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:

• Initiate prophylactic anticonstipation measures in all patients (except those with diarrhea) before or during opiate administration. (Refer to the Constipation section in the Side Effects of Opioids section of this summary for more information.)
• Discuss pain and its management with patients and their families.
• Encourage patients to be active participants in their care.
• Reassure patients who are reluctant to report pain that there are many safe and effective ways to relieve pain.
• Consider the cost of proposed drugs and technologies.
• Share documented pain assessment and management with other clinicians treating the patient.
• Know state/local regulations for controlled substances.

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials for 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 website.

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. [PubMed: 11343734]
2. Pachman DR, Barton DL, Swetz KM, et al.: Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain. J Clin Oncol 30 (30): 3687-96, 2012. [PubMed: 23008320]
3. 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. [PubMed: 11514084]
4. 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. [PubMed: 12902440]
5. Breivik H, Cherny N, Collett B, et al.: Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes. Ann Oncol 20 (8): 1420-33, 2009. [PubMed: 19244085]
6. Sun V, Borneman T, Piper B, et al.: Barriers to pain assessment and management in cancer survivorship. J Cancer Surviv 2 (1): 65-71, 2008. [PMC free article: PMC2556887] [PubMed: 18648988]
7. 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. [PubMed: 15480817]
8. Rustøen T, Valeberg BT, Kolstad E, et al.: The PRO-SELF(©) Pain Control Program improves patients' knowledge of cancer pain management. J Pain Symptom Manage 44 (3): 321-30, 2012. [PubMed: 22704056]
9. 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. [PubMed: 12001130]
10. 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. [PubMed: 11731509]
11. 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. [PubMed: 16965886]
12. 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. [PMC free article: PMC2742681] [PubMed: 12145378]
13. 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. [PubMed: 12967730]

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.[8][Level of evidence: II] 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.[9][Level of evidence: IV] The following are essential to the initial assessment:

• Detailed medical and pain history.
• Physical examination.
• Psychosocial and spiritual assessment.[10][Level of evidence: IV]
• History of substance abuse in patient and family.
• Diagnostic evaluation.

The experience of cancer pain is complex and includes physical, psychosocial, and spiritual dimensions. There is no universally accepted pain classification measure that assists 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 as 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.[11,12] This system has been further refined in two reports that have gathered construct validity evidence using an international panel of content experts [13] and a multicenter study to determine interrater reliability and predictive value.[14] 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.[15][Level of evidence: II]

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.[16,17][Level of evidence: II] 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%).[18][Level of evidence: III]

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.[19,20][Level of evidence: IV] 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.[21][Level of evidence: II] 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:

Pain

• Listen to the patient’s descriptive words about the quality of the pain; these provide valuable clues to its etiology. Elicit the temporal features including onset, duration, and diurnal variation. Ask about breakthrough pain (BP) or episodic pain (EP) (a transitory increase in pain that occurs in addition to persistent pain). Some patients may have EP without persistent pain.[22][Level of evidence: IV] The prevalence of BP-EP varies widely, depending on which definition is used and based on the clinical scenario and cultural setting. An appropriately designed, cross-sectional, multicenter study that evaluated BP-EP in patients with chronic cancer-related pain was completed.[23] The primary aim of the study was to assess the prevalence and characteristics of BP-EP on the basis of clinical assessment and through the use of a previously validated, culturally adapted tool, the Questionnaire for Intense Episodic Pain (QUDEI-Italian), which utilizes a patient interview technique. Physicians who participated in the study were trained to define and recognize BP-EP. Patient evaluation and use of the questionnaire were carried out by different sets of providers. There was an estimated prevalence of 73% when a BP-EP diagnosis was made by physicians and 66% when the QUDEI was applied. When patients with baseline pain levels of 6 or lower (based on a numerical rating scale from 0 to 10) were analyzed, the physician prevalence decreased to 67%, versus 60% with tool utilization. The authors concluded that because of the frequent occurrence of BP-EP, a more widely accepted general definition of this phenomenon and specific validated tools to assist in education and screening are needed.[23]

Location

• Ask the patient to indicate the exact location of the pain on his or her body, or on a body diagram, and whether the pain radiates.

Changes in Pattern

• Changes in pain pattern or the development of new pain should trigger diagnostic reevaluation and modification of the treatment plan. Persistent pain indicates the need to consider other etiologies (e.g., related to disease progression or treatment) and alternative (perhaps more invasive) treatments.

Intensity or Severity

• Encourage the patient to keep a log of pain-intensity scores to report during follow-up visits or by telephone. Examples of simple self-report pain-intensity scales include the simple, descriptive, numeric, and visual analog scales.

Aggravating and Relieving Factors

• Ask the patient to identify factors that cause the most pain and also what relieves the pain.

Cognitive Response to Pain

• Cognitive appraisals of pain can be based on a range of psychological variables such as perceived control, meaning attributed to pain experience, fear of death, and hopelessness.[24] All these variables appear to contribute to the experience of cancer pain and suffering. A study of women with metastatic breast cancer found that although the site of metastasis did not predict the intensity of pain report, greater depression and the belief that pain represented the spread of disease significantly predicted the degree of pain experienced.[25] It was also reported that patients who thought that their pain represented disease progression reported more pain-related interference with function.[26][Level of evidence: II]

Cognitive Impairment

• Note behavior that suggests pain in patients who are cognitively impaired or who have communication problems relating to education, language, ethnicity, or culture. Cognitive impairment itself and the degree of cognitive impairment may impact patient self-report of pain. Preliminary data suggest that mild degrees of cognitive impairment are associated with increased intensity of pain-report in older patients with cancer who are receiving hospice care.[16] In contrast, cognitively impaired nursing home residents are less likely to report pain. Use appropriate (e.g., simpler or translated) pain assessment tools.

Goals for Pain Control

• Document the patient’s preferred pain assessment tool and the goals for pain control (such as scores on a pain scale).
• Encourage use of the pain diary: The daily pain diary is a well-established tool in symptom management research and in clinical practice. Benefits of using a pain diary include heightened awareness of pain, guidance for pain management behaviors, enhanced sense of control, and a tool for communication.[27] It is difficult to get good pain-diary compliance with adolescents who are experiencing intense chronic pain.

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.

Information obtained from the synthesis of history, physical examination, and diagnostic evaluations is used to generate a pain diagnosis with respect to etiology (cancer, its treatment, or other) and pathophysiology (somatic, visceral, and/or neuropathic). This diagnosis, in conjunction with contributing psychosocial and spiritual factors, is used to generate a comprehensive pain treatment plan.

