National Cancer Institute
Last Modified: July 20, 2012
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 often cannot 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.
The U.S. Food and Drug Administration Amendments Act of 2007 requires manufacturers to provide risk evaluation and mitigation strategies (REMS) for selected drugs to ensure that benefits outweigh risks. A major component of REMS requires prescribers to obtain training so that these drugs can be safely used.
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.
In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.
Check NCI's list of cancer clinical trials for U.S. supportive and palliative care trials about pain that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Identifying the etiology of pain is important to its management. Clinicians treating patients with cancer should recognize the common cancer pain syndromes (see lists below). Prompt diagnosis and treatment of these syndromes can reduce morbidity associated with unrelieved pain. Distinct cultural components may need to be incorporated into a multidimensional assessment of pain. 1 2 3 4 Reviews of cancer pain with a focus on neuropathic pain describes pathophysiologies as well as available and investigational pharmacotherapies. 5 6[Level of evidence: II]
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. 7[Level of evidence: II] Factors that may influence analgesic response and result in persistent pain include changing nociception due to disease progression, intractable side effects, tolerance, neuropathic pain, and opioid metabolites. 8[Level of evidence: IV] The following are essential to the initial assessment:
The experience of cancer pain is complex and includes physical, psychosocial, and spiritual dimensions. There is no universally accepted pain classification measure that assists with predicting the complexity of pain management, particularly for cancer pain patients, who may be more difficult to treat. Clinicians and researchers lack a common language to discuss and compare outcomes of cancer pain assessment and management. Oncologists use the tumor, nodes, metastases (TNM) system as a universal language to describe a variety of cancers. The need for a similar classification system for cancer pain resulted in the development of the Edmonton Staging System. 10 11 This system has been further refined in two reports that have gathered construct validity evidence using an international panel of content experts 12 and a multicenter study to determine interrater reliability and predictive value. 13 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. 14[Level of evidence: II]
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. 15 16[Level of evidence: II] Differences in clinician assessment of pain intensity are also significant. A retrospective review of 41 patient charts using pain ratings of palliative care consultants as the gold standard found high agreement with assessments performed by bedside nurses (registered nurses [RNs] and clinical nurse assistants [CNAs]) when pain was not present or was mild but poor agreement for moderate or severe pain (sensitivity: RNs, 45%; CNAs, 30%). 17[Level of evidence: III]
Pain assessment tools may be unidimensional or multidimensional. Multiple assessment tools exist. Among the more commonly used bedside tools are numeric rating scales, verbal rating scales, visual analog scales, and picture scales. 18 19[Level of evidence: IV] Pain intensity at initial assessment has been demonstrated to be a significant predictor of subsequent pain management complexity (i.e., the need for more pharmacological and multidimensional approaches) and length of time to achieve stable pain control. 20[Level of evidence: II] To enhance pain management across all settings, clinicians should teach families to use pain assessment tools in their homes. The clinician should help the patient to describe:
A thorough physical examination is required to determine the pathophysiology of pain. Specific features of the neurologic examination such as altered sensation (hypoesthesia, hyperesthesia, hyperpathia, allodynia) in a painful area are suggestive of neuropathic pain. Physical findings of tumor growth and metastasis are also important to identify.
Information obtained from the synthesis of history, physical examination, and diagnostic evaluations is used to generate a pain diagnosis with respect to etiology (cancer, its treatment, or other) and pathophysiology (somatic, visceral, and/or neuropathic). This diagnosis, in conjunction with contributing psychosocial and spiritual factors, is used to generate a comprehensive pain treatment plan.
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. 26 27
Drug-taking outcomes: Clinicians prescribing chronic opioids should also monitor and document patients' drug-taking behaviors. Outcomes related to addiction in cancer patients are rare but nonetheless should be periodically assessed; these assessments can be reassuring to patients. Tolerance and dependence are not addiction related. Documentation of patients' compliance with regard to changes in dosing and duration of prescriptions is essential in all pain practice.
The clinical assessment of drug-taking behaviors in medically ill patients with pain is complex. Aberrant drug-taking behavior from cancer pain management is related to premorbid history of drug addiction and the likelihood of other pain treatment. A pilot questionnaire was used to characterize drug-related behaviors and attitudes in cancer and AIDS patients. Despite limitations, this study highlights wide potential variation among different palliative care populations in patterns of past and present aberrant drug-taking behaviors and the need for a clinically useful screening approach. The implications for psychosocial and pharmacological management of symptoms such as pain, as well as any aberrant behavior, remain unclear. 28 29 30
Previous drug abuse is likely to lead to specific needs for appropriate dosing during cancer pain therapy. A prospective open-label study compared morphine dosage and effectiveness in AIDS patients with and without previous substance abuse. Results demonstrated that both groups benefited, but patients with a history of drug use required and tolerated substantially higher morphine doses to achieve stable pain control. 31[Level of evidence: II] This study should increase confidence in providing appropriate pain management to patients who have a history of drug use. 32[Level of evidence: IV]
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 the patient's individual circumstances and physical condition.
