guidelines should be reviewed and the patients should be monitored more closely during the switching phase. A recent review has highlighted some important issues related to these tables. [77] Wide ranges in ratios are noted. In the case of methadone, it is much more potent than previously thought (on average ten times more potent), and its equianalgesic dose-ratio compared to other opioids changes according to the dose of the previous opioid; the higher the dose, the higher the ratio. (Note that potency does not denote more effectiveness but denotes the equivalent dose required to obtain the same effect.)

Route of administration

Oral administration is preferred in patients with intact gastrointestinal tracts because it is convenient and usually inexpensive. When patients cannot take oral medications, other less invasive routes (e.g., rectal or transdermal) should be offered. Parenteral methods should be used only when simpler, less demanding, and less costly methods are inappropriate, ineffective, or unacceptable to the patient. In general, assessing the patient’s response to several different oral opioids is advisable before abandoning the oral route in favor of anesthetic, neurosurgical, or other invasive approaches.

Table 4. Advantages and Disadvantages of Intraspinal Drug Administration

System Advantages Disadvantages
Percutaneous temporary catheter Used extensively both intraoperatively and postoperatively. Mechanical problems include catheter dislodgment, kinking, or migration.
Useful when prognosis is limited (<1 month).Increased risk of infection. 
Permanent silicone-rubber epiduralCatheter implantation is a minor procedure. 
Dislodgment and infection less common than with temporary catheters.  
Can deliver bolus injections, continuous infusions, or PCA (with or without continuous delivery).  
Subcutaneous implanted injection port Increased stability, less risk of dislodgment. Implantation more invasive than external catheters.
Can deliver bolus injections or continuous infusions (with or without PCA). Approved only for epidural catheter in United States. 
Potential for infection increases with frequent injections.  
Subcutaneous reservoir Potentially reduced infection in comparison with external system. Difficult to access, and fibrosis may occur after repeated injection.
Implanted pumps (continuous and programmable)Potentially decreased risk of infection. Need for more extensive operative procedure.
Need for specialized equipment with programmable systems.   

Drugs and routes to be avoided

Table 5 and Table 6 present data on drugs and routes of administration not recommended for the management of cancer pain.

Table 5. Drugs To Be Avoided for Treatment of Cancer Pain

ClassDrugRationale for NOT Recommending
Opioids meperidine (Demerol)Short duration (2–3 h) of analgesia.
Repeated administration may lead to CNS toxicity (tremor, confusion, or seizures).  
Opioid agonist-antagonists pentazocine (Talwin), butorphanol (Stadol), nalbuphine (Nubain)Risk of precipitating withdrawal in opioid-dependent patients.
Analgesic ceiling.  
Possible production of unpleasant psychotomimetic effects (e.g., dysphoria, delusions, hallucinations).  
Partial agonistbuprenorphine (Buprenex)Analgesic ceiling.
May precipitate withdrawal.  
Antagonistsnaloxone (Narcan), naltrexone (ReVia)May precipitate withdrawal.
Limit use to treatment of life-threatening respiratory depression. Give in diluted form to opioid-tolerant patients.  
Combination preparationsBrompton's cocktailNo evidence of analgesic benefit to using Brompton's cocktail over single-opioid analgesics.
DPT (meperidine, promethazine, and chlorpromazine)Efficacy is poor compared with that of other analgesics. 
High incidence of adverse effects.  
Anxiolytics alone benzodiazepine (e.g., alprazolam, Xanax; diazepam, Valium; lorazepam, Ativan)Analgesic properties not demonstrated except for some instances of neuropathic pain.
Added sedation from anxiolytics may compromise neurologic assessment in patients receiving opioids.  
Sedative/hypnotic drugs alonebarbiturates, benzodiazepineAnalgesic properties not demonstrated.
Added sedation from sedative/hypnotic drugs limits opioid dosing.  

Table 6. Routes of Administration To Be Avoided for Treatment of Cancer Pain

Routes of AdministrationRationale for Not Recommending
IntramuscularPainful.
Absorption unreliable. 
Should not be used in children or patients prone to develop dependent edema or patients with thrombocytopenia. 
TransnasalThe only drug approved by the FDA for transnasal administration is butorphanol, an agonist-antagonist drug that generally is not recommended. (See opioid agonist-antagonists above.)

Side effects of opioids

Clinicians should anticipate and monitor for side effects. The more common adverse effects include nausea, somnolence, and constipation. These should be discussed with patients before starting opioids. Somnolence and nausea are more often encountered with initiation of opioid treatment but tend to resolve within a few days. Clinicians who follow patients during long-term opioid treatment should watch for potential side effects and manage them as the need arises.