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.[28,29]

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, remain unclear.[30-32]

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 required and tolerated substantially higher morphine doses to achieve stable pain control.[33][Level of evidence: II] This study should increase confidence in providing appropriate pain management to patients who have a history of drug use.[34][Level of evidence: IV]

References

1. Yennurajalingam S, Kang JH, Hui D, et al.: Clinical response to an outpatient palliative care consultation in patients with advanced cancer and cancer pain. J Pain Symptom Manage 44 (3): 340-50, 2012. [PubMed: 22699092]
2. Chung JW, Wong TK, Yang JC: The lens model: assessment of cancer pain in a Chinese context. Cancer Nurs 23 (6): 454-61, 2000. [PubMed: 11128124]
3. 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. [PubMed: 8951920]
4. Greenwald HP: Interethnic differences in pain perception. Pain 44 (2): 157-63, 1991. [PubMed: 2052381]
5. Bates MS, Edwards WT, Anderson KO: Ethnocultural influences on variation in chronic pain perception. Pain 52 (1): 101-12, 1993. [PubMed: 8446431]
6. 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. [PubMed: 15605922]
7. Mañas A, Monroy JL, Ramos AA, et al.: Prevalence of neuropathic pain in radiotherapy oncology units. Int J Radiat Oncol Biol Phys 81 (2): 511-20, 2011. [PubMed: 20832183]
8. 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. [PubMed: 17006114]
9. Mercadante S, Portenoy RK: Opioid poorly-responsive cancer pain. Part 1: clinical considerations. J Pain Symptom Manage 21 (2): 144-50, 2001. [PubMed: 11226765]
10. 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. [PubMed: 12027971]
11. Bruera E, MacMillan K, Hanson J, et al.: The Edmonton staging system for cancer pain: preliminary report. Pain 37 (2): 203-9, 1989. [PubMed: 2748193]
12. 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. [PubMed: 7673767]
13. 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. [PubMed: 16218159]
14. 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. [PubMed: 15781173]
15. 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. [PubMed: 18320239]
16. 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. [PMC free article: PMC2742681] [PubMed: 12145378]
17. Black B, Herr K, Fine P, et al.: The relationships among pain, nonpain symptoms, and quality of life measures in older adults with cancer receiving hospice care. Pain Med 12 (6): 880-9, 2011. [PMC free article: PMC3117028] [PubMed: 21539700]
18. 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. [PubMed: 15480817]
19. 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.
20. 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. [PubMed: 17157759]
21. 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. [PubMed: 19103733]
22. 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. [PubMed: 11857319]
23. Caraceni A, Bertetto O, Labianca R, et al.: Episodic (breakthrough) pain prevalence in a population of cancer pain patients. Comparison of clinical diagnoses with the QUDEI--Italian questionnaire for intense episodic pain. J Pain Symptom Manage 43 (5): 833-41, 2012. [PubMed: 22560355]
24. 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. [PubMed: 17556108]
25. Spiegel D, Bloom JR: Pain in metastatic breast cancer. Cancer 52 (2): 341-5, 1983. [PubMed: 6861077]
26. Daut RL, Cleeland CS: The prevalence and severity of pain in cancer. Cancer 50 (9): 1913-8, 1982. [PubMed: 7116316]
27. 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. [PubMed: 12370700]
28. 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. [PubMed: 11208844]
29. 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. [PubMed: 11888717]
30. 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. [PubMed: 10799794]
31. 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. [PubMed: 12479254]
32. 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. [PubMed: 15189752]
33. 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. [PubMed: 10799793]
34. Whitcomb LA, Kirsh KL, Passik SD: Substance abuse issues in cancer pain. Curr Pain Headache Rep 6 (3): 183-90, 2002. [PubMed: 12003688]

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 favor of Step 2 or Step 3 in patients presenting at the onset with moderate-to-severe pain. 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 the 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][Level of evidence: I] Side effects can occur at any time, and patients who take acetaminophen or NSAIDs, especially elderly patients, should be followed up carefully.[3-5] 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][Level of evidence: I] Patients taking NSAIDs are at risk for platelet dysfunction that may impair blood clotting. Table 1 lists NSAIDs with minimal antiplatelet activity.

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 that COX-1 was the source of the same prostaglandins in gastric epithelium, with the potential advantage of less gastrointestinal ulceration and bleeding and the absence of platelet inhibition over traditional NSAIDs. 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][Level of evidence: I]

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 who took 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.

Dosage

• Use patient response to determine the effective dosing interval for aspirin, acetaminophen, and other NSAIDs listed in Table 1. When pain relief is not attained with the maximum dosage of one NSAID, try other drugs within this category before abandoning NSAID therapy.

Route of administration

• Use readily available oral tablets, capsules, or liquid. During intervals of nausea and vomiting, use suppositories, unless the nausea is NSAID related. Ketorolac tromethamine is the only NSAID available for parenteral use.

Contraindications

• Patients taking NSAIDs are at risk of platelet dysfunction that may impair blood clotting. Table 1 lists NSAIDs with minimal antiplatelet activity.

Other side effects

• Observe patients carefully for adverse effects, which range from mild gastrointestinal discomfort to more serious problems, including the following:

  -

  Gastric ulceration.

  -

  Hepatic dysfunction.

  -

  Myocardial infarction.

  -

  Renal failure.

  Because both NSAIDs and other drugs (e.g., warfarin, methotrexate, digoxin, cyclosporine, oral antidiabetic agents, and sulfonamide-containing drugs) are highly protein-bound, there is potential for altered efficacy or toxicity when they are given simultaneously.

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.

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.[199][Level of evidence: IV] Adverse drug reactions are common, however, and there are wide interindividual and ethnic differences in drug metabolism.[200][Level of evidence: IV] 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%.[201][Level of evidence: III] 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.[200] A further note of caution appears in another study that questioned the concept of opioid-sparing effects of co-analgesics.[202][Level of evidence: III] 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).[203-206][Level of evidence: IV] Few trials compare adjuvant analgesics in the cancer setting. Not all analgesic agents have been shown to provide clinical benefit when used in conjunction with opioids. In a dose escalation, double-blind, randomized placebo-controlled phase III trial of ketamine in patients with uncontrolled pain on opioids, delivered subcutaneously over 3 to 5 days, versus placebo, there was no difference noted in pain response between arms. There was almost twice the incidence of adverse effects in the ketamine group than was in the placebo arm.[207][Level of evidence: I]

Antidepressants

• The analgesic benefits of tricyclic antidepressants have been well established and are generally considered first-line therapy for many neuropathic pain syndromes.[203-206,234][Level of evidence: IV] Supporting evidence is strong for amitriptyline and desipramine, and there is endorsement of other newer antidepressants such as maprotiline and paroxetine. Patients with neuropathic pain characterized by continuous dysesthesias are generally believed to be the most likely to benefit from antidepressant management; however, a randomized placebo-controlled study of amitriptyline for neuropathic pain in cancer patients found only slight analgesic benefit with significantly worse adverse effects.[209][Level of evidence: I]
• The most common side effects of tricyclic antidepressants are the following:

  -

  Constipation.

