Purpose of This PDQ Summary
Overview

Highlights of Patient Management

Pain Assessment

Initial Assessment Patient Self-Report Physical Examination Assessment of the Outcomes of Pain Management

Pharmacologic Management

Basic Principles of Cancer Pain Management Acetaminophen and Nonsteroidal Anti-inflammatory Drugs Opioids         Opioid types         Principles of opioid administration         Route of administration         Drugs and routes to be avoided         Side effects of opioids Adjuvant Drugs

Physical and Psychosocial Interventions

Physical Modalities Cognitive-Behavioral Interventions

Antineoplastic Interventions

Radiation Therapy Radiofrequency Ablation Surgery

Invasive Interventions

Nerve Blocks Neurologic Interventions Management of Procedural Pain

Discharge Planning
Treating Elderly Patients
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Changes to This Summary (07/10/2008)
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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:

• Assessment.
• Pharmacological management.
• Intervention.

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.

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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.

Barriers to Effective Pain Management

• Problems related to health care professionals:
  • Inadequate knowledge of pain management.
  • Poor assessment of pain.[4]
  • Concern about regulation of controlled substances.
  • Fear of patient addiction.
  • Concern about side effects of analgesics.
  • Concern about patients becoming tolerant to analgesics.



• Problems related to patients:
  • Reluctance to report pain.
  • Concern about distracting physicians from treatment of underlying disease.
  • Fear that pain means disease is worse.
  • Concern about not being a “good” patient.
  • Reluctance to take pain medications.
  • Fear of addiction or of being thought of as an addict (this fear may be more pronounced in minority patients).[5]
  • Worries about unmanageable side effects.
  • Concern about becoming tolerant to pain medications.
  • Poor adherence with the prescribed analgesic regimen.[6]



• Problems related to the health care system:
  • Low priority given to cancer pain treatment.
  • Inadequate reimbursement.
  • The most appropriate treatment may not be reimbursed or may be too costly for patients and families.
  • Restrictive regulation of controlled substances.
  • Problems of availability of treatment or access to it.
  • Opioids unavailable in the patient’s pharmacy.

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.

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 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.

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 Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   

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Pain Assessment

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

• At regular intervals after initiation of treatment.
• At each new report of pain.
• At a suitable interval after pharmacologic or nonpharmacologic intervention, e.g., 15 to 30 minutes after parenteral drug therapy and 1 hour after oral administration.

Identifying the etiology of pain is important to its management. Clinicians treating patients with cancer should recognize the common cancer pain syndromes (see table 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.[1-4] 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]

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:

• Detailed history.



• Physical examination.



• Psychosocial assessment.[8]



• 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 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.

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.[13] 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%).[14]

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.[15,16] 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 or episodic pain (a transitory increase in pain that occurs in addition to persistent pain). Some patients may have episodic pain without persistent pain.[17]

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.

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.[18] 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.[19] It was also reported that patients who thought that their pain represented disease progression reported more pain-related interference with function.[20]

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.[13] 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.[21] It is difficult to get good pain-diary compliance with adolescents who are experiencing intense chronic pain.

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.

Changes in pain pattern or the development of new pain should trigger diagnostic evaluation 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.

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.[22,23]

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.[24-26]

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.[27] This study should increase confidence in providing appropriate pain management to patients who have a history of drug use.[28]

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
3. Greenwald HP: Interethnic differences in pain perception. Pain 44 (2): 157-63, 1991.  [PUBMED Abstract]
   
   
4. Bates MS, Edwards WT, Anderson KO: Ethnocultural influences on variation in chronic pain perception. Pain 52 (1): 101-12, 1993.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
7. Mercadante S, Portenoy RK: Opioid poorly-responsive cancer pain. Part 1: clinical considerations. J Pain Symptom Manage 21 (2): 144-50, 2001.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
9. Bruera E, MacMillan K, Hanson J, et al.: The Edmonton staging system for cancer pain: preliminary report. Pain 37 (2): 203-9, 1989.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
13. 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.  [PUBMED Abstract]
    
    
14. 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 Abstract]
    
    
15. 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. 
    
    
16. 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 Abstract]
    
    
17. 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 Abstract]
    
    
18. 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 Abstract]
    
    
19. Spiegel D, Bloom JR: Pain in metastatic breast cancer. Cancer 52 (2): 341-5, 1983.  [PUBMED Abstract]
    
    
20. Daut RL, Cleeland CS: The prevalence and severity of pain in cancer. Cancer 50 (9): 1913-8, 1982.  [PUBMED Abstract]
    
    
21. 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 Abstract]
    
    
22. 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 Abstract]
    
    
23. 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 Abstract]
    
    
24. 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 Abstract]
    
    
25. 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 Abstract]
    
    
26. 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 Abstract]
    
    
27. 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 Abstract]
    
    
28. Whitcomb LA, Kirsh KL, Passik SD: Substance abuse issues in cancer pain. Curr Pain Headache Rep 6 (3): 183-90, 2002.  [PUBMED Abstract]
    
    

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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.

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.[3-5] 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.

Dosage

• Use patient response to determine the effective dosing interval for aspirin, acetaminophen, and other NSAIDs listed in the Dosing Recommendations for Acetaminophen and NSAIDs table. 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. Ketorolac tromethamine is the only NSAID available for parenteral use.

Contraindications

• Patients taking NSAIDs are at risk for platelet dysfunction that may impair blood clotting. The table below lists NSAIDs with minimal antiplatelet activity.

Other side effects

• Follow 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, 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.

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 the Approximate Dose Equivalents for Opioid Analgesics table in the Principles of Opioid Administration section of this summary.)

Full agonists

• Morphine, hydromorphone, codeine, oxycodone, hydrocodone, methadone, levorphanol, and fentanyl are classified as full agonists because their effectiveness with increasing doses is not limited by a ceiling. Full agonists will not reverse or antagonize the effects of other full agonists given simultaneously.

Morphine

• The most commonly used opioid, morphine, is readily available in several forms, including sustained-release (8–24 hours duration of effectiveness) formulations for oral administration.

Other agonists

• For the patient who experiences dose-limiting side effects with one oral opioid (e.g., hallucinations, nightmares, dysphoria, nausea, or mental clouding), other oral opioids should be tried before abandoning one route in favor of another.