Constipation

Anticipate the constipating effects of analgesics. Opioids compromise gastrointestinal tract peristaltic function (a nearly universal side effect). Consequently, stool within the gut lumen becomes excessively dehydrated. The cornerstone of effective prophylaxis, therefore, is measurement aimed at keeping the patient well hydrated to maintain well-hydrated stool. Unless there are existing alterations in bowel patterns, such as bowel obstruction or diarrhea, all patients using opioids should be started on a laxative bowel regimen and receive education for bowel management. Patients who do not adequately respond to an aggressive regimen with stool softeners may benefit from the addition of mild osmotic agents (e.g., 70% sorbitol solution, lactulose, milk of magnesia), lubricants (e.g., mineral oil), bulk-forming laxatives (e.g., psyllium) with appropriate orally administered hydration, or mild cathartic laxatives (e.g., senna). Stimulant cathartics (e.g., senna, bisacodyl) may be useful in severely constipated patients; however, they may be relatively ineffective in situations in which stool has become desiccated. Opioid-induced constipation is a frequent cause of chronic nausea and is observed in 40% to 70% of patients receiving opioids. [63] It appears to be dose-related, is characterized by large variability in individuals, and is opioid-receptor mediated via both central and peripheral mechanisms. Opioids extend the gastrointestinal transit time and desiccate the intraluminal content. [116] Unlike nausea, complete tolerance to this effect does not generally develop, and most patients require laxative/stool-softener therapy for as long as they take opioids. A plain x-ray of the abdomen may be helpful in assessing the extent of fecal load. [117]

Initiating a regular laxative regimen emphasizes prevention of opioid-induced constipation. Recommendations regarding laxative treatment have been largely based on clinical experiences and observations. Combinations of a sennoside and a stool softener such as docusate are generally suggested. [118] Reports that fentanyl causes less constipation than oral morphine are interesting but need to be confirmed in further prospective studies. [117] [119] [62] A recent study demonstrated decreased laxative use in patients on transdermal fentanyl as compared with patients receiving oral morphine treatment. [62] One meta-analysis has revealed a significant difference in favor of transdermal fentanyl for constipation, although this included only three randomized controlled clinical trials. [120] Whether this decrease in laxative usage is clinically significant, however, and whether the decrease relates to the route of administration instead of the opioid type need to be demonstrated. In a single small series, opioid switching of morphine to methadone resulted in a reduction in constipation. [121] Severe opioid-induced constipation may occur. At an extreme it may be present as a severe ileus and pseudo bowel obstruction. [122] As is the case with opioid-induced nausea and constipation, management relies on the use of gastrointestinal prokinetic agents. The use of orally administered opioid-antagonists such as naloxone is being studied. [123] [124] Although the oral bioavailability of these medications is very limited, opioid withdrawal syndromes have been noted when higher doses have been used. Methylnaltrexone, a quaternary derivative of naltrexone, is an opioid antagonist that does not cross the blood-brain barrier. Preliminary studies suggest that it may be effective when given subcutaneously in the management of opioid-associated constipation without causing opioid withdrawal. [125] [126] [127] (Refer to the PDQ summaries on Gastrointestinal Complications; Nausea and Vomiting; and Nutrition in Cancer Care for more information.)

Nausea and vomiting

Nausea and vomiting occurs in approximately one third to two thirds of patients taking opioids. [128] [129] [130] It is a common complication of early exposure to opioids and usually disappears within the first week of treatment. Appropriate antiemetic coverage during the opioid-initiation phase is usually effective in limiting this adverse effect. Nausea alone does not represent an allergic reaction to the opioid. Occasionally, nausea may be experienced when an opioid dose is significantly increased. An antiemetic should be available on an as-needed basis to address this situation.

Three main mechanisms underlie this opioid-related adverse effect. [131] The predominant mechanism appears to be stimulation of the chemoreceptor trigger zone, where dopamine is the main neurotransmitter. Another is reduced gastrointestinal motility, including delayed gastric emptying. Nausea via increased vestibular sensitivity is uncommon.

Multiple antiemetic regimens have been proposed for the management of opioid-induced emesis, but prospective studies comparing one regimen over another are lacking. [131] Metoclopramide or domperidone are generally recommended as first-line agents because they improve gastrointestinal motility and are antidopaminergic. [131] [132] Metoclopramide can be administered orally or subcutaneously at doses of 10 mg 4 times a day or every 4 hours, depending on the severity of the nausea. Rescue doses should also be ordered on an as-needed basis. Extrapyramidal-related adverse effects are a potential complication of these medications. The incidence of extrapyramidal reactions is low with domperidone, but this drug is not available in a parenteral formulation. The antihistamines act on the histamine receptors in the vomiting center and on vestibular afferents. They are generally reserved for cases in which vestibular sensitivity, often manifesting as motion-induced nausea, is suspected or for cases in which bowel obstruction precludes the use of gastrointestinal prokinetic agents. Haloperidol may also be used under the latter circumstances. The phenothiazines are an alternative group of antiemetics, but extrapyramidal and anticholinergic adverse effects may be dose-limiting. Chlorpromazine has modest antiemetic activity but a high incidence of sedation, postural hypotension, and anticholinergic adverse effects, whereas piperazine derivatives such as prochlorperazine are stronger antiemetics but cause more extrapyramidal side effects. Anticholinergic side effects also limit the use of anticholinergic agents such as hyoscine hydrobromide (scopolamine) in opioid-induced nausea, particularly in patients with advanced cancer. These patients seem to be more vulnerable to these adverse effects. The role of 5-HT3-receptor antagonists such as ondansetron in ameliorating opioid-induced nausea is not clear. [133]