  -

  Dry mouth.

  -

  Blurred vision.

  -

  Cognitive changes.

  -

  Tachycardia.

  -

  Urinary retention.

  Caution has also been advised in treating patients with cardiac disease, and an electrocardiogram is sometimes recommended as a prudent measure. A slow upward titration is suggested as a good way to avoid side effects.[216][Level of evidence: I]

Anticonvulsants

• The group of commonly used anticonvulsants as adjuvant analgesics for neuropathic pain includes carbamazepine, valproate, phenytoin, and clonazepam.[203-206,234][Level of evidence: IV]
  Clinical experience with carbamazepine is extensive, but use of this drug is limited in the cancer population because of concern that it causes bone marrow suppression, in particular leukopenia. Other common adverse effects include nystagmus, dizziness, diplopia, cognitive impairment, and mood and sleep disturbance.
  Dosing guidelines for phenytoin are similar to those for the treatment for seizures.[203] This drug can be administered using a loading dose, which may be particularly useful in patients with severe pain.
  Gabapentin is increasingly reported as useful for the management of neuropathic pain associated with cancer and its treatment.[221][Level of evidence: I];[222,235][Level of evidence: II];[236][Level of evidence: III];[237,238][Level of evidence: IV] Commonly reported side effects include somnolence, dizziness, ataxia, and fatigue.[206,236] One randomized open-label trial of gabapentin combined with an opioid (n = 38) versus an opioid alone (n = 37) for the management of neuropathic cancer pain suggests that the combination group achieved better relief than those receiving opioid monotherapy.[239][Level of evidence: I]
  Clonazepam is an anticonvulsant from the benzodiazepine class and is commonly used for treating lancinating or paroxysmal neuropathic pain.[203] The patient must be monitored carefully for drowsiness and cognitive impairment.

Local anesthetics

• The use of mexiletine has been described for chronic neuropathic pain.[203,204,206] Side effects are reported as common and include gastrointestinal toxicity, in particular nausea, and CNS side effects such as dizziness. Patients with a history of cardiac disease and those on higher doses are at increased risk of adverse effects, and it is recommended that they receive appropriate cardiac evaluation, including an electrocardiogram.

Corticosteroids

• These drugs have achieved wide acceptance in the management of patients with cancer pain. They are indicated as adjuvant analgesics for cancer pain of bone, visceral, and neuropathic origin. Adverse effects include neuropsychiatric syndromes, gastrointestinal disturbances, proximal myopathy, hyperglycemia, aseptic necrosis, capillary fragility, and immunosuppression. The risk of adverse effects increases with the duration of use. As a result, use is often restricted to patients with a limited life expectancy; in addition, once effective pain control is obtained, it is commonly recommended that the dose be tapered as much as possible. Dosage recommendations vary from a trial of low-dose therapy such as dexamethasone 1 to 2 mg or prednisone 5 to 10 mg once or twice daily,[203] to a starting dose of dexamethasone 10 mg twice daily with subsequent tapering to the minimal effective dose.[240]
  Another suggested use of corticosteroids is in high doses for short periods in patients with severe pain. This empirical approach recommends a regime of a single bolus of dexamethasone 100 mg IV followed by a small amount given 4 times per day and then tapered over the next few weeks.[203]
  Although there is widespread acceptance of steroid therapy, mostly via the oral route but also subcutaneously and intravenously, data remain inadequate for definitive conclusions regarding efficacy and dosing guidelines.[241][Level of evidence: I];[203];[205,206,240,242-245][Level of evidence: IV]

Bisphosphonates

• These drugs have been recommended for the management of bone pain as well as the prevention of skeletal complications in patients with metastatic bone disease.[246][Level of evidence: II];[203];[204-206,247-249][Level of evidence: IV] Their use in a study of breast cancer patients resulted in improved quality of life compared with that of patients not using bisphosphonates.[250][Level of evidence: I] The bisphosphonates most frequently used are clodronate, pamidronate,[251] and zoledronic acid.[252][Level of evidence: I]
• Clodronate can be given orally or intravenously. Dosage recommendations are oral clodronate, 1,600 mg/d; or IV clodronate, 600 to 1,500 mg every 2 to 3 weeks. Clodronate is not available in the United States.
• Pamidronate has been recommended in the dose range of 60 to 90 mg IV over 2 hours every 3 to 4 weeks; however, pooled results from two multicenter, double-blind, randomized, placebo-controlled trials (n = 350) using pamidronate (90 mg every 3 weeks) failed to demonstrate a benefit for bone pain.[253][Level of evidence: I]
• Zoledronic acid is a potent bisphosphonate that can be given as an IV bolus over 15 to 30 minutes in the dose range of 4 to 8 mg; however, the 8-mg dose has been associated with deterioration of renal function.[254-257][Level of evidence: I] The few studies to date suggest administration at 3- to 4-week intervals.[258][Level of evidence: IV]
• Ibandronate can be given orally or intravenously. Dosing recommendations are 50 mg orally daily or 6 mg intravenously every 3 to 4 weeks.[259][Level of evidence: I]
• Denosumab is a monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL), which is a form of the tumor necrosis factor superfamily. RANKL inhibition prevents osteoclast development and activation, resulting in decreased bone resorption, increased bone density, and reduction in the risk of fractures.[260]
• The FDA has highlighted the possibility of severe and sometimes incapacitating bone, joint, and/or muscle pain in patients who are taking bisphosphonates. The musculoskeletal pain may occur within days, months, or years after starting treatment with a bisphosphonate. This pain contrasts with the acute-phase response characterized by fever, chills, bone pain, myalgias, and arthralgias that may sometimes accompany initial administration of intravenous bisphosphonates. The FDA recommends that bisphosphonates be considered a possible cause of severe musculoskeletal pain in patients who present with these symptoms, and health care professionals should consider temporary or permanent discontinuation of the drug. The risk factors and the incidence of the association of this musculoskeletal pain with bisphosphonates remain unknown.[261]
• The use of bisphosphonates carries a risk of developing bisphosphonate-associated osteonecrosis (BON). (Refer to the Oral Toxicities Not Related to Chemotherapy or Radiation Therapy section in the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation for more information.)