Methadone

• Methadone has had a revival in interest for the management of cancer pain. Published reports have been in the form of case reports,[14-20] outcome surveys,[21-25] and reviews.[26-28]Success has been reported with oral, intravenous (IV), and suppository methadone use. Subcutaneous methadone has been reported to cause tissue irritation at the injection site but has been used effectively in some patients without clinically significant local toxicity.[29]

  Methadone is a synthetic opioid agonist that has been reported to have a number of unique characteristics. These include excellent oral and rectal absorption, no known active metabolites, prolonged duration of action resulting in longer administration intervals, and lower cost than other opioids. Methadone is available as a pill, an elixir, and for parenteral use. Methadone has an average oral bioavailability of approximately 80% (range, 41%–99%).[30]

  Morphine is the international gold standard for first-line treatment of cancer pain. Methadone, however, can be considerably less expensive than existing rapid-release or sustained-release morphine or other opioid options. A randomized trial of 103 patients compared the effectiveness and side effects of morphine and methadone as first-line treatments for cancer pain. The outcome of successful pain management was similar for both groups; however, there were significantly more opioid-related dropouts in the methadone group. This study did not demonstrate superior analgesic effectiveness or overall tolerability of methadone over morphine as a first-line treatment for cancer pain. Despite this finding, the authors of this report suggested that study limitations did not allow definitive conclusions that methadone could not be a useful first-line opioid. Further research exploring other doses and schedules of methadone should still be explored.[31]

  Because of its long and unpredictable half-life and relatively unknown equianalgesic dose as compared with other opioids, methadone has been generally used by pain specialists with experience in its use. The utility of methadone in cancer pain and difficult cancer pain syndromes such as neuropathic pain has become more widely appreciated and has gained increasing acceptance for use in hospital and hospice settings and by clinicians who are not pain specialists.[32] The methadone preparation widely used in the United States is a racemic mix of the d-isomer and l-isomer of methadone. The d-isomer has antagonist activity at the N-methyl-D-aspartate (NMDA) receptor and may be beneficial in controlling neuropathic pain.

  Another controversy related to methadone concerns possible prolongation of QTc interval, leading to torsades de pointes and ventricular arrhythmia. A number of studies have raised the concern that methadone may be associated with prolonged QT interval and may lead to torsades de pointes. Several retrospective case reports suggest that parenteral methadone or oral methadone in high doses could be associated with this adverse effect.[33-36] Chlorobutanol has been implicated; although this substance is present in parenteral solutions, it is not found in oral formulations.[37] Another series of 132 patients taking methadone revealed statistically significant mean increases in QTc of 10.2 to 13.2 milliseconds, yet no episodes of torsades de pointes were reported.[36] This result raises the issue of the clinical significance of this effect. In another retrospective review of 520 patients treated with methadone for cancer pain, no change in QTc was seen in the 56 patients who had electrocardiograms 3 months before and after starting methadone.[38,39] Avoidance of concomitant medications that prolong QT interval [37] or that share common metabolism pathways with methadone [38] is recommended. In high-risk situations, clinicians could consider electrocardiogram monitoring and other clinical precautions such as correcting electrolyte abnormalities.

  When converting from another opioid to methadone, the calculated equianalgesic dose ratio of methadone varies depending on the oral morphine-equivalent daily dose (MEDD) of the previous opioid.[40,22] One guideline for choosing an appropriate initial dose of methadone based on the oral MEDD of the previous opioid is shown in the table below. For example, a patient who has been using sustained-release morphine at 80 mg every 8 hours (240 mg/day) would be appropriately switched to methadone at a dose of 10 mg every 8 hours (30 mg/day, an 8:1 conversion ratio). In contrast, a patient who is taking sustained-release morphine at a total daily dose of 60 mg/day might be switched to an oral methadone dose of 5 mg every 8 hours (15 mg/day, a 4:1 conversion ratio).

  Method 1: Initial Methadone Dose Based on Oral MEDD*
  Enlarge

  Oral MEDD (mg/d)	Initial Dose Ratio (oral morphine:oral methadone)
  <30	2:1
  30–99	4:1
  100–299	8:1
  300–499	12:1
  500–999	15:1
  >1,000	20:1 or greater**

  
  

  *Reprinted with permission from Fisch and Cleeland [41]

  **Great caution must be used when converting to methadone when very high opioid doses have been used. Often, only a portion of the total opioid dose is converted initially, with further conversions taking place over several days to weeks.

  
  

  To be conservative, one might estimate that methadone is roughly twice as potent when administered via IV versus oral administration. Thus, a patient with well-controlled pain on a stable oral methadone dose of 10 mg every 8 hours might be given IV methadone at an initial dose of 5 mg every 8 hours if IV use is necessary. Subcutaneous use of methadone may cause skin irritation in some patients but has been used successfully.

  In addition to the method described in the table above, several methods of switching to methadone have been proposed.[42,22,43-46] Some rely on patient-controlled analgesia with fixed doses and flexible intervals, some require fixed intervals and fixed doses, while others stagger the conversion over a few days. Whatever method is chosen, this kind of switch can be safe and effective as long as regular assessments are provided over time, and there is an appreciation of the equianalgesic dose ratio of methadone to morphine in opioid-tolerant patients.

  • Method 2: Staggered or 3-day Switchover

    One approach calls for a gradual switch over 3 to 5 days to decrease the risk of relative overdosing. An equianalgesic dose of methadone is first calculated, using an equianalgesic dose ratio of morphine to methadone of 10:1 (i.e., methadone being approximately ten times more potent than morphine). The caveat in using a ratio of 10:1 is that variations in ratios have been noted, depending on the dose of the previous opioid. The ratio may be much higher (12:1 or even higher) in patients being switched from high doses of morphine to methadone. The following example is given to illustrate this method: A patient who is on the equivalent of 450 mg per day of oral morphine (quick-release morphine 75 mg orally every 4 hours) needs to be switched to methadone. Using a ratio of 10:1, the predicted equivalent daily oral dose of methadone, once the switch is completed, will be 45 mg. On day 1 of the switch, the daily morphine dose is reduced by one third to approximately 300 mg per day (morphine 50 mg orally every 4 hours) and one third of the predicted daily methadone dose is added, divided into three doses per 24 hours (i.e., methadone 5 mg orally every 8 hours). Morphine continues to be given for rescue doses. On day 2 of the switch the patient is reassessed, and if no problems have developed, the morphine dose is reduced by another third (i.e., morphine 25 mg orally every 4 hours) and the methadone dose is increased by another third (i.e., methadone 10 mg orally every 8 hours). On day 3, the patient is reassessed. If there are complications such as significant somnolence, but the pain is still not under good control, the methadone dose is increased to 15 mg every 8 hours and the morphine is discontinued. On day 3, methadone or a short half-life opioid is added as a rescue dose as needed. The rescue dose is calculated at 5% to 15% of the total daily dose. On day 3, if the patient has good pain control but shows signs of relative overdosing such as significant somnolence, the morphine is discontinued without any increase in the methadone dose (i.e., it remains at the day 2 level or may even be decreased if needed).