There appear to be differences between individual patients in the extent to which different opioids cause nausea. [134] These differences form the basis for the strategy of switching from one opioid to another when a particular opioid produces persistent nausea. [135] [136] Switching the route, specifically from the oral to the parenteral, has also been suggested, but the study supporting this strategy is small. [137]

Nausea and vomiting can sometimes persist beyond the opioid-initiation phase or occur de novo in patients on long-term opioid treatment. It may become chronic in nature. The multicausal nature of the problem needs to be recognized since management is directed at identifying and addressing the various causes. [138] Chronic nausea has been associated with the accumulation of active opioid metabolites. [91] A number of strategies are suggested to manage chronic nausea, including switching the opioid or decreasing the dose when pain is well controlled. (Refer to the PDQ summary on Nausea and Vomiting for more information.)

Cognitive and other neurotoxic side effects of opioids

Opioid-related neurotoxicity may manifest as cognitive impairment, hallucinations, delirium, generalized myoclonus, hyperalgesia and/or allodynia. Patients who have renal impairment or who are taking higher doses of opioids are at greater risk of developing these side effects. The mechanisms underlying these side effects are unclear, but the opioid metabolites are implicated. When patients present with generalized pain of an unknown source and the opioid dose has been recently increased, hyperalgesia should be considered as a possible diagnosis. [139] [140] The etiological contribution of opioids to cognitive impairment and delirium in the cancer patient is often difficult to determine. This is the case particularly in patients with advanced disease in which the baseline vulnerability is associated with multisystem impairment, and the concurrent administration of other psychotropic agents can complicate the assessment of etiology. Nonetheless, opioid-induced cognitive problems have been reported with increasing frequency in the last decade. [72] [141] [142] In addition to cognitive impairment within the context of delirium, other effects include myoclonus, hyperalgesia, perceptual disturbance, and seizures. [143] Although the remarkable characteristics, potential severity, and impact of delirium contribute to its dominance in the spectrum of opioid-related cognitive dysfunction, more subtle psychomotor and cognitive opioid effects have been described. Neuropsychological testing has been used to study these more-subtle effects in less-advanced cancer disease, [144] chronic nonmalignant pain, [128] [145] and in healthy volunteers. [146] Collectively, studies of neuropsychological testing have demonstrated somewhat mixed findings, [147] with some detecting opioid-associated impairment in certain aspects of psychomotor or cognitive function [145] [146] and others detecting minimal or no impairment. [128] [144] Clinical experience and some studies suggest that patients become tolerant of the sedating effects that accompany either the initiation of opioid therapy or dose increases, [148] thereby allowing patients who are otherwise physically able, and on stable opioid doses, to safely engage in activities such as driving. [144] [149]

Decreased brain cholinergic activity is recognized as one of the potential underlying pathophysiological mechanisms of delirium. [150] [151] [152] In the case of meperidine, the anticholinergic activity associated with its active metabolite normeperidine is suspected to be the basis of the cognitive impairment and delirium occurring in association with this opioid. [153] [154] Other opioid metabolites have been studied in relation to the generation of neuroexcitatory states in animal laboratory models and delirium in human subjects. A series of animal studies have demonstrated neuroexcitatory states in association with morphine metabolites, morphine-3-glucuronide (M-3-G) [155] and normorphine-3-glucuronide, [156] and the hydromorphone metabolite, hydromorphone-3-glucuronide. [157] In a hospice study of 36 patients with advanced cancer receiving morphine, both M-3-G and morphine-6-glucuronide (M-6-G) levels were studied in relation to the development of side effects, which included nausea and vomiting in 10 patients and cognitive impairment in 9 patients. [158] Creatinine levels, and plasma levels of M-3-G, M-6-G, and dose-corrected M-3-G and M-6-G, were higher in the 19 patients with side effects, suggesting that the elevation of morphine metabolites in association with renal impairment was associated with opioid toxicity, including cognitive impairment. Evidence is extensive demonstrating elevation of opioid-metabolite levels in the setting of renal impairment, [90] [97] [158] [159] [160] and some studies have noted an association with features of neurotoxicity, including cognitive impairment. [142] [158] An accumulation of opioid metabolites possibly also occurs during dehydration, which was suggested as a contributory factor in a prospective study of predominantly opioid-related delirium. [161] Switching to another opioid is one strategy for abating the side effects in cases in which accumulation of active metabolites is considered responsible for side effects such as generalized myoclonus, sedation, confusion, or chronic nausea. [26]