Miscellaneous

• Baclofen

  -

  This drug is generally used for spasticity but may also be used for the treatment of neuropathic pain.[203,204,206][Level of evidence: IV] Side effects include drowsiness, dizziness, ataxia, confusion, and nausea and vomiting.

• Calcitonin

  -

  Although the mechanism by which calcitonin produces analgesia is unknown, historically it has been recommended for the treatment of both bone and neuropathic pain.[203,204,206,247,248] However, a systematic review of randomized double-blind clinical trials assessing the efficacy of calcitonin for control of metastatic bone pain does not support its use.[262][Level of evidence: IV] Because only two of these studies were evaluated as well designed, further research is necessary. The utility of calcitonin for bone pain is unclear.

• Clonidine

  -

  This traditional antihypertensive can be given via the oral, epidural, or transdermal route and has been recommended as a trial for the management of neuropathic pain. Reported side effects include dry mouth, dizziness and hypotension, sedation, and constipation.[203,204,206][Level of evidence: IV] The maximum recommended dose is 2.4 mg/d.

• Psychostimulants

  -

  Psychostimulants such as dextroamphetamine, methylphenidate, and modafinil may enhance the analgesic effects of opioids.[184][Level of evidence: I];[185][Level of evidence: II];[205][Level of evidence: IV] They may also be used to diminish opioid-induced sedation when reducing the dose is not possible.

• NMDA Receptor Antagonists

  -

  There is increasing evidence for the importance of NMDA receptors and the possibility that NMDA antagonists may have a role in refractory cancer pain management.[203,263][Level of evidence: III] Ketamine in subanesthetic doses has been used in this setting.[264][Level of evidence: II] The severe psychomimetic adverse effects associated with this treatment, including vivid hallucinations, limit widespread use of ketamine. Coadministration of a neuroleptic or benzodiazepine is recommended to limit the emergence of these effects. Ketamine is generally given subcutaneously at a low starting dose such as 0.1 mg per kg of body weight per hour, with a gradual escalation. Oral ketamine may be a more potent analgesic and have a more favorable side-effect profile than parenteral ketamine.[249][Level of evidence: IV] One study suggests short-duration therapy of a continuous subcutaneous infusion of ketamine over 3 to 5 days. The initial dose is 100 mg/d; if pain control is inadequate, the dose is escalated to 300 mg/d and then to a maximum dose of 500 mg/d. Treatment is continued for 3 days at either the lowest effective dose or 500 mg/d and then discontinued.[263] A systematic review of the benefits and harms of ketamine in managing cancer pain revealed a general lack of studies and small subject numbers,[265,266][Level of evidence: IV] precluding a definitive conclusion on benefits and harms.

  -

  Methadone, particularly the racemic mixture, appears to have significant NMDA-antagonist properties.[267] The d-isomer blocks the NMDA receptor and as a result may yield independent analgesic effects and perhaps reverse some analgesic tolerance to the opioid.[268][Level of evidence: II] This may explain the often-unanticipated high potency of methadone.

  -

  Dextromethorphan (DM), a commonly prescribed antitussive, may also have NMDA-blocking properties.[268][Level of evidence: II] The clinical significance of this effect, however, is unclear and studies have not been able to determine at what dose these effects may manifest. Oral DM in doses of 60 or 90 mg given preoperatively and postoperatively has been shown to reduce pain intensity and opioid use after orthopedic oncology surgery.[269,270][Level of evidence: I] A randomized, double-blind, placebo-controlled study of 65 patients evaluated the efficacy and safety of DM or placebo with slow-release morphine. The dose of DM was 60 mg 4 times daily, increased after 7 days to 120 mg 4 times daily if tolerated. While the DM group showed somewhat more improvement than the placebo group, the differences were not significant; furthermore, the DM group experienced more toxic effects, particularly dizziness.[271][Level of evidence: I] The authors concluded that DM does not enhance opioid analgesia or modulate opioid tolerance enough in cancer patients to warrant continued use.

• Octreotide

  -

  Data from a case series of 16 patients with symptomatic hepatic metastases from a variety of nonneuroendocrine primary sites suggest that octreotide palliates pain and improves a variety of quality-of-life indices as measured by the EORTC QLQ-C30 questionnaire.[272][Level of evidence: II]

Under Investigation

• Tetrodotoxin

  -

  A randomized, placebo-controlled study of subcutaneous tetrodotoxin was carried out on 77 cancer patients across 22 centers in Canada. While results did not achieve statistical significance, there was a trend toward improved pain control. This drug remains experimental and is not commercially available.[273][Level of evidence: I]

• Cannabinoids

  -

  Cannabis contains more than 60 cannabinoids and has been proposed as a potentially useful treatment for cancer-related pain. A multicenter, double-blind, randomized, placebo-controlled study included 177 cancer patients in a trial of an endocannabinoid system modulator. Positive analgesic effects were observed and merit further study.[274][Level of evidence: I] Another randomized, double-blind, placebo-controlled, graded-dose study was conducted in patients with advanced cancer who had opioid-refractory pain.[275] Patients received either placebo or nabiximols (a cannabinoid formulation) intranasally; nabiximols consisted of 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD) per 100-μL spray. Patients were randomly assigned to low-dose (2.7–10.8 mg THC and 2.5–10 mg CBD), medium-dose (16.2–27 mg THC and 15–25 mg CBD), or high-dose (29.7–43.2 mg THC and 27.5–40 mg CBD) levels and were assigned to placebo or active drug within each dose group. A total of 263 patients completed the study, which measured average pain, worst pain, sleep disturbance, and other quality-of-life issues. There was no significant difference in the 30% responder rate, which was the primary analysis. However, in a continuous responder analysis evaluating average daily pain from baseline to end of study, there was a statistically significant greater analgesia for nabiximols (P < .05) versus placebo overall, specifically in the low- and medium-dose groups. Only the high-dose group compared unfavorably with placebo because of adverse events. The authors concluded that nabiximols may be a useful adjunct in treating opioid-refractory pain.[275]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials for 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 website.