  
  
  
  • Method 3: Ad Libitum [42]

    This approach calls for the previous dose to be discontinued and a single fixed-dose of methadone to be given at the start, calculated using an equianalgesic dose ratio of morphine to methadone of 10:1 (i.e., morphine 10 mg being roughly equivalent to 1 mg of methadone), but to a maximum of 50 mg of methadone per dose. After the initial single priming dose, the same dose is administered every 3 hours as needed. The clinician observes the patient and when the demand for rescue doses reduces or stabilizes (indicating steady-state being reached), which is usually on day 4 to 7, the daily requirement is calculated and the dose is given every 8 to 12 hours.

  
  
  
  • Method 4: Initial Priming Followed By Variable Conversion [43]

    In this method, an opioid-naïve patient is started on 3 to 5 mg of methadone every 8 hours and a nonnaïve patient is started on a dose of methadone that is equivalent to 50% of the estimated daily morphine dose. These doses are initially given for 3 days. Once the patient has acceptable pain relief for 6 to 8 hours, the dose is changed to a single fixed-dose once a day and rescue doses are given as needed. This method is probably best suited for opioid-naïve patients (in relatively unlikely situations where more frequently used opioids such as morphine are not available) or patients who are, for one reason or another, being switched from relatively low doses of morphine or other opioids.

  
  
  
  • Method 5: German Model [45]

    This method is suggested when patients are being switched from high equivalent daily doses of morphine (>600 mg orally per day). The morphine or other opioid the patient is receiving is stopped. Methadone at a dose of 5 to 10 mg orally is started every 4 hours and rescue-doses of 5 to 10 mg every hour are allowed as needed. On the second to third days of the switch, the methadone dose is increased by up to 30% every 4 hours until sufficient pain relief is achieved and no significant adverse effects are noted. After exactly 72 hours following the switch to methadone, the dose is changed from every 4 hours to every 8 hours, and the interval of rescue doses is increased to every 3 hours as needed at the same single dose as established on days 2 to 3. The dose can then be increased by up to 30% if further upward titration is required.

  
  
  

  In some countries there are restrictions that do not apply to other opioids on the ability of physicians to prescribe methadone. In the United States, this pertains to methadone for maintenance of addiction. Methadone is not restricted when used for pain management; however, physicians should carefully document the use of methadone.[47] It should be noted that ratios are different for switching from methadone to a morphine-like opioid.[22]

Meperidine (Demerol)

• Useful for brief courses (a few days) to treat acute pain, meperidine is not recommended in treating persistent cancer pain because of its short duration of action (2.5–3.5 hours) and its neurotoxic metabolite, normeperidine. Accumulation of this metabolite, particularly when renal function is impaired, causes central nervous system (CNS) stimulation that may lead to delirium or seizures. Seizures are typically preceded by development of multifocal myoclonus, which can be used as a warning sign.

Tramadol

• Tramadol can be considered an atypical opioid analgesic that has a dual action. It is a weak mu opioid agonist that also inhibits the reuptake of norepinephrine and serotonin.[48,49] It is believed that both mechanisms work synergistically to provide analgesic benefit with a potency that is approximately one-tenth that of morphine [50] and approximately equivalent to codeine. The most common side effects reported with tramadol are drowsiness, constipation, dizziness, nausea, and orthostatic hypotension.[48] There is also a risk of precipitating seizures in patients with a previous history or in patients who are receiving medications that could reduce the seizure threshold. The use of other serotonergic medications (e.g., selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]) together with tramadol has the potential to increase the risk of the serotonin syndrome. Tramadol is available in short- and long-acting formulations and in fixed combination with acetaminophen. The recommended starting dose of oral tramadol is 50 mg 1 or 2 times a day, with gradual titration up to a maximum of 400 mg per day.[48] There is also the option of using tramadol via the rectal or subcutaneous route in patients who are unable to tolerate oral medication.[51,52]

Partial agonists

• Partial agonists such as buprenorphine have less effect than full agonists at opioid receptors. They are subject to a ceiling effect and thus are less effective analgesics.

Mixed agonist-antagonists

• Mixed agonist-antagonists block or are neutral at one type of opioid receptor while activating a different opioid receptor. Mixed agonist-antagonists are contraindicated for use in the patient receiving an opioid agonist because they may precipitate a withdrawal syndrome and increase pain. Mixed agonist-antagonists include pentazocine (Talwin), butorphanol tartrate (Stadol), dezocine (Dalgan), and nalbuphine hydrochloride (Nubain). Their analgesic effectiveness is limited by a dose-related ceiling effect.

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]

Dosage

• The appropriate dosing interval is determined by the opioid and formulation used. The analgesic effects of short-acting oral opioids such as morphine, hydromorphone, codeine, and oxycodone begin within a half hour after administration and last for approximately 4 hours. The dosing interval of these drugs is usually 4 hours. In patients given controlled-release formulations of morphine, hydromorphone, codeine, or oxycodone, relief should begin in 1 hour, peak in 2 to 3 hours, and last for 12 hours (controlled-release hydromorphone and codeine are not available in the United States); these formulations are usually prescribed in 12-hour intervals. A small group of patients, however (10%–20% of those on 12-hour controlled-release formulations), may require administration every 8 hours. The analgesic effect of transdermal fentanyl begins approximately 12 hours after the application of the patch, peaks in 24 to 48 hours, and lasts for approximately 72 hours. Patches are therefore changed every 72 hours. In a select group of patients who consistently experience end-of-dose failure despite increases in the patch doses, the dosing interval can be increased to every 48 hours (<10% of patients on fentanyl patches). Transdermal fentanyl is not recommended for control of acute pain or poorly controlled pain because there is a delayed onset of action until reaching steady-state either with new use or with a change in the dose. Patients receiving transdermal fentanyl may be switched to a continuous IV or subcutaneous infusion of fentanyl using a conversion ratio of 1:1 to facilitate more rapid titration.[58]

Dose titration

• To date, dose titration is largely patient-driven, as determined by the balance of analgesia with side effects. For example, while morphine dose correlates with peak-and-trough plasma concentrations of a parent drug and its metabolites morphine-3-glucuronide and morphine-6-glucuronide, studies are conflicting with regard to the association between plasma levels of morphine and its metabolites versus analgesia as measured by pain scores.[59] The strong opioid agonists have no maximum dose or ceiling dose. The appropriate dose is the amount of opioid that controls pain with the fewest side effects. Dose titration should continue until good pain relief is achieved or intolerable side effects develop that cannot otherwise be controlled. The goal is to achieve a favorable balance between analgesia and side effects through gradual adjustment of the dose. If analgesic tolerance appears to be occurring, the dose can be increased or consideration given to switching the opioid, especially if higher doses are required.