Managing cognitive and other neurotoxic effects of opioids

The general management approach to opioid-induced delirium requires a multidimensional assessment to determine the presence of other potentially treatable contributory factors such as dehydration, other centrally acting medications, sepsis, and hypercalcemia. [141] [161] [162] Clinical experience suggests that the presence of tactile hallucinations and myoclonus, [83] although not exclusively associated with opioid toxicity, raise the suspicion of this cause. A careful assessment can also identify prognostic factors associated with greater difficulty in achieving pain control, the need for higher opioid doses, and consequently greater risk of opioid-induced delirium. (Refer to the PDQ summary on Cognitive Disorders and Delirium for further information.) These factors include neuropathic pain, incidental pain, tolerance, somatization of psychological distress, and a positive history of drug or alcohol abuse. [163]

In addition to searching for underlying reversible causes of delirium, the symptomatic management of delirium requires the addition of a neuroleptic agent to control agitation and perceptual or delusional disturbance. Haloperidol is regarded as the drug of choice in this context, [164] and methotrimeprazine and chlorpromazine are considered useful alternatives, [165] [166] especially when a greater level of sedation is required. Midazolam, a sedating and short-acting benzodiazepine given by continuous infusion, is sometimes necessary, especially in the case of nonreversible delirium. [167] Typical anxiolytics, including lorazepam, can be used to manage comorbid anxiety. Early data suggest that some atypical antipsychotics may be beneficial in improving pain control and decreasing opioid requirements in the cancer patient with mild cognitive impairment and/or anxiety. It is unclear whether this benefit is due to a primary effect or to its secondary impact on cognitive impairment and/or anxiety. [168]

The specific management approach to opioid-induced cognitive and other neurotoxic side effects involves either a dose reduction, a change in route, or an opioid switch. [169] If the pain is well controlled, and the cognitive and neurotoxic side effects are not severe, modest opioid dose reduction may be effective. The rationale for switching opioids, commonly referred to as opioid switching, is that a more favorable balance between analgesia and side effects can be achieved, often with a lower dose than that predicted by the conventional analgesic table. [84] [141] [170] This can reflect incomplete cross-tolerance among opioids in relation to analgesic and other effects. [171] It is also possible that switching to a new opioid could allow for the elimination of potentially toxic opioid metabolites. [172] [173] [141] Reduction in opioid dose in the context of an opioid-induced delirium has not been systematically evaluated but is also likely to have beneficial results. Although there is growing evidence to suggest a beneficial role for opioid switching, [172] [174] [136] controversy persists over the relative value of opioid switching versus dose reduction. [82]

Cognitive benefit has been reported with the use of methylphenidate in patients receiving a continuous infusion of opioids for cancer pain. [175] The psychostimulant benefit is likely to relate to mitigation of sedation associated with upward dose titration of opioid. [176] Although psychostimulants have been advocated for hypoactive delirium, [177]any evidence of perceptual or delusional disturbance is considered a contraindication. An open-label study of donepezil, a long-acting selective acetylcholinesterase inhibitor, suggests that it relieves opioid-associated fatigue and sedation in patients who are receiving opioids for cancer pain. [178]

Respiratory depression

Patients receiving long-term opioid therapy generally develop tolerance to the respiratory-depressant effects of these agents. However, concerns about respiratory depression with opioid use remain prevalent among clinicians and patients. Clinicians experienced in end-of-life care recognize that such concerns are generally exaggerated, though empirical research in the area is sparse. One observational study of 30 patients that evaluated the effect of parenteral opioid titration for the control of acute exacerbation of cancer pain showed no association between parenteral opioid titration and hypoventilation at pain control, as measured by change in end-tidal CO2 respiratory rate or oxygen saturation. [179]

When indicated for reversal of opioid-induced respiratory depression, naloxone titrated in small increments or as an infusion should be administered to improve respiratory function without reversing analgesia. The patient should be monitored carefully until the episode of respiratory depression resolves. The opioid antagonists have a short half-life and may have to be given repeatedly until the agonist drug is sufficiently cleared. [180]

Subacute overdose

Perhaps more common than acute respiratory depression, subacute overdose may manifest as slowly progressive (hours to days) somnolence and respiratory depression. Before analgesic doses are reduced, advancing disease must be considered, especially in the dying patient. Generally, withholding one or two doses of an opioid analgesic is adequate to assess whether mental and respiratory depression are opioid related. If symptoms resolve after temporary opioid withdrawal, reduce the scheduled opioid dosage by 25%. If symptoms do not abate, but the patient complains of or exhibits signs of increased pain, or if symptoms referable to opioid withdrawal occur, consider alternative causes for CNS depression and reinstate analgesic treatment. Ongoing assessment is essential to maintain adequate pain relief.