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253. Small EJ, Smith MR, Seaman JJ, et al.: Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 21 (23): 4277-84, 2003. [PubMed: 14581438]
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256. Rosen LS, Gordon D, Tchekmedyian S, et al.: Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial--the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21 (16): 3150-7, 2003. [PubMed: 12915606]
257. Saad F, Gleason DM, Murray R, et al.: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94 (19): 1458-68, 2002. [PubMed: 12359855]
258. Neville-Webbe H, Coleman RE: The use of zoledronic acid in the management of metastatic bone disease and hypercalcaemia. Palliat Med 17 (6): 539-53, 2003. [PubMed: 14526888]
259. Body JJ, Diel IJ, Bell R, et al.: Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Pain 111 (3): 306-12, 2004. [PubMed: 15363874]
260. Smith MR, Egerdie B, Hernández Toriz N, et al.: Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361 (8): 745-55, 2009. [PMC free article: PMC3038121] [PubMed: 19671656]
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262. Martinez MJ, Roqué M, Alonso-Coello P, et al.: Calcitonin for metastatic bone pain. Cochrane Database Syst Rev (3): CD003223, 2003. [PubMed: 12917954]
263. Jackson K, Ashby M, Martin P, et al.: "Burst" ketamine for refractory cancer pain: an open-label audit of 39 patients. J Pain Symptom Manage 22 (4): 834-42, 2001. [PubMed: 11576800]
264. Lossignol DA, Obiols-Portis M, Body JJ: Successful use of ketamine for intractable cancer pain. Support Care Cancer 13 (3): 188-93, 2005. [PubMed: 15480820]
265. Bell R, Eccleston C, Kalso E: Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev (1): CD003351, 2003. [PubMed: 12535471]
266. Bell RF, Eccleston C, Kalso E: Ketamine as adjuvant to opioids for cancer pain. A qualitative systematic review. J Pain Symptom Manage 26 (3): 867-75, 2003. [PubMed: 12967737]
267. Shimoyama N, Shimoyama M, Elliott KJ, et al.: d-Methadone is antinociceptive in the rat formalin test. J Pharmacol Exp Ther 283 (2): 648-52, 1997. [PubMed: 9353381]
268. Elliott K, Hynansky A, Inturrisi CE: Dextromethorphan attenuates and reverses analgesic tolerance to morphine. Pain 59 (3): 361-8, 1994. [PubMed: 7708410]
269. Weinbroum AA, Gorodetzky A, Nirkin A, et al.: Dextromethorphan for the reduction of immediate and late postoperative pain and morphine consumption in orthopedic oncology patients: a randomized, placebo-controlled, double-blind study. Cancer 95 (5): 1164-70, 2002. [PubMed: 12209704]
270. Weinbroum AA, Bender B, Bickels J, et al.: Preoperative and postoperative dextromethorphan provides sustained reduction in postoperative pain and patient-controlled epidural analgesia requirement: a randomized, placebo-controlled, double-blind study in lower-body bone malignancy-operated patients. Cancer 97 (9): 2334-40, 2003. [PubMed: 12712491]
271. Dudgeon DJ, Bruera E, Gagnon B, et al.: A phase III randomized, double-blind, placebo-controlled study evaluating dextromethorphan plus slow-release morphine for chronic cancer pain relief in terminally ill patients. J Pain Symptom Manage 33 (4): 365-71, 2007. [PubMed: 17397698]
272. Pistevou-Gombaki K, Eleftheriadis N, Plataniotis GA, et al.: Octreotide for palliative treatment of hepatic metastases from non-neuroendocrine primary tumours: evaluation of quality of life using the EORTC QLQ-C30 questionnaire. Palliat Med 17 (3): 257-62, 2003. [PubMed: 12725479]
273. Hagen NA, du Souich P, Lapointe B, et al.: Tetrodotoxin for moderate to severe cancer pain: a randomized, double blind, parallel design multicenter study. J Pain Symptom Manage 35 (4): 420-9, 2008. [PubMed: 18243639]
274. Johnson JR, Burnell-Nugent M, Lossignol D, et al.: Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage 39 (2): 167-79, 2010. [PubMed: 19896326]
275. Portenoy RK, Ganae-Motan ED, Allende S, et al.: Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain 13 (5): 438-49, 2012. [PubMed: 22483680]

Radiation Therapy

Radiation therapy (RT) has been established as an effective treatment for pain caused by bony metastases. Local, half-body, or whole-body RT enhances the effectiveness of analgesic drugs and other noninvasive therapies by directly affecting the cause of pain (i.e., reducing primary and metastatic tumor bulk).[1][Level of evidence: I] RT reduces pain and its interference with function among ambulatory cancer patients with symptomatic bone metastases.[2]

Invasive Palliative 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.