  The severity of the pain and the opioid formulation chosen determine the rate of titration. The dose of immediate-release formulations can be increased on a daily basis if necessary until pain relief is adequate. Among patients receiving relatively low doses of opioids, those with uncontrolled moderate-intensity pain require daily increases of between 25% and 50% to their previous dose, while patients with severe uncontrolled pain may require a higher increase. At higher opioid doses, increases of 20% to 30% would be more prudent. Rapid dose escalation requires close monitoring for both efficacy and side effects. Preliminary data suggest that titration with sustained-release daily morphine is equivalent to titration with immediate-release morphine administered every 4 hours by an expert group of clinicians, but standard practice is to use a short-acting opioid for initial titration.[60]

  Occasionally, doses may need to be reduced or, rarely, stopped. This may occur when patients become pain free as a result of cancer treatment, including treatments such as nerve blocks and radiation therapy. Another time to consider reducing the dose is when a patient experiences significant opioid-related sedation that is accompanied by good pain control. In situations where interventions achieve complete pain relief, rapid opioid tapering rather than abrupt discontinuation is recommended and usually adequate.

Different types of opioids

• The debate regarding whether any individual opioid causes fewer side effects or is more effective is characterized by much speculation but little clinical evidence. These inconclusive findings have prompted expert working groups of the European Association of Palliative Care to recommend that there is currently little evidence of the clinical superiority of one opioid over another regarding the side-effect profile and/or analgesia.[12,13] Even constipation and other side effects may be positively affected by a switch. Compared with morphine, fentanyl may cause less constipation.[61,62] Studies suggesting that oxycodone and hydromorphone may cause less nausea and hallucinations than morphine [63] are juxtaposed with other studies that found no significant differences between them.[64-66] One study found that transdermal fentanyl was better tolerated than sustained-release oral morphine and equally effective.[67]

Tolerance

• Assume that patients actively abusing heroin or prescription opioids (including methadone) have some pharmacologic tolerance that will require higher starting doses and shorter dosing intervals.

Opioid therapy in special populations

• Health professionals should check current recommendations for opioid use in older people, children, people who are cognitively impaired, and known or suspected drug abusers.

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.[17,23,68-70] 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.[71-74] 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.[75]

• Guidelines for switching from one opioid to another

  Guidelines for opioid switching are intended to reduce the risk of relative overdosing or underdosing as one opioid is replaced by another. These guidelines require a working knowledge of an equianalgesic-dose table.[13,76] The equianalgesic-dose table provides only a broad guide for dose selection when switching from one opioid to another. Wide ranges in interindividual responses to the various opioids have been noted.[76] Therefore, because of incomplete cross-tolerance in most cases, the calculated dose-equivalent of a new drug must be reduced by 25% to 50% to ensure safety. These figures are based on clinical experience rather than empiric data. The selection of an alternative opioid is largely empirical. There is little clinical evidence to indicate that one opioid has therapeutic superiority over another opioid. A patient, for example, who requires a switch from morphine to another opioid can be switched to hydromorphone, oxycodone, fentanyl, or methadone.[77-79] In one prospective study of 186 cancer patients being treated with morphine, 25% did not respond and required switching to another opioid (oxycodone). The primary reasons for switching included pain, confusion, drowsiness, nightmares, and nausea. Of the 47 patients who required switching to an alternative opioid, 37 (79%) obtained good relief. This result provides beginning evidence for the prevalence of the need to switch, as well as determining the success rate once switching occurs.[80] Patients should be followed closely after a switch and should be reassessed, and the new opioid dose should be adjusted according to the intensity of pain and lack or presence of adverse effects.

Note: The values that appear in the table below 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.

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.[81,82] 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.[81-83]

Morphine, as the strong opioid of choice for the management of cancer pain, was used increasingly during the 1970s and 1980s.[84] 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.[84-91]

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.[92-96]

Switching from one opioid to another requires familiarity with a range of opioids and the use of opioid dose-conversion tables.[13,76] 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.[76] 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.)

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.

Rectal

• Use this safe, inexpensive, effective route for delivery of opioids as well as nonopioids when patients have nausea or vomiting. Rectal administration is inappropriate for the patient who has diarrhea, anal/rectal lesions, mucositis, thrombocytopenia, or neutropenia. The use of suppositories is not always culturally acceptable and may not be practical for patients who are obese, have fractures, are physically unable to place the suppository in the rectum, or prefer other routes. When changing from the oral to the rectal route, begin with the same dosage as had been given orally, then titrate as needed.

Transdermal (fentanyl)

• Patches currently available are formulated to provide analgesia lasting up to 72 hours. This preparation is not suitable for rapid dose titration and should be used for relatively stable analgesic requirements when rapid increases or decreases in dosage are not likely to be needed.[97,98] In the chronic setting, considerable inter- and intraindividual variability may exist in the rate of absorption of fentanyl from transdermal patches in patients receiving a stable dose of transdermal fentanyl.[99] Based on a case series, it has been proposed that conversion from transdermal to IV fentanyl using a 1:1 conversion ratio can be safe and effective during acute exacerbations of cancer pain.[58] Although other opioids are sometimes compounded into gel form for transdermal application, there is insufficient evidence to support this practice.

Transmucosal/Buccal (fentanyl)

• Oral transmucosal fentanyl citrate is used for the relief of breakthrough pain. The lipid solubility of fentanyl allows rapid onset of pain relief. In open-label studies, 72% to 92% of patients found a dose that provided relief from breakthrough pain. Side effects in these studies were consistent with other opioid therapies, including sedation, constipation, stomatitis, and nausea.[100,101] There is growing interest in the use of rapidly acting, highly lipophilic opioids such as fentanyl for the management of difficult breakthrough pain syndromes. An oral transmucosal fentanyl citrate compound for buccal administration has become available for this purpose.[102,103] A double-blind, randomized, placebo-controlled study included 77 patients assigned to dose sequences of fentanyl buccal tablets (FBT). Results demonstrated that FBT was efficacious and safe in treating cancer-related breakthrough pain.[104] Other opioids such as morphine, hydromorphone, and oxycodone are not very lipophilic and therefore not suited for buccal or sublingual administration. In the home setting, opioids are sometimes administered buccally or sublingually with erratic absorption that is likely via the lower gastrointestinal tract.

Parenteral: IV and subcutaneous

• IV administration provides a rapid onset of analgesia within 2 to 10 minutes. The duration of action after a bolus dose may be shorter than with other routes. This route may be useful if a patient cannot swallow and IV access is established.