Effects of opioids on sexual function

Reduced libido is a well-known phenomenon for those using heroin or those in a methadone maintenance program; however, clinicians prescribing opioids for pain poorly understand this effect. Early case studies of persons using heroin or methadone described diminished libido, sexual dysfunction, reduced testosterone levels in men, and amenorrhea in women. [181] [182] [183] [184] [185] [186] These effects resolve after the opioid has been discontinued. More recent case reports of patients receiving opioids for relief of chronic pain suggest these same findings. [187] [188] The long-term effects of reduced testosterone and amenorrhea are not well known. Sexuality is an essential component of quality of life in many patients, including patients with advanced disease. [189] Patients should be assessed for changes in libido and sexual dysfunction. If these changes are distressing to the patient, serum testosterone levels may be obtained. Should the patient seek improvement in libido and performance, treatment is often empirical, keeping in mind that there are many potential causes of changes in sexual function. Treatment includes using nonopioids for pain, adding adjuvant analgesics in the hope the opioid dose may be reduced, or replacing testosterone through injections or a patch (if not contraindicated). More research is needed to understand the relationship between opioids and sexual function, as well as the most effective treatment strategies. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.)

Other opioid side effects

Dry mouth, urinary retention, pruritus, dysphoria, euphoria, sleep disturbances, and inappropriate secretion of antidiuretic hormone are less common.

Adjuvant Drugs

Adjuvant drugs are valuable during all phases of pain management to enhance analgesic efficacy, treat concurrent symptoms, and provide independent analgesia for specific types of pain. [190] Adverse drug reactions are common, however, and there are wide interindividual and ethnic differences in drug metabolism. [191] A survey on symptom severity and management in 593 cancer patients treated for an average of 51 days reported that during this time, anticonvulsants were used in 11.8% of patients, antidepressants in 16%, corticosteroids in 28%, and bisphosphonates in 7.3%. [192] Patients with advanced cancer on palliative medicine services are reported to receive on average five medications for symptom relief, and as a result are at high risk of drug interactions. [191] A further note of caution appears in another study that questioned the concept of opioid-sparing effects of co-analgesics. [193] Nevertheless, adjuvant analgesics have been extensively studied and reviewed in noncancer settings and are generally endorsed as an important intervention in the provision of adequate pain management (see Table 7). [194] [195] [196] [197] Few trials compare adjuvant analgesics in the cancer setting.

Table 7. Adjuvant Medications With Possible Analgesic Activity

ClassDrug Daily Dose RangeaStudies Conducted in:
   Cancer PatientsNoncancer Patients
Antidepressants amitriptyline (Elavil) 10–25 mg every day [198] [199] [200]
desipramine (Norpramin) 10–150 mg every day [201] [202] 
maprotiline (Ludiomil) 25 mg bid–50 mg tid  [203] 
duloxetine (Cymbalta)20 mg bid–30 mg bid  [204] 
nortriptyline (Pamelor, Aventyl) 10–100 mg every day  [205] 
venlafaxine (Effexor) 37.5–225 mg every day [206] [207] [208] 
Anticonvulsantscarbamazepine (Tegretol) 100 mg tid–400 mg tid  [209]
valproate (Depacon) 500 mg tid–1,000 mg tid  [210] 
gabapentin (Neurontin) 100 mg tid–1,000 mg tid [211] [212] [213] 
clonazepam (Klonopin) 0.5 mg bid–4 mg bid [214]  
lamotrigine (Lamictal)25 mg bid–100 mg bid  [215] 
pregabalin (Lyrica)150 mg divided into 2 or 3 doses; increase to 300 mg starting at day 3–7; if needed, increase to 600 mg 7 days later  [216] 
Local anestheticsmexiletine (Mexitil) 100 mg bid–300 mg tid  [217]
lidocaine patch (Lidoderm) 5% patch contains 700 mg; one patch, 12 hours on, 12 hours off  [218] 
Corticosteroidsdexamethasone (Decadron) See text  
prednisone See text   
Bisphosphonates clodronate See text  
pamidronate (Aredia) See text   
zoledronic acid (Zometa)See text [219]  
NSAIDsSee the Dosing Recommendations for Acetaminophen and NSAIDs table    
Miscellaneous baclofen (Lioresal) 5 mg tid–20 mg tid  [220]
calcitonin (Calcimar) 100–200 IU (subcutaneous or intranasal)   
clonidine (Catapres) 0.1 mg bid–0.3 mg bid  [221] 
methylphenidate (Ritalin) 2.5 mg bid–20 mg bid [222] [223] 
ketamine (Ketalar) See NMDA Receptor Antagonists section   
bid = twice a day; tid = three times a day.
aStarting doses should incorporate the lowest possible dose.