References

1. 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. [PubMed: 11395246]
2. 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. [PubMed: 16969984]
3. Chow E, Harris K, Fan G, et al.: Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 25 (11): 1423-36, 2007. [PubMed: 17416863]
4. 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. [PubMed: 15928300]
5. Howell DD, James JL, Hartsell WF, et al.: Single-fraction radiotherapy versus multifraction radiotherapy for palliation of painful vertebral bone metastases-equivalent efficacy, less toxicity, more convenient: a subset analysis of Radiation Therapy Oncology Group trial 97-14. Cancer 119 (4): 888-96, 2013. [PMC free article: PMC5746185] [PubMed: 23165743]
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. [PubMed: 18556080]
7. Sande TA, Ruenes R, Lund JA, et al.: Long-term follow-up of cancer patients receiving radiotherapy for bone metastases: results from a randomised multicentre trial. Radiother Oncol 91 (2): 261-6, 2009. [PubMed: 19307034]
8. Kaasa S, Brenne E, Lund JA, et al.: Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy x 1) versus multiple fractions (3 Gy x 10) in the treatment of painful bone metastases. Radiother Oncol 79 (3): 278-84, 2006. [PubMed: 16793154]
9. Roos DE, Turner SL, O'Brien PC, et al.: Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol 75 (1): 54-63, 2005. [PubMed: 15878101]
10. Lutz S, Berk L, Chang E, et al.: Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys 79 (4): 965-76, 2011. [PubMed: 21277118]
11. 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. [PubMed: 17093912]
12. Hird A, Chow E, Zhang L, et al.: Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: results from three canadian cancer centers. Int J Radiat Oncol Biol Phys 75 (1): 193-7, 2009. [PubMed: 19167840]
13. Atahan L, Yildiz F, Cengiz M, et al.: Zoledronic acid concurrent with either high- or reduced-dose palliative radiotherapy in the management of the breast cancer patients with bone metastases: a phase IV randomized clinical study. Support Care Cancer 18 (6): 691-8, 2010. [PubMed: 19484483]
14. Cheng A, Chen S, Zhang Y, et al.: The tolerance and therapeutic efficacy of rhenium-188 hydroxyethylidene diphosphonate in advanced cancer patients with painful osseous metastases. Cancer Biother Radiopharm 26 (2): 237-44, 2011. [PubMed: 21539455]
15. Liepe K, Runge R, Kotzerke J: Systemic radionuclide therapy in pain palliation. Am J Hosp Palliat Care 22 (6): 457-64, 2005 Nov-Dec. [PubMed: 16323716]
16. 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. [PubMed: 15134985]
17. 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. [PubMed: 16985364]
18. 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. [PubMed: 17167764]
19. Baczyk M, Czepczyński R, Milecki P, et al.: 89Sr versus 153Sm-EDTMP: comparison of treatment efficacy of painful bone metastases in prostate and breast carcinoma. Nucl Med Commun 28 (4): 245-50, 2007. [PubMed: 17325585]
20. Dupuy DE, Liu D, Hartfeil D, et al.: Percutaneous radiofrequency ablation of painful osseous metastases: a multicenter American College of Radiology Imaging Network trial. Cancer 116 (4): 989-97, 2010. [PMC free article: PMC2819592] [PubMed: 20041484]
21. Callstrom MR, Charboneau JW: Image-guided palliation of painful metastases using percutaneous ablation. Tech Vasc Interv Radiol 10 (2): 120-31, 2007. [PubMed: 18070690]
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23. 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. [PubMed: 14722039]
24. Thacker PG, Callstrom MR, Curry TB, et al.: Palliation of painful metastatic disease involving bone with imaging-guided treatment: comparison of patients' immediate response to radiofrequency ablation and cryoablation. AJR Am J Roentgenol 197 (2): 510-5, 2011. [PubMed: 21785102]
25. Wyse JM, Carone M, Paquin SC, et al.: Randomized, double-blind, controlled trial of early endoscopic ultrasound-guided celiac plexus neurolysis to prevent pain progression in patients with newly diagnosed, painful, inoperable pancreatic cancer. J Clin Oncol 29 (26): 3541-6, 2011. [PubMed: 21844506]
26. 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. [PubMed: 12195764]

Physical Modalities

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

Heat

• Avoid burns by wrapping the heat source (e.g., hot pack or heating pad) in a towel. A timing device is useful to prevent burns from an electrical heating pad. The use of heat on recently irradiated tissue is contraindicated, and diathermy and ultrasound are not recommended for use over tumor sites.

Cold

• Apply flexible ice packs that conform to body contours for periods not to exceed 15 minutes. Cold treatment reduces swelling and may provide longer-lasting relief than heat but should be used cautiously in patients with peripheral vascular disease and on tissue damaged by radiation therapy.

Exercise

• Exercise strengthens weak muscles, mobilizes stiff joints, helps restore coordination and balance, and provides cardiovascular conditioning. Therapists and trained family or other caregivers can assist the functionally limited patient with range-of-motion exercises to help preserve strength and joint function. During episodes of acute pain, exercise should be limited to self-administered range-of-motion. Weight-bearing exercise should be avoided when bone fracture is likely.

Repositioning

• Reposition the immobilized patient frequently to maintain correct body alignment, to prevent or alleviate pain, and to prevent pressure ulcers.

Immobilization

• Use restriction of movement to manage acute pain or to stabilize fractures or otherwise compromised limbs or joints. Use adjustable elastic or thermoplastic braces to help maintain correct body alignment. Keep joints in positions of maximal function rather than maximal range. Avoid prolonged immobilization.

Stimulation Techniques

• Transcutaneous Electrical Nerve Stimulation (TENS): Controlled low-voltage electrical stimulation applied to large myelinated peripheral nerve fibers via cutaneous electrodes to inhibit pain transmission. Patients with mild-to-moderate pain may benefit from a trial of TENS to see if it is effective in reducing the pain. TENS is a low-risk intervention. A small crossover study (N = 41) found that 72% of users rated TENS as effective or very effective, compared to those using the comparison intervention (27%) or placebo intervention (36%). Furthermore, a clinically meaningful number of participants was still using the TENS a year later (n = 10), in contrast to the other two conditions (combined n = 5). All three treatment arms were well tolerated, but there is no conclusive evidence demonstrating any benefit from TENS or transcutaneous spinal electroanalgesia (TSE) over placebo in this cancer pain population.[2][Level of evidence: I]

Integrative Modalities

Massage, Pressure, and Vibration

• Physical stimulation techniques have direct mechanical effects on tissues and enhance relaxation when applied gently. Tumor masses should not be aggressively manipulated.
  Massage therapy is an integrative modality that has been investigated as an adjunct to supportive care interventions in managing cancer-related pain. Preclinical and clinical trials have found that massage reduces pain by reducing cortisol levels, increasing serotonin and dopamine levels, stimulating the release of endorphins, and stimulating blood and lymphatic circulation. Massage may enhance the effects of analgesic medications and decrease inflammation and edema. There is a large body of evidence supporting the role of massage in reducing pain associated with muscle-related conditions such as muscle spasms and tension.[3-6] Massage may also play a role in the management of procedural pain.
  In one of the largest randomized trials, 380 adults with advanced cancer received six sessions of either massage therapy or touch therapy for 30 minutes over a 2-week period.[3] While immediate improvements from massage therapy were significantly greater than those from touch therapy, the benefits were not sustained, according to the Brief Pain Inventory. However, a large number of patients were not included in the assessments of immediate outcomes or sustained outcomes. Data collectors were also not blinded to the study arm, which may have led to overreporting the effects of massage therapy or touch therapy.
  A number of reviews exploring the role of massage in the management of cancer pain or other areas of supportive care have been published. In a Cochrane review of the role of massage therapy with or without aromatherapy as a component of supportive care,[7] three studies found a reduction in pain following intervention and reported reductions of 30% to 39% in pain scores after massage therapy, compared to usual care. Another study reported on the role of massage within the context of supportive care in cancer, highlighted pain, and concluded that evidence is encouraging but effect sizes are small.[5] Additional trials are needed.
  While the benefit of massage therapy on cancer pain may be mixed, existing trials suggest that massage therapy is safe in patients with cancer. However, certain precautions should be taken when providing massage therapy to patients with cancer:

  -

  Avoid directly massaging any open wounds, hematomas, or areas with skin breakdown.

  -

  Avoid massaging the site of the tumor.

  -

  Avoid massaging areas with acute deep venous thrombosis.