• The subcutaneous route is as effective as the IV route.[12,105] In some situations, it may even be more convenient, especially if patients are being cared for at home or in a hospice. To facilitate administration via this route, a 25- or 27-gauge butterfly needle can be inserted subcutaneously and left in place for up to 7 days at a time. The anterior thighs, abdomen, upper arms, subclavicular area, and upper back are possible areas for needle insertion. The site should be monitored for signs of infection or irritation and should be changed if these are noted.



• The bioavailability of parenterally administered opioids (morphine, hydromorphone, oxycodone, and codeine) is generally 2 to 3 times that of the oral route. The dose therefore needs to be halved or decreased by a third when switching from the oral to the subcutaneous and IV routes, respectively (refer to the Approximate Dose Equivalents for Opioid Analgesics table). Opioids administered parenterally may be given either intermittently (usually every 4 hours) or by a continuous infusion. With some exceptions, these two methods appear to be similarly effective.

Other routes

• Some studies suggest that the use of inhaled opioids for the management of pain and cancer-related shortness of breath are, with some exceptions, not more effective than systemic administration.[106,107] Their absorption via this route is unpredictable.



• The intramuscular administration of opioids is not recommended.

Patient-Controlled Analgesia

• Patient-controlled analgesia (PCA) may be used to determine the opioid dose needs when initiating opioid therapy. Once the pain is well controlled, a regular opioid dose can be instituted on the basis of the PCA doses required. This method is contraindicated in patients with cognitive impairment or patients with significant psychological undercurrents to their pain experience.

Intraspinal

• The intraspinal administration of opioids (epidural or intrathecal), especially when combined with a local anesthetic, can be helpful in a very small select group of patients with intractable pain. Use of the epidural or intrathecal route requires skill and expertise that may not be available in all settings. The table below presents the advantages and disadvantages of intraspinal administration. Although intrathecal opioid therapy has been FDA approved since 1991, the utility of an implantable drug delivery system (IDDS) to deliver spinal opioids was only recently compared with comprehensive medical management (CMM) (based on the Agency for Health Care Policy and Research 1994 cancer pain management guidelines) in a randomized trial. There were 202 patients enrolled in this unblinded study. Of the 101 patients randomized to the IDDS, 51 actually received this therapy. Sixteen of these patients (31%) had serious adverse effects. Patients using the IDDS experienced more than 20% reduction in both pain and opioid toxicity more often than the CMM group (P = .02). These data and further analysis in follow-up reports [108,109] suggest that the use of an IDDS delivery system may offer benefit for some cancer patients. More research is needed to determine which subsets of patients will benefit the most from this device, and what the proper timing should be for a trial of intrathecal opioids.[110,111] An open-label study demonstrated that patients with refractory cancer pain experienced better pain relief, fewer opioid-associated side effects, and decreased systemic opioid use when managed with patient-activated intrathecal delivery of morphine via an implanted delivery system. The device was implanted in 119 patients. There were 7 serious adverse events related to the device and 55 serious adverse events related to the implant and delivery-system refill procedures. The FDA denied the application for market approval of this system.[78]

The following two tables present data on drugs and routes of administration not recommended for the management of cancer pain.

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.

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. All patients using opioid medications should be prescribed a scheduled regimen of stool-softening agents (e.g., docusate sodium) at the commencement of opioid treatment. 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.[62] 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.[112] 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.[113]

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.[114] Reports that fentanyl causes less constipation than oral morphine are interesting but need to be confirmed in further prospective studies.[113,115,61] A recent study demonstrated decreased laxative use in patients on transdermal fentanyl as compared with patients receiving oral morphine treatment.[61] 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.[116] Severe opioid-induced constipation may occur. At an extreme it may be present as a severe ileus and pseudo bowel obstruction.[117] 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.[118,119] 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 in the management of opioid-associated constipation without causing opioid withdrawal.[120] (Refer to the PDQ summaries on Gastrointestinal Complications; Nausea and Vomiting; and Nutrition in Cancer Care for more information.)

Nausea and vomiting occurs in approximately one third to two thirds of patients taking opioids.[121-123] 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.[124] 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.[124] Metoclopramide or domperidone are generally recommended as first-line agents because they improve gastrointestinal motility and are antidopaminergic.[124,125] 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.[126]

There appear to be differences between individual patients in the extent to which different opioids cause nausea.[127] These differences form the basis for the strategy of switching from one opioid to another when a particular opioid produces persistent nausea.[128,129] Switching the route, specifically from the oral to the parenteral, has also been suggested, but the study supporting this strategy is small.[130]

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.[131] Chronic nausea has been associated with the accumulation of active opioid metabolites.[90] 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.)

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.[132,133] 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.[71,134,135] In addition to cognitive impairment within the context of delirium, other effects include myoclonus, hyperalgesia, perceptual disturbance, and seizures.[136] 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,[137] chronic nonmalignant pain,[121,138] and in healthy volunteers.[139] Collectively, studies of neuropsychological testing have demonstrated somewhat mixed findings,[140] with some detecting opioid-associated impairment in certain aspects of psychomotor or cognitive function [138,139] and others detecting minimal or no impairment.[121,137] 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,[141] thereby allowing patients who are otherwise physically able, and on stable opioid doses, to safely engage in activities such as driving.[137,142]

Decreased brain cholinergic activity is recognized as one of the potential underlying pathophysiological mechanisms of delirium.[143-145] 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.[146,147] 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) [148] and normorphine-3-glucuronide,[149] and the hydromorphone metabolite, hydromorphone-3-glucuronide.[150] 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.[151] 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,[89,96,151-153] and some studies have noted an association with features of neurotoxicity, including cognitive impairment.[135,151] 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.[154] 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]

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.[134,154,155] Clinical experience suggests that the presence of tactile hallucinations and myoclonus,[82] 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.[156]

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,[157] and methotrimeprazine and chlorpromazine are considered useful alternatives,[158,159] 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.[160] 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.[161]

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.[162] 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.[83,134,163] This can reflect incomplete cross-tolerance among opioids in relation to analgesic and other effects.[164] It is also possible that switching to a new opioid could allow for the elimination of potentially toxic opioid metabolites.[165,166,134] 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,[165,167,129] controversy persists over the relative value of opioid switching versus dose reduction.[81]

Cognitive benefit has been reported with the use of methylphenidate in patients receiving a continuous infusion of opioids for cancer pain.[168] The psychostimulant benefit is likely to relate to mitigation of sedation associated with upward dose titration of opioid.[169] Although psychostimulants have been advocated for hypoactive delirium,[170]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.[171]

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.[172]

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.[173]

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.