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Physical and Psychosocial Interventions

Patients should be encouraged to remain active and participate in self-care when possible. Noninvasive physical and psychosocial modalities can be used concurrently with drugs and other interventions to manage pain during all phases of treatment. The effectiveness of these modalities depends on the patient’s participation and communication of which methods best alleviate pain. Minority patients of various ethnicities have been noted to experience worse control of their pain, which may result from miscommunication issues within the medical setting. In a post hoc analysis of a small trial, minority (various ethnicities) (n = 15) and white (n = 52) cancer patients were randomly assigned either to a 20-minute individualized education-and-coaching session regarding pain management (including how to discuss their concerns with their physician) or to usual care. At baseline, minority patients reported significantly more pain than white patients (6.0 vs. 5.0), whereas at follow-up, disparities had been eliminated in the intervention group (4.0 vs. 4.3) but remained in the control group (6.4 vs. 4.7). [1]

Physical Modalities

Generalized weakness, deconditioning, and musculoskeletal pain associated with cancer diagnosis and therapy may be treated by:

Cognitive-Behavioral Interventions

Cognitive-behavioral interventions are an important part of a multimodal approach to pain management. They help the patient obtain a sense of control and develop coping skills to deal with the disease and its symptoms. Guidelines by a National Institutes of Health assessment panel suggest integration of pharmacologic and behavioral approaches for treatment of pain and insomnia. [4] Recent studies suggest that behavioral interventions targeted to specific symptoms, such as pain and fatigue, can significantly reduce symptom burden and improve the quality of life for patients with cancer. [5] Realistic expectations are needed for delivery of cognitive-behavioral interventions. One study [6] of cognitive-behavioral interventions for pain management randomly assigned 57 patients (most of whom were women with metastatic breast cancer who were maintained on daily opioid use for pain) to three 20-minute interventions delivered by audiotape (progressive muscle relaxation [PMR], positive mood induction, or a distraction condition) or to a no-intervention control. The patients were provided the audiotapes by a research nurse, given brief instructions, and asked to use the tapes at least five times a week for 2 weeks; more than half of the patients reported complying with these instructions. The relaxation condition and the “distraction” condition (self-selected informational tapes) produced significant immediate effects on pain, but the positive mood induction tapes showed no effects. The effects, however, neither carried over to general symptom management nor affected pain management at other times. One conclusion of this study is that ideally, interventions should be matched to patient preferences; for more extended effects, additional instruction and support may be needed, as suggested by other studies.

Interventions introduced early in the course of illness are more likely to succeed because they can be learned and practiced by patients while they have sufficient strength and energy. Patients and their families should be given information about and encouraged to try several strategies, and to select one or more of these cognitive-behavioral techniques to use regularly:

References:

  1. Kalauokalani D, Franks P, Oliver JW, et al.: Can patient coaching reduce racial/ethnic disparities in cancer pain control? Secondary analysis of a randomized controlled trial. Pain Med 8 (1): 17-24, 2007 Jan-Feb.
  2. Kutner JS, Smith MC, Corbin L, et al.: Massage therapy versus simple touch to improve pain and mood in patients with advanced cancer: a randomized trial. Ann Intern Med 149 (6): 369-79, 2008.
  3. Robb KA, Newham DJ, Williams JE: Transcutaneous electrical nerve stimulation vs. transcutaneous spinal electroanalgesia for chronic pain associated with breast cancer treatments. J Pain Symptom Manage 33 (4): 410-9, 2007.
  4. Integration of behavioral and relaxation approaches into the treatment of chronic pain and insomnia. NIH Technology Assessment Panel on Integration of Behavioral and Relaxation Approaches into the Treatment of Chronic Pain and Insomnia. JAMA 276 (4): 313-8, 1996 Jul 24-31.
  5. Given B, Given CW, McCorkle R, et al.: Pain and fatigue management: results of a nursing randomized clinical trial. Oncol Nurs Forum 29 (6): 949-56, 2002.
  6. Anderson KO, Cohen MZ, Mendoza TR, et al.: Brief cognitive-behavioral audiotape interventions for cancer-related pain: Immediate but not long-term effectiveness. Cancer 107 (1): 207-14, 2006.
  7. Montgomery GH, Bovbjerg DH, Schnur JB, et al.: A randomized clinical trial of a brief hypnosis intervention to control side effects in breast surgery patients. J Natl Cancer Inst 99 (17): 1304-12, 2007.
  8. Oliver JW, Kravitz RL, Kaplan SH, et al.: Individualized patient education and coaching to improve pain control among cancer outpatients. J Clin Oncol 19 (8): 2206-12, 2001.
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  11. Redinbaugh EM, Baum A, DeMoss C, et al.: Factors associated with the accuracy of family caregiver estimates of patient pain. J Pain Symptom Manage 23 (1): 31-8, 2002.
  12. Aubin M, Vézina L, Parent R, et al.: Impact of an educational program on pain management in patients with cancer living at home. Oncol Nurs Forum 33 (6): 1183-8, 2006.
  13. West CM, Dodd MJ, Paul SM, et al.: The PRO-SELF(c): Pain Control Program--an effective approach for cancer pain management. Oncol Nurs Forum 30 (1): 65-73, 2003 Jan-Feb.
  14. Lin CC, Chou PL, Wu SL, et al.: Long-term effectiveness of a patient and family pain education program on overcoming barriers to management of cancer pain. Pain 122 (3): 271-81, 2006.
  15. Keefe FJ, Ahles TA, Sutton L, et al.: Partner-guided cancer pain management at the end of life: a preliminary study. J Pain Symptom Manage 29 (3): 263-72, 2005.