  -

  Avoid directly massaging radiated soft tissue.[8]

Acupuncture

• Acupuncture applies needles, heat, pressure, and other treatments to one or more places on the skin known as acupuncture points and is often sought by patients with cancer for the management of pain. (Refer to the PDQ summary on Acupuncture for a comprehensive review of the evidence supporting the role of acupuncture for the management of pain.)

Music Interventions for Pain

• Music Therapy and Music Medicine
  There are generally two broad categories of music-based interventions referenced within health care research.

  -

  Music therapy is the clinical and evidence-based use of active and receptive, tailored, music-based interventions to accomplish individualized goals within a therapeutic relationship, delivered by a credentialed professional (music therapist-board certified, or MT-BC) who has completed an approved program in music therapy.[9]

  Music therapists use a variety of music-based interventions that include live, interactive music making or carefully selected recorded music. Some examples include music improvisation, song writing and singing, and music relaxation.

  A music therapist chooses interventions on the basis of an assessment of a patient’s immediate and long-term needs (e.g., pain management, anxiety reduction, coping strategies, and skills).

  -

  Music medicine is the use of passive music listening (usually prerecorded music) for distraction, delivered by a medical professional without specialized music training.[10]

  Music therapy and music medicine interventions have been used to relieve acute and chronic pain related to noxious procedures and treatments and the disease process. Music reduces pain via the mutually inhibitory neuroanatomical pathways that are shared between pain and reward processing.[11] Neuroscience studies are consistent in suggesting that pleasant emotional responses to music activate brain structures related to reward, emotion, and attention and decrease activation in areas associated with aversive events.[12-14] Music from an individual’s personal collection that elicits a positive emotional response has the most robust effect in increasing pain tolerance, decreasing anxiety, and increasing perceived control.[15-17]
  Meta-analyses summarizing the effect of music on pain indicate small to moderate benefit, with a high level of heterogeneity. There is preliminary evidence that music interventions delivered by music therapists are more effective than music medicine interventions.[10,18]
  Studies reporting rates of 50% pain reduction indicate that participants in music listening had a 70% greater probability of experiencing at least a 50% pain reduction than did controls (n = 4 studies).[19] There is also preliminary evidence that music reduces opioid requirements, but the benefits are small and the clinical importance is unclear.[19] Music-based interventions specifically for cancer patients found a moderate pain-reducing effect of a 0.54 standardized unit difference between music and usual-care groups (5 studies, n = 391).[20]
  While initial results are promising, the quality of evidence for music and cancer pain studies is low, often because of wide confidence intervals and high variability in study quality.[20] Common sources of bias and low quality include nonblinding of participant and study personnel, lack of theory guiding music selection and delivery, and incomplete reporting of intervention details.[13,21,22]
• Characteristics of Music Interventions for Pain
  Characteristics of music interventions for pain include the following:

  -

  Music interventions can be used as adjuncts to analgesic medications.

  -

  When available, live music is preferred, delivered by a board-certified music therapist.

  -

  When recorded music is to be used, patients should be encouraged to choose music from their personal collections that is emotionally meaningful to them.

  -

  When several pieces of music are to be used, they should be played so that up-tempo and more complex pieces are heard at the beginning, with tempo and overall complexity decreasing from beginning to end.

  -

  A general orientation to music listening should be provided to patients and caregivers, to include the operation of any equipment and instructions to patients for when they need additional assistance.

  -

  Music listening through headphones may be contraindicated during painful procedures because it prevents patients from hearing instructions or comments from physicians.[23]

  -

  Music introduced before a procedure is more effective than music introduced during or after a procedure.[18]

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.[24] Other 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.[25][Level of evidence: I] Realistic expectations are needed for delivery of cognitive-behavioral interventions. One study [26][Level of evidence: I] 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:

Relaxation and Imagery

• Simple relaxation techniques (see examples listed below) should be used for episodes of brief pain (e.g., during procedures). Brief, simple techniques are preferred when the patient’s ability to concentrate is compromised by severe pain, a high level of anxiety, or fatigue.

Hypnosis

• Hypnotic techniques may be used to induce relaxation and may be combined with other cognitive-behavioral strategies.[27][Level of evidence: I] Hypnosis is effective in relieving pain in individuals who can concentrate well, can use imagery, and are motivated to practice. A randomized but unblinded study of preoperative hypnosis in women undergoing excisional breast biopsy or lumpectomy revealed that women who underwent hypnosis required less propofol and lidocaine use during surgery and scored lower on measures of pain, nausea, fatigue, discomfort, and emotional upset at discharge.[28][Level of evidence: I]

Cognitive Distraction and Reframing

• Focusing attention on stimuli other than pain or negative emotions accompanying pain may involve distractions that are internal (e.g., counting, praying, or making self-statements such as “I can cope”) or external (e.g., listening to music, watching television, talking, listening to someone read, or using a visual focal point). In the related technique, cognitive reappraisal, patients learn to monitor and evaluate negative thoughts and replace them with more positive thoughts and images.

Patient/Family Education

• Both oral and written information and instructions should be provided about pain, pain assessment, and the use of drugs and other methods of pain relief.[29-31][Level of evidence: I] Patient education should emphasize that almost all pain can be effectively managed. Major barriers to effective pain management (refer to the list of Barriers to Effective Cancer Pain Management in the Overview section of this summary) should be discussed to correct patient and family misconceptions. Health care providers need to take into consideration family members’ interpretation of patient pain when providing pain management education services, as some caregivers overestimate patient pain.[32][Level of evidence: II] Educational intervention programs to help patients who have cancer and their families manage pain have been described and may improve clinical outcomes.[33][Level of evidence: II] These programs are based on adult learning principles and incorporate key strategies, including provision of information using academic detailing, skill building with ongoing nurse-coaching, and interactive nursing support.[34][Level of evidence: IV];[35][Level of evidence: I] Training partners to participate in management of cancer pain increases partner self-efficacy for controlling their loved one's pain and other symptoms.[36][Level of evidence: II]

Psychotherapy and Structured Support

• Some patients benefit from short-term psychotherapy provided by trained professionals. Patients whose pain is particularly difficult to manage and who develop symptoms of clinical depression or adjustment disorder should be referred to a psychiatrist or psychologist for diagnosis. The relationship between poorly controlled pain, depression, and thoughts of suicide should not be ignored.

Support Groups and Pastoral Counseling

• Because many patients benefit from peer support groups, clinicians should be aware of locally active groups and offer this information to patients and their families. Pastoral counseling members of the health care team should participate in meetings to discuss patients’ needs and treatment. They should also be a source of information on community resources for spiritual care and social support.