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.[174-179] 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.[180,181] 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.[182] 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.)

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

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.[183] Adverse drug reactions are common, however, and there are wide interindividual and ethnic differences in drug metabolism.[184] 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%.[185] 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.[184] A further note of caution appears in another study that questioned the concept of opioid-sparing effects of co-analgesics.[186] 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.[187-190] Few trials compare adjuvant analgesics in the cancer setting.

Antidepressants

• The analgesic benefits of tricyclic antidepressants have been well established and are generally considered first-line therapy for many neuropathic pain syndromes.[187-190,217] 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.[192]



• 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.[199]

Anticonvulsants

• The group of commonly used anticonvulsants as adjuvant analgesics for neuropathic pain includes carbamazepine, valproate, phenytoin, and clonazepam.[187-190,217]

  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.[187] 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.[218-221,204,205] Commonly reported side effects include somnolence, dizziness, ataxia, and fatigue.[190,221] 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.[222]

  Clonazepam is an anticonvulsant from the benzodiazepine class and is commonly used for treating lancinating or paroxysmal neuropathic pain.[187] The patient must be monitored carefully for drowsiness and cognitive impairment.

Local anesthetics

• The use of mexiletine has been described for chronic neuropathic pain.[187,188,190] 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,[187] to a starting dose of dexamethasone 10 mg twice daily with subsequent tapering to the minimal effective dose.[223]

  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.[187]

  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.[187,224,189,190,223,225-228]

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.[187-190,229-232] Their use in a study of breast cancer patients resulted in improved quality of life compared with that of patients not using bisphosphonates.[233] The bisphosphonates most frequently used are clodronate, pamidronate,[234] and zoledronic acid.[235]



• Clodronate can be given orally or intravenously. Dosage recommendations are oral clodronate, 1,600 mg per day; 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.[236]



• 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.[237-240] The few studies to date suggest administration at 3- to 4-week intervals.[241]



• Ibandronate can be given orally or intravenously. Dosing recommendations are 50 mg orally daily or 6 mg intravenously every 3 to 4 weeks.[242]



• 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.[243]



• 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.[187,188,190] 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.[187,188,190,229,230] 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.[244] 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.[187,188,190] The maximum recommended dose is 2.4 mg per day.



• Psychostimulants
  • Psychostimulants such as dextroamphetamine, methylphenidate, and modafinil may enhance the analgesic effects of opioids.[168,169,189] 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.[187,245] Ketamine in subanesthetic doses has been used in this setting.[246] 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.[231] One study suggests short-duration therapy of a continuous subcutaneous infusion of ketamine over 3 to 5 days. The initial dose is 100 mg per day, and if pain control is inadequate, the dose is escalated to 300 mg per day and then to a maximum dose of 500 mg per day. Treatment is continued for 3 days at either the lowest effective dose or 500 mg per day and then discontinued.[245] A systematic review of the benefits and harms of ketamine in managing cancer pain revealed a general lack of studies and small subject numbers,[247,248] precluding a definitive conclusion on benefits and harms.
  
  
  
  • Methadone, particularly the racemic mixture, appears to have significant NMDA-antagonist properties.[249] 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.[250] This may explain the often-unanticipated high potency of methadone.
  
  
  
  • Dextromethorphan (DM), a commonly prescribed antitussive, may also have NMDA-blocking properties.[250] 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.[251,252] 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.[253] 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.[254]

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169. Bruera E, Fainsinger R, MacEachern T, et al.: The use of methylphenidate in patients with incident cancer pain receiving regular opiates. A preliminary report. Pain 50 (1): 75-7, 1992.  [PUBMED Abstract]
     
     
170. Stiefel F, Bruera E: Psychostimulants for hypoactive-hypoalert delirium? J Palliat Care 7 (3): 25-6, 1991 Autumn.  [PUBMED Abstract]
     
     
171. Bruera E, Strasser F, Shen L, et al.: The effect of donepezil on sedation and other symptoms in patients receiving opioids for cancer pain: a pilot study. J Pain Symptom Manage 26 (5): 1049-54, 2003.  [PUBMED Abstract]
     
     
172. Estfan B, Mahmoud F, Shaheen P, et al.: Respiratory function during parenteral opioid titration for cancer pain. Palliat Med 21 (2): 81-6, 2007.  [PUBMED Abstract]
     
     
173. O'Mahony S, Coyle N, Payne R: Current management of opioid-related side effects. Oncology (Huntingt) 15 (1): 61-73, 77; discussion 77-8, 80-2, 2001.  [PUBMED Abstract]
     
     
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175. Pelosi MA, Sama JC, Caterini H, et al.: Galactorrhea-amenorrhea syndrome associated with heroin addiction. Am J Obstet Gynecol 118 (7): 966-70, 1974.  [PUBMED Abstract]
     
     
176. Cicero TJ, Bell RD, Wiest WG, et al.: Function of the male sex organs in heroin and methadone users. N Engl J Med 292 (17): 882-7, 1975.  [PUBMED Abstract]
     
     
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178. Chan V, Wang C, Yeung RT: Effects of heroin addiction on thyrotrophin, thyroid hormones and porlactin secretion in men. Clin Endocrinol (Oxf) 10 (6): 557-65, 1979.  [PUBMED Abstract]
     
     
179. Spagnolli W, Torboli P, Mattarei M, et al.: Calcitonin and prolactin serum levels in heroin addicts: study on a methadone treated group. Drug Alcohol Depend 20 (2): 143-8, 1987.  [PUBMED Abstract]
     
     
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181. Paice JA, Penn RD: Amenorrhea associated with intraspinal morphine. J Pain Symptom Manage 10 (8): 582-3, 1995.  [PUBMED Abstract]
     
     
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187. Portenoy RK, Frager G: Pain management: pharmacological approaches. In: von Gunten CF, ed.: Palliative Care and Rehabilitation of Cancer Patients. Boston, Mass: Kluwer Academic Publishers, 1999, pp 1-29. 
     