Antineoplastic Interventions

Radiation therapy, radiofrequency ablation, and surgery are discussed as pain relief measures rather than as cures for primary disease. Chemotherapy may also play a role in management of cancer-associated pain for some malignancies. [1]

Radiation Therapy

Local, half-body, or whole-body radiation enhances the effectiveness of analgesic drug and other noninvasive therapy by directly affecting the cause of pain (i.e., reducing primary and metastatic tumor bulk). [2] Radiation reduces both pain and its interference with function among ambulatory cancer patients with symptomatic bone metastases. [3] Single or multifraction regimens of external-beam radiation therapy are equally effective when radiation is administered for pain relief; however, retreatment is needed more frequently after single-fraction therapy. [4] [5] [6] Dosages must be chosen to achieve a balance between the amount of radiation required to kill tumor cells and that which would adversely affect normal cells or allow the repair of damaged tissue. Pain flare after radiation therapy can occur, but the incidence has not been well documented. A relatively small prospective randomized controlled trial comparing 8 Gy in one fraction to 20 Gy in five fractions reported pain flare in 15 (34%) of 44 patients for a median duration of 3 days. The flare occurred in 10 (44%) of 23 patients in the 8-Gy group and 5 (24%) of 21 patients in the 20-Gy group. [7]

A single intravenous injection of beta particle-emitting agents such as iodine131, phosphorus-32-orthophosphate, and strontium89, as well as the investigational new drugs rhenium186 and samarium153, [8] [9] [10] can relieve pain of widespread bony metastases. Half the patients so treated respond to a second treatment if pain recurs. A prospective multicenter open-label trial of samarium Sm-153 suggests that multiple doses (i.e., more than two) may be administered to patients with advanced cancer and painful multifocal bone metastases with repeated benefit and adequate safety, if pain responds to the initial dose of samarium at week 4 posttreatment and then recurs. [11]

Radiofrequency Ablation

Radiofrequency ablation (RFA) of painful osteolytic bony metastases may provide pain relief. In a nonconsecutive 27-month period, 43 patients from nine sites across the United States and Europe underwent RFA. Of the 43 patients, 41 (95%) experienced a decrease in worst pain (at least 2 points on an 11-point scale) that continued for up to 24 hours. After peaking at week 1, the morphine equivalent daily dose decreased significantly at weeks 8 and 12, before rising again at week 24. Three patients experienced adverse events that included a second-degree skin burn at the grounding pad site, transient bladder and bowel incontinence after treatment of a sacral lesion, and an acetabular fracture 6 weeks after RFA of a lesion involving the ileum, ischium, and acetabulum. Other uncontrolled case reports confirm these findings. [12] Further study to determine potential risks and benefits may be warranted. [13]

Surgery

Curative excision or palliative debulking of a tumor has potential to reduce pain directly, relieve symptoms of obstruction or compression, and improve prognosis, even increasing long-term survival. Oncologic surgeons and other health care providers should be familiar with the interactions of chemotherapy, radiation therapy, and surgical interventions to avoid or anticipate iatrogenic complications. They should also recognize characteristic pain syndromes that follow specific surgical procedures.

References:

  1. Beer TM, Eilers KM, Garzotto M, et al.: Quality of life and pain relief during treatment with calcitriol and docetaxel in symptomatic metastatic androgen-independent prostate carcinoma. Cancer 100 (4): 758-63, 2004.
  2. Salazar OM, Sandhu T, da Motta NW, et al.: Fractionated half-body irradiation (HBI) for the rapid palliation of widespread, symptomatic, metastatic bone disease: a randomized Phase III trial of the International Atomic Energy Agency (IAEA). Int J Radiat Oncol Biol Phys 50 (3): 765-75, 2001.
  3. Wu JS, Monk G, Clark T, et al.: Palliative radiotherapy improves pain and reduces functional interference in patients with painful bone metastases: a quality assurance study. Clin Oncol (R Coll Radiol) 18 (7): 539-44, 2006.
  4. Saarto T, Janes R, Tenhunen M, et al.: Palliative radiotherapy in the treatment of skeletal metastases. Eur J Pain 6 (5): 323-30, 2002.
  5. Hartsell WF, Scott CB, Bruner DW, et al.: Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97 (11): 798-804, 2005.
  6. Foro Arnalot P, Fontanals AV, Galcerán JC, et al.: Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction. Radiother Oncol 89 (2): 150-5, 2008.
  7. Loblaw DA, Wu JS, Kirkbride P, et al.: Pain flare in patients with bone metastases after palliative radiotherapy--a nested randomized control trial. Support Care Cancer 15 (4): 451-5, 2007.
  8. Sartor O, Reid RH, Hoskin PJ, et al.: Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology 63 (5): 940-5, 2004.
  9. Liepe K, Runge R, Kotzerke J: The benefit of bone-seeking radiopharmaceuticals in the treatment of metastatic bone pain. J Cancer Res Clin Oncol 131 (1): 60-6, 2005.
  10. Coronado M, Redondo A, Coya J, et al.: Clinical role of Sm-153 EDTMP in the treatment of painful bone metastatic disease. Clin Nucl Med 31 (10): 605-10, 2006.
  11. Sartor O, Reid RH, Bushnell DL, et al.: Safety and efficacy of repeat administration of samarium Sm-153 lexidronam to patients with metastatic bone pain. Cancer 109 (3): 637-43, 2007.
  12. Locklin JK, Mannes A, Berger A, et al.: Palliation of soft tissue cancer pain with radiofrequency ablation. J Support Oncol 2 (5): 439-45, 2004 Sep-Oct.
  13. Goetz MP, Callstrom MR, Charboneau JW, et al.: Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol 22 (2): 300-6, 2004.