NSAIDs are effective for relief of mild pain and may have an opioid dosesparing effect that helps reduce side effects when given with opioids for moderate-to-severe pain. Acetaminophen is included with aspirin and other NSAIDs because it has similar analgesic potency, though it lacks peripheral anti-inflammatory activity. 2[Level of evidence: I] Side effects can occur at any time, and patients who take acetaminophen or NSAIDs, especially elderly patients, should be followed up carefully. 3 4 5 There is growing debate about whether NSAIDs are useful and have significant opioid-sparing effects. One meta-analysis 6 suggests that the usefulness of NSAIDs is limited and that they do not significantly spare opioid doses. Another study suggests that NSAIDs are useful and reduce the need for opioid dose increases; however, only patients with pain progression after 1 week of opioid stabilization were selected for the study. 7[Level of evidence: I]
The coxibs are a subclass of NSAIDs designed to selectively inhibit cyclooxygenase-2 (COX-2). 8 Development of these drugs was based on the hypothesis that COX-2 was the source of prostaglandins E2 and I2, which mediate inflammation, and that COX-1 was the source of the same prostaglandins in gastric epithelium, with the potential advantage of less gastrointestinal ulceration and bleeding and the absence of platelet inhibition over traditional NSAIDs. Direct comparisons between COX-2 inhibitors are few. A systematic meta-analysis of COX-2 inhibitors compared with traditional NSAIDs or different COX-2 inhibitors for postoperative pain suggests that rofecoxib, 50 mg, and parecoxib, 40 mg, are equipotent to traditional NSAIDs for postoperative pain after minor and major surgical procedures and have a longer duration of action after dental surgery. Rofecoxib was found to provide superior analgesic effect compared with celecoxib, 200 mg. There were insufficient data to comment on toxicity. 9[Level of evidence: I]
There are three coxibs that were approved by the U.S. Food and Drug Administration (FDA): celecoxib, rofecoxib, and valdecoxib. On September 30, 2004, rofecoxib was withdrawn from the market after a study demonstrated that subjects in a colon cancer prevention trial who took the drug at higher-than-typical doses on a long-term basis had a significant increase in the incidence of serious thromboembolic complications. The question that remains unanswered is whether the increased risk applies to all COX-2 inhibitors, with the caution that the burden of proof rests with those who might claim that this is a problem for rofecoxib alone and does not extend to other coxibs. 8 10 On April 7, 2005, valdecoxib was withdrawn from the market. FDA is also asking manufacturers of all marketed prescription NSAIDs, including celecoxib (Celebrex), to revise the labeling (package insert) for their products to include a boxed warning, highlighting the potential for increased risk of cardiovascular events and/or the serious, potentially life-threatening gastrointestinal bleeding associated with use of these drugs.
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.
|Drug||Usual Dose for Adults and Children 50 kg Body Weight||Usual Dose for Adults and Childrenb <50 kg Body Weight|
|Orally Administered Acetaminophen and Over-the-counter NSAIDs|
|acetaminophenc||650 mg q4h||1015 mg/kg q4h|
|975 mg q6h||1520 mg/kg q4h (rectal)|
|aspirind||650 mg q4h||1015 mg/kg q4h|
|975 mg q6h||1520 mg/kg q4h (rectal)|
|ibuprofen (Motrin, Advil)||400600 mg q6h||510 mg/kg q46h|
|magnesium salicylate (Doan's, Magan, Mobidin, others)||650 mg q4h|
|naproxen (Naprosyn, Aleve)||250275 mg q68h||5 mg/kg q8h|
|naproxen sodium (Anaprox)||275 mg q68h|
|carprofen (Rimadyl)||100 mg tid|
|choline magnesium trisalicylatee (Trilisate)||1,0001,500 mg q68h||25 mg/kg q68h|
|choline salicylatee (Arthropan)||870 mg q34h|
|diclofenac (oral) (Voltaren - 1% topical; Pennsaid - 1.5% topical)||50 mg bidtid oral; 32 g/d topical||Flector (patch): 1 patch bid|
|diflunisalf (Dolobid)||500 mg q12h|
|etodolac (Lodine)||200400 mg q68h|
|fenoprofen calcium (Nalfon)||300600 mg q6h|
|ketoprofen (Orudis)||2560 mg q68h|
|ketorolac tromethamineg (Toradol)||10 mg q46h to a maximum of 40 mg/d|
|IV administration should not exceed 5 days|
|meclofenamate sodiumh (Meclomen)||50100 mg q6h|
|mefenamic acid (Ponstel)||250 mg q6h|
|sodium salicylate (Anacin, Bufferin)||325650 mg q34h|
|acetaminophen injection||1,000 mg q6h (adults)||15 mg/kg max, 75 mg/kg in 24 h (children aged <13 y)|
|ketorolac tromethamineg,i (Toradol)||60 mg initially, then 30 mg q6h|
|IV administration should not exceed 5 days|
|bid = twice a day; IV = intravenous; NSAID = nonsteroidal anti-inflammatory drug; q = every; tid = 3 times a day.|
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 administrationtolerance and physical dependenceare 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, oxymorphone, methadone, and fentanyl. Knowledge of several medications and formulations gives the caregiver much more flexibility in tailoring a regime to a particular patient's needs.
Short-acting opioids are generally recommended when opioid therapy is being initiated for the first time or when patients are medically unstable or the pain intensity is highly variable. Once stable, patients can be switched to a controlled-release or slow-release formulation. This is more convenient and promotes compliance. (Refer to Table 3 in the Principles of Opioid Administration section of this summary for more information.)
Methadone has had a revival in interest for the management of cancer pain. Published reports have been in the form of case reports, 14 15 16 17 18 19 20[[Level of evidence: IIILevel of evidence: III] outcome surveys,] outcome surveys, 21 22 23 24 25[[Level of evidence: IILevel of evidence: II][Level of evidence: IIILevel of evidence: III] and reviews.] and reviews. 26 27 28[[Level of evidence: IVLevel of evidence: IV] Success has been reported with oral, intravenous (IV), and suppository methadone use. Subcutaneous ] 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.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[[Level of evidence: IILevel of evidence: II]]
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[[Level of evidence: ILevel of evidence: I]]
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 clinician