     
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197. Raskin J, Pritchett YL, Wang F, et al.: A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 6 (5): 346-56, 2005 Sep-Oct.  [PUBMED Abstract]
     
     
198. Raja SN, Haythornthwaite JA, Pappagallo M, et al.: Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 59 (7): 1015-21, 2002.  [PUBMED Abstract]
     
     
199. Tasmuth T, Härtel B, Kalso E: Venlafaxine in neuropathic pain following treatment of breast cancer. Eur J Pain 6 (1): 17-24, 2002.  [PUBMED Abstract]
     
     
200. Reuben SS, Makari-Judson G, Lurie SD: Evaluation of efficacy of the perioperative administration of venlafaxine XR in the prevention of postmastectomy pain syndrome. J Pain Symptom Manage 27 (2): 133-9, 2004.  [PUBMED Abstract]
     
     
201. Rowbotham MC, Goli V, Kunz NR, et al.: Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain 110 (3): 697-706, 2004.  [PUBMED Abstract]
     
     
202. Harke H, Gretenkort P, Ladleif HU, et al.: The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study. Anesth Analg 92 (2): 488-95, 2001.  [PUBMED Abstract]
     
     
203. Kochar DK, Garg P, Bumb RA, et al.: Divalproex sodium in the management of post-herpetic neuralgia: a randomized double-blind placebo-controlled study. QJM 98 (1): 29-34, 2005.  [PUBMED Abstract]
     
     
204. Caraceni A, Zecca E, Bonezzi C, et al.: Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol 22 (14): 2909-17, 2004.  [PUBMED Abstract]
     
     
205. Ross JR, Goller K, Hardy J, et al.: Gabapentin is effective in the treatment of cancer-related neuropathic pain: a prospective, open-label study. J Palliat Med 8 (6): 1118-26, 2005.  [PUBMED Abstract]
     
     
206. Levendoglu F, Ogün CO, Ozerbil O, et al.: Gabapentin is a first line drug for the treatment of neuropathic pain in spinal cord injury. Spine 29 (7): 743-51, 2004.  [PUBMED Abstract]
     
     
207. Hugel H, Ellershaw JE, Dickman A: Clonazepam as an adjuvant analgesic in patients with cancer-related neuropathic pain. J Pain Symptom Manage 26 (6): 1073-4, 2003.  [PUBMED Abstract]
     
     
208. Simpson DM, McArthur JC, Olney R, et al.: Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology 60 (9): 1508-14, 2003.  [PUBMED Abstract]
     
     
209. Lesser H, Sharma U, LaMoreaux L, et al.: Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 63 (11): 2104-10, 2004.  [PUBMED Abstract]
     
     
210. Oskarsson P, Ljunggren JG, Lins PE: Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. The Mexiletine Study Group. Diabetes Care 20 (10): 1594-7, 1997.  [PUBMED Abstract]
     
     
211. Meier T, Wasner G, Faust M, et al.: Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 106 (1-2): 151-8, 2003.  [PUBMED Abstract]
     
     
212. Polascik TJ, Given RW, Metzger C, et al.: Open-label trial evaluating the safety and efficacy of zoledronic acid in preventing bone loss in patients with hormone-sensitive prostate cancer and bone metastases. Urology 66 (5): 1054-9, 2005.  [PUBMED Abstract]
     
     
213. Dapas F, Hartman SF, Martinez L, et al.: Baclofen for the treatment of acute low-back syndrome. A double-blind comparison with placebo. Spine 10 (4): 345-9, 1985.  [PUBMED Abstract]
     
     
214. Lavand'homme PM, Eisenach JC: Perioperative administration of the alpha2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression. Pain 105 (1-2): 247-54, 2003.  [PUBMED Abstract]
     
     
215. Bruera E, Chadwick S, Brenneis C, et al.: Methylphenidate associated with narcotics for the treatment of cancer pain. Cancer Treat Rep 71 (1): 67-70, 1987.  [PUBMED Abstract]
     
     
216. Cantello R, Aguggia M, Gilli M, et al.: Analgesic action of methylphenidate on parkinsonian sensory symptoms. Mechanisms and pathophysiological implications. Arch Neurol 45 (9): 973-6, 1988.  [PUBMED Abstract]
     
     
217. George RM, Ahmedzai SH: The management of neuropathic pain in cancer: clinical guidelines for the use of adjuvant analgesics. Indian J Cancer 37 (1): 4-9, 2000.  [PUBMED Abstract]
     
     
218. Caraceni A, Zecca E, Martini C, et al.: Differences in gabapentin efficacy for cancer pain more apparent than real? J Pain Symptom Manage 21 (2): 93-4, 2001.  [PUBMED Abstract]
     
     
219. Chandler A, Williams JE: Gabapentin, an adjuvant treatment for neuropathic pain in a cancer hospital. J Pain Symptom Manage 20 (2): 82-6, 2000.  [PUBMED Abstract]
     
     
220. Caraceni A, Zecca E, Martini C, et al.: Gabapentin as an adjuvant to opioid analgesia for neuropathic cancer pain. J Pain Symptom Manage 17 (6): 441-5, 1999.  [PUBMED Abstract]
     
     
221. Oneschuk D, al-Shahri MZ: The pattern of gabapentin use in a tertiary palliative care unit. J Palliat Care 19 (3): 185-7, 2003 Fall.  [PUBMED Abstract]
     
     
222. Keskinbora K, Pekel AF, Aydinli I: Gabapentin and an opioid combination versus opioid alone for the management of neuropathic cancer pain: a randomized open trial. J Pain Symptom Manage 34 (2): 183-9, 2007.  [PUBMED Abstract]
     
     
223. Watanabe S, Bruera E: Corticosteroids as adjuvant analgesics. J Pain Symptom Manage 9 (7): 442-5, 1994.  [PUBMED Abstract]
     
     
224. Lussier D, Huskey AG, Portenoy RK: Adjuvant analgesics in cancer pain management. Oncologist 9 (5): 571-91, 2004.  [PUBMED Abstract]
     
     
225. Hardy J, Ling J, Mansi J, et al.: Pitfalls in placebo-controlled trials in palliative care: dexamethasone for the palliation of malignant bowel obstruction. Palliat Med 12 (6): 437-42, 1998.  [PUBMED Abstract]
     
     
226. Hardy J: Corticosteroids in palliative care. European Journal of Palliative Care 5(2): 46-50, 1998. 
     
     
227. Feuer DJ, Broadley KE: Corticosteroids for the resolution of malignant bowel obstruction in advanced gynaecological and gastrointestinal cancer. Cochrane Database Syst Rev (2): CD001219, 2000.  [PUBMED Abstract]
     
     
228. Wooldridge JE, Anderson CM, Perry MC: Corticosteroids in advanced cancer. Oncology (Huntingt) 15 (2): 225-34; discussion 234-6, 2001.  [PUBMED Abstract]
     
     
229. Ripamonti C, Fulfaro F: Malignant bone pain: pathophysiology and treatments. Curr Rev Pain 4 (3): 187-96, 2000.  [PUBMED Abstract]
     
     
230. Ripamonti C, Fulfaro F: Pathogenesis and pharmacological treatment of bone pain in skeletal metastases. Q J Nucl Med 45 (1): 65-77, 2001.  [PUBMED Abstract]
     
