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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.
The highest prevalence of severe pain occurs in adult patients with advanced cancer. Chronic pain is an issue in cancer patients, with up to 33% continuing to have pain after curative therapy. During active cancer treatment and in advanced disease states, tumors cause most pain. However, survivors are affected more by pain related to modalities such as surgery, chemotherapy, or radiation therapy than by cancer-related pain. One summary provides an excellent review of troublesome symptoms in cancer survivors, including pain.[Level of evidence: IV]
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. Despite the wide range of available pain management therapies, data are insufficient to guide their use in children, adolescents, older adults, and special populations.
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.
Barriers to Effective Pain Management
Flexibility is the key to managing cancer pain. As patients vary in diagnosis, stage of disease, responses to pain and interventions, and personal preferences, so must pain management. The recommended clinical approach outlined below emphasizes a focus on patient involvement.
Highlights of Patient Management
Effective pain management is best achieved by a team approach involving patients, their families, and health care providers. The clinician should:
In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.
Current Clinical Trials
Check 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.
Failure to assess pain is a critical factor leading to undertreatment. Assessment involves both the clinician and the patient. Assessment should occur at the following times:
Effective pain management requires close monitoring of patient response to initiation of treatment. In a review of 1,612 patients referred to an outpatient palliative care center where patients with advanced cancer were seen by both a palliative care nurse and a physician, more than half of patients with moderate to severe pain did not respond to an initial palliative care consultation, with response defined as a two-point or more reduction or a 30% or more reduction from baseline. Also, one-third of patients with mild pain actually progressed to moderate to severe pain by the time of their first follow-up visit. The authors concluded that more frequent follow-up visits, calls, and interdisciplinary clinics should be considered in an effort to optimize pain control. The study also identified baseline pain intensity, fatigue, and Edmonton Symptom Assessment System symptom burden as factors predicting response.[Level of evidence: III]
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.[2,3,4,5] Reviews of cancer pain with a focus on neuropathic pain describes pathophysiologies as well as available and investigational pharmacotherapies.[6,7][Level of evidence: II]
Common Pain Syndromes: Pain Associated with Tumor
Common Pain Syndromes: Pain Secondary to Treatment
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.[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.[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.[11,12] This system has been further refined in two reports that have gathered construct validity evidence using an international panel of content experts  and a multicenter study to determine interrater reliability and predictive value. 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.[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.[16,17][Level of evidence: II] Differences in clinician assessment of pain intensity are also significant. A retrospective review of 41 patient charts using pain ratings of palliative care consultants as the gold standard found high agreement with assessments performed by bedside nurses (registered nurses [RNs] and clinical nurse assistants [CNAs]) when pain was not present or was mild but poor agreement for moderate or severe pain (sensitivity: RNs, 45%; CNAs, 30%).[Level of evidence: III]
Pain assessment tools may be unidimensional or multidimensional. Multiple assessment tools exist. Among the more commonly used bedside tools are numeric rating scales, verbal rating scales, visual analog scales, and picture scales.[19,20][Level of evidence: IV] Pain intensity at initial assessment has been demonstrated to be a significant predictor of subsequent pain management complexity (i.e., the need for more pharmacological and multidimensional approaches) and length of time to achieve stable pain control.[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:
Changes in Pattern
Intensity or Severity
Aggravating and Relieving Factors
Cognitive Response to Pain
Goals for Pain Control
A thorough physical examination is required to determine the pathophysiology of pain. Specific features of the neurologic examination such as altered sensation (hypoesthesia, hyperesthesia, hyperpathia, allodynia) in a painful area are suggestive of neuropathic pain. Physical findings of tumor growth and metastasis are also important to identify.
Information obtained from the synthesis of history, physical examination, and diagnostic evaluations is used to generate a pain diagnosis with respect to etiology (cancer, its treatment, or other) and pathophysiology (somatic, visceral, and/or neuropathic). This diagnosis, in conjunction with contributing psychosocial and spiritual factors, is used to generate a comprehensive pain treatment plan.
Assessment of the Outcomes of Pain Management
Pain-related outcomes: Clinicians should document and be aware of outcomes of pain therapy. It is helpful to think of pain-related outcomes as primarily measured in two ways: decreased pain intensity and improvement in psychosocial functioning. Using rating scales of pain intensity at its worst and on average and using pain interference scales can help clinicians monitor outcomes. Measurement of the percentage of pain relief is also useful, though measuring patient satisfaction is less useful because of the low expectations patients sometimes hold for pain control.[28,29]
Drug-taking outcomes: Clinicians prescribing chronic opioids should also monitor and document patients' drug-taking behaviors. Outcomes related to addiction in cancer patients are rare but nonetheless should be periodically assessed; these assessments can be reassuring to patients. Tolerance and dependence are not addiction related. Documentation of patients' compliance with regard to changes in dosing and duration of prescriptions is essential in all pain practice.
The clinical assessment of drug-taking behaviors in medically ill patients with pain is complex. Aberrant drug-taking behavior from cancer pain management is related to premorbid history of drug addiction and the likelihood of other pain treatment. A pilot questionnaire was used to characterize drug-related behaviors and attitudes in cancer and AIDS patients. Despite limitations, this study highlights wide potential variation among different palliative care populations in patterns of past and present aberrant drug-taking behaviors and the need for a clinically useful screening approach. The implications for psychosocial and pharmacological management of symptoms such as pain, as well as any aberrant behavior, remain unclear.[30,31,32]
Previous drug abuse is likely to lead to specific needs for appropriate dosing during cancer pain therapy. A prospective open-label study compared morphine dosage and effectiveness in AIDS patients with and without previous substance abuse. Results demonstrated that both groups benefited, but patients with a history of drug use required and tolerated substantially higher morphine doses to achieve stable pain control.[Level of evidence: II] This study should increase confidence in providing appropriate pain management to patients who have a history of drug use.[Level of evidence: IV]
Basic Principles of Cancer Pain Management
The World Health Organization (WHO) has described a three-step analgesic ladder as a framework for pain management. It involves a stepped approach based on the severity of the pain. If the pain is mild, one may begin by prescribing a Step 1 analgesic such as acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). Potential adverse effects should be noted, particularly the renal and gastrointestinal adverse effects of the NSAIDs. If pain persists or worsens despite appropriate dose increases, a change to a Step 2 or Step 3 analgesic is indicated. Most patients with cancer pain will require a Step 2 or Step 3 analgesic. Step 1 can be skipped in favor of Step 2 or Step 3 in patients presenting at the onset with moderate-to-severe pain. At each step, an adjuvant drug or modality such as radiation therapy may be considered in selected patients. WHO recommendations are based on worldwide availability of drugs and not strictly on pharmacology.
Analgesics should be given "by mouth, by the clock, by the ladder, and for the individual." This requires regular scheduling of the analgesic, not just as needed. In addition, rescue-doses for breakthrough pain need to be added. The oral route is preferred as long as a patient is able to swallow. Each analgesic regimen should be adjusted for the patient's individual circumstances and physical condition.
Acetaminophen and Nonsteroidal Anti-inflammatory Drugs
NSAIDs are effective for relief of mild pain and may have an opioid dose–sparing effect that helps reduce side effects when given with opioids for moderate-to-severe pain. Acetaminophen is included with aspirin and other NSAIDs because it has similar analgesic potency, though it lacks peripheral anti-inflammatory activity.[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  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.[Level of evidence: I] Patients taking NSAIDs are at risk for platelet dysfunction that may impair blood clotting. Table 1 lists NSAIDs with minimal antiplatelet activity.
The coxibs are a subclass of NSAIDs designed to selectively inhibit cyclooxygenase-2 (COX-2). 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.[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.
Route of administration
Other side effects
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.
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; 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. 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: III] outcome surveys,[21,22,23,24,25][Level of evidence: II][Level of evidence: III] and reviews.[26,27,28][Level of evidence: IV] 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.[Level 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%).
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.[Level 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 clinicians who are not pain specialists.[