Relaxation Exercises [Note: Adapted and reprinted with permission from McCaffery M, Beebe A: Pain: Clinical Manual for Nursing Practice. St. Louis, Mo: CV Mosby Co, 1989.]

• Exercise 1. Slow Rhythmic Breathing for Relaxation

  1. Breathe in slowly and deeply, keeping your stomach relaxed and your shoulders relaxed.
  2. As you breathe out slowly, feel yourself beginning to relax; feel the tension leaving your body.
  3. Now breathe in and out slowly and regularly, at whatever rate is comfortable for you. Let the breath come all the way down to your stomach, as it completely relaxes.
  4. To help you focus on your breathing and breathe slowly and rhythmically: (a) breathe in as you say silently to yourself, “in, two, three”; (b) breathe out as you say silently to yourself, “out, two, three.” Or, each time you breathe out, say silently to yourself a word such as “peace” or “relax.”
  5. Do steps 1 through 4 only once or repeat steps 3 and 4 for up to 20 minutes.
  6. End with a slow deep breath. As you breathe out say to yourself, “I feel alert and relaxed.”
• Exercise 2. Simple Touch, Massage, or Warmth for Relaxation

  1. Touch and massage are age-old methods of helping others relax. Examples include the following:

     -

     Brief touch or massage (e.g., handholding or briefly touching or rubbing a person’s shoulder).

     -

     Warm foot soak in a basin of warm water, or wrap the feet in a warm, wet towel.

     -

     Massage (3–10 minutes) may consist of whole body or be restricted to back, feet, or hands. If the patient is modest or cannot move or turn easily in bed, consider massage of the hands and feet.

  2. Use a warm lubricant (e.g., a small bowl of hand lotion may be warmed in the microwave oven, or a bottle of lotion may be warmed by placing it in a sink of hot water for about 10 minutes).
  3. Massage for relaxation is usually done with smooth, long, slow strokes. (Rapid strokes, circular movements, and squeezing of tissues tend to stimulate circulation and increase arousal.) However, try several degrees of pressure along with different types of massage (e.g., kneading and stroking). Determine which is preferred.
  4. Especially for the older person, a back rub that effectively produces relaxation may consist of no more than 3 minutes of slow, rhythmic stroking (about 60 strokes per minute) on both sides of the spinous process from the crown of the head to the lower back. Continuous hand contact is maintained by starting one hand down the back as the other hand stops at the lower back and is raised. Set aside a regular time for the massage. This gives the patient something to look forward to and depend on.
• Exercise 3. Peaceful Past Experiences
  Something may have happened to you a while ago that brought you peace and comfort. You may be able to draw on that past experience to bring you peace or comfort now. Think about these questions:

  1. Can you remember any situation, even when you were a child, when you felt calm, peaceful, secure, hopeful, or comfortable?
  2. Have you ever daydreamed about something peaceful? What were you thinking of?
  3. Do you get a dreamy feeling when you listen to music? Do you have any favorite music?
  4. Do you have any favorite poetry that you find uplifting or reassuring?
  5. Have you ever been religiously active? Do you have favorite readings, hymns, or prayers? Even if you haven’t heard or thought of them for many years, childhood religious experiences may still be very soothing.
  Additional points: Some of the things you think of in answer to these questions, such as your favorite music or a prayer, can probably be recorded for you. Then you can listen to the tape whenever you wish. If your memory is strong, you may simply be able to close your eyes and recall the events or words.
• Exercise 4. Active Listening to Recorded Music

  1. Obtain the following:

     -

     A cassette player or tape recorder. (Small battery-operated machines are more convenient.)

     -

     Earphones or a headset. (This is a more compelling stimulus than a speaker a few feet away, and it avoids disturbing others.)

     -

     Cassette recording of music you like. (Most people prefer fast, lively music, but some people select relaxing music. Other options are comedy routines, sporting events, old radio shows, or stories.)

  2. Mark time to the music, e.g., tap out the rhythm with your finger or nod your head. This helps you concentrate on the music rather than your discomfort.
  3. Keep your eyes open and focus steadily on one stationary spot or object. If you wish to close your eyes, picture something about the music.
  4. Listen to the music at a comfortable volume. If the discomfort increases, try increasing the volume; decrease the volume when the discomfort decreases.
  5. If these steps are not effective enough, try adding or changing one or more of the following: massage your body in rhythm to the music; try other music; mark time to the music in more than one manner (e.g., tap your foot and finger at the same time).
  Additional points: Many patients have found this technique to be helpful. It tends to be very popular, probably because the equipment is usually readily available and is a part of daily life. Other advantages are that it is easy to learn and is not physically or mentally demanding. If you are very tired, you may simply listen to the music and omit marking time or focusing on a spot.

References

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13. Blood AJ, Zatorre RJ, Bermudez P, et al.: Emotional responses to pleasant and unpleasant music correlate with activity in paralimbic brain regions. Nat Neurosci 2 (4): 382-7, 1999. [PubMed: 10204547]
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18. Standley JM: Music research in medical treatment. In: Smith DS, ed.: Effectiveness of Music Therapy Procedures: Documentation of Research and Clinical Practice. 3rd ed. Silver Spring, Md: American Music Therapy Association, 2000, pp 1-64.
19. Cepeda MS, Carr DB, Lau J, et al.: Music for pain relief. Cochrane Database Syst Rev (2): CD004843, 2006. [PubMed: 16625614]
20. Bradt J, Dileo C, Grocke D, et al.: Music interventions for improving psychological and physical outcomes in cancer patients. Cochrane Database Syst Rev (8): CD006911, 2011. [PubMed: 21833957]
21. Burns DS: Theoretical rationale for music selection in oncology intervention research: an integrative review. J Music Ther 49 (1): 7-22, 2012. [PubMed: 22803255]
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24. 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. [PubMed: 8656544]
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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of pain. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Pain are:

• Joseph Bubalo, PharmD, BCPS, BCOP (Oregon Health and Science University Hospital)
• Mary K. Buss, MD (Beth Israel Deconess Medical Center)
• David Hui, MD, MSC (M.D. Anderson Cancer Center)
• Eric E. Prommer, MD (UCLA School of Medicine)
• Amy Wachholtz, PhD (University of Massachusetts Medical School & UMass Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Pain. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/about-cancer/treatment/side-effects/pain/pain-hp-pdq. Accessed <MM/DD/YYYY>.

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