     
231. McDonnell FJ, Sloan JW, Hamann SR: Advances in cancer pain management. Curr Pain Headache Rep 5 (3): 265-71, 2001.  [PUBMED Abstract]
     
     
232. Rodrigues P, Hering F, Campagnari JC: Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients. Prostate Cancer Prostatic Dis 7 (4): 350-4, 2004.  [PUBMED Abstract]
     
     
233. Diel IJ, Body JJ, Lichinitser MR, et al.: Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer. Eur J Cancer 40 (11): 1704-12, 2004.  [PUBMED Abstract]
     
     
234. Lucas LK, Lipman AG: Recent advances in pharmacotherapy for cancer pain management. Cancer Pract 10 (Suppl 1): S14-20, 2002 May-Jun.  [PUBMED Abstract]
     
     
235. Weinfurt KP, Anstrom KJ, Castel LD, et al.: Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol 17 (6): 986-9, 2006.  [PUBMED Abstract]
     
     
236. 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 Abstract]
     
     
237. Berenson JR, Rosen LS, Howell A, et al.: Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 91 (7): 1191-200, 2001.  [PUBMED Abstract]
     
     
238. Rosen LS, Gordon D, Antonio BS, et al.: Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 7 (5): 377-87, 2001 Sep-Oct.  [PUBMED Abstract]
     
     
239. 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 Abstract]
     
     
240. 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 Abstract]
     
     
241. 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 Abstract]
     
     
242. 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 Abstract]
     
     
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245. 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 Abstract]
     
     
246. Lossignol DA, Obiols-Portis M, Body JJ: Successful use of ketamine for intractable cancer pain. Support Care Cancer 13 (3): 188-93, 2005.  [PUBMED Abstract]
     
     
247. Bell R, Eccleston C, Kalso E: Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev (1): CD003351, 2003.  [PUBMED Abstract]
     
     
248. 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 Abstract]
     
     
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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]

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.

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 is not a substitute for active exercise in ambulatory patients.

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 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]



• Acupuncture: Pain is treated by inserting small, solid needles into the skin, with or without the application of electrical current. Needle placement follows the Eastern theory of vital energy flow. (Refer to the PDQ summary on Acupuncture for more information.)

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.[3] 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.[4] Realistic expectations are needed for delivery of cognitive-behavioral interventions. One study [5] 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. Hypnosis is effective in relieving pain in individuals who can concentrate well, can use imagery, and are motivated to practice.

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.[6-8] 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.[9] Educational intervention programs to help patients who have cancer and their families manage pain have been described and may improve clinical outcomes.[10] 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.[11,12] Training partners to participate in management of cancer pain increases partner self-efficacy for controlling their loved one's pain and other symptoms.[13]

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

• 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. Some examples are
     • 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.

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

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.  [PUBMED Abstract]
   
   
2. 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.  [PUBMED Abstract]
   
   
3. 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 Abstract]
   
   
4. 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.  [PUBMED Abstract]
   
   
5. 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.  [PUBMED Abstract]
   
   
6. 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.  [PUBMED Abstract]
   
   
7. Miaskowski C, Dodd M, West C, et al.: Randomized clinical trial of the effectiveness of a self-care intervention to improve cancer pain management. J Clin Oncol 22 (9): 1713-20, 2004.  [PUBMED Abstract]
   
   
8. Miaskowski C, Dodd M, West C, et al.: The use of a responder analysis to identify differences in patient outcomes following a self-care intervention to improve cancer pain management. Pain 129 (1-2): 55-63, 2007.  [PUBMED Abstract]
   
   
9. 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.  [PUBMED Abstract]
   
   
10. 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.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. 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.  [PUBMED Abstract]
    
    

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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]

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 somewhat more often after single-fraction therapy.[4,5] 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.[6]

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,[7-9] 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.[10]

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.[11] Further study to determine potential risks and benefits may be warranted.[12]

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
6. 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 Abstract]
   
   
7. 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 Abstract]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. 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 Abstract]
   
   
10. 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 Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
12. 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 Abstract]
    
    

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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.

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:

• Diagnostic: To determine the source of pain (e.g., somatic versus sympathetic pathways).



• Therapeutic: To treat painful conditions that respond to nerve blocks (e.g., celiac block for pain of pancreatic cancer).



• Prognostic: To predict the outcome of long-lasting interventions (e.g., infusions, neurolysis, rhizotomy).



• Preemptive: To prevent procedure-related pain.

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]

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.

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.  [PUBMED Abstract]
   
   

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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.

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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:

• Multiple chronic diseases and sources of pain.

  Age and complex medication regimens place them at increased risk for drug-drug and drug-disease interactions.




• Visual, hearing, motor, and cognitive impairments.

  The use of simple descriptive, numeric, and visual-analog pain-assessment instruments may be impeded. Cognitively impaired patients may require simpler scales and more frequent pain assessment.




• Nonsteroidal anti-inflammatory drug (NSAID) side effects.

  Although effective alone or as adjuncts to opioids, NSAIDs are more likely to cause gastric and renal toxicity and other drug reactions such as cognitive impairment, constipation, and headaches in older patients. Alternative NSAIDs (e.g., choline magnesium trisalicylate) or coadministration of misoprostol with NSAIDs should be considered to reduce gastric toxicity.




• Opioid effectiveness.

  Older persons tend to be more sensitive to the analgesic and central nervous system depressant effects of opioids. Peak opioid effects are generally greater and the duration of pain relief may be longer.




• Patient-controlled analgesia.

  Slower drug clearance and increased sensitivity to undesirable drug effects (e.g., cognitive impairment) indicate the need for cautious initial dosing and subsequent titration and monitoring of continuous parenteral infusions.




• Alternative routes of administration.

  Although useful for patients who have nausea or vomiting, the rectal route may be inappropriate for elderly or infirm patients who are physically unable to place the suppository in the rectum.




• Postoperative pain control.

  Following surgery, surgeons and other health care team members should maintain frequent direct contact with the elderly patient to reassess the quality of pain management.




• Change of setting.

  Reassessment of pain management and appropriate changes should be made whenever the elderly patient moves (e.g., from hospital to home or nursing home).

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Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.

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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 our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most closely related to your search term will be listed as Best Bets at the top of the list of search results.

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), TTY at 1-800-332-8615.

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Changes to This Summary (07/10/2008)

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.

Editorial changes were made to this summary.

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• PDQ® - NCI's Comprehensive Cancer Database.

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Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)

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• PDQ® Cancer Information Summaries: Genetics

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• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine

  Information about complementary and alternative forms of treatment for patients with cancer.

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