Invasive Interventions

Less-invasive analgesic approaches should precede invasive palliative approaches; however, for a minority of patients in whom behavioral, physical, and drug therapy do not alleviate pain, invasive therapies are useful.

Nerve Blocks

Control of otherwise intractable pain can be achieved by the application of a local anesthetic or neurolytic agent. Nerve blocks are performed for several reasons:

A single injection of a nondestructive agent such as lidocaine or bupivacaine, alone or in combination with an anti-inflammatory corticosteroid for a longer-lasting effect, can provide local relief from nerve or root compression. Placement of an infusion catheter at a sympathetic ganglion extends the sympathetic blockade from hours to days or weeks. Destructive agents such as ethanol or phenol can be used to effect neurolysis at sites identified by local anesthesia as appropriate for permanent pain relief and may also be used to cause destruction of central nervous system structures. The efficacy of neurolytic sympathetic blocks may vary depending on the underlying pain mechanisms involved. For patients with multiple pain mechanisms, neurolytic sympathetic blocks may serve as adjuvant techniques to analgesic medications. [1]

Neurologic Interventions

Neurosurgery can be performed to implant devices to deliver drugs or to electrically stimulate neural structures. Surgical ablation of pain pathways should, like neurolytic blockade, be reserved for situations in which other therapies are ineffective or poorly tolerated. In general, the choice of neurosurgical procedure is based on location and type of pain (somatic, visceral, deafferentation), the patient’s general condition and life expectancy, and the expertise and follow-up available.

Management of Procedural Pain

Many diagnostic and therapeutic procedures are painful to patients. Treat anticipated procedure-related pain prophylactically and integrate pharmacologic and nonpharmacologic interventions in a complementary style.

Use local anesthetics and short-acting opioids to manage procedure-related pain, allowing adequate time for the drug to achieve full therapeutic effect. Anxiolytics and sedatives may be used to reduce anxiety or to produce sedation.

Cognitive-behavioral interventions, such as imagery or relaxation, are useful in managing procedure-related pain and anxiety. (Refer to the Cognitive-Behavioral Interventions section of this summary for examples of relaxation exercises.) Patients generally tolerate procedures better when they are informed of what to expect.

Offer the option for a relative or friend to accompany the patient for support.

References:

  1. Mercadante S, Fulfaro F, Casuccio A: Pain mechanisms involved and outcome in advanced cancer patients with possible indications for celiac plexus block and superior hypogastric plexus block. Tumori 88 (3): 243-5, 2002 May-Jun.

Discharge Planning

Patients and families may have difficulty remembering details of the pain management plan and should be given a written pain-management plan. The patient and family should receive clear instructions regarding telephone contact for more urgent questions relating to pain management.

Treating Elderly Patients

Like other adults, older patients require comprehensive assessment and aggressive management of cancer pain. Older patients are at risk for undertreatment of pain, however, because of underestimation of their sensitivity to pain, the expectation that they tolerate pain well, and misconceptions about their ability to benefit from the use of opioids. Issues in assessing and treating cancer pain in older patients include:

Current Clinical Trials

Check NCI’s PDQ Cancer Clinical Trials Registry for U.S. supportive and palliative care trials about pain that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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For more information from the NCI, please write to this address:

Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).

Changes to This Summary (10/02/2009)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Pain Assessment

Added text on pain intensity (cited Fainsinger et al. as reference 18).

Pharmacologic Management

Added De Conno et al. as reference 59.

Antineoplastic Interventions

Added Foro Arnalot et al. as reference 6.

Questions or Comments About This Summary

If you have questions or comments about this summary, please send them to Cancer.gov through the Web site’s Contact Form. We can respond only to email messages written in English.

More Information

About PDQ

Additional PDQ Summaries

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Date last modified: 2009-10-02

Sponsors:
The following organisations have financed parts of our PhD research project on improving the quality of online cancer information.

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Dr. G. Quade
This page was last modified on Tuesday, 17-Nov-2009 16:38:46 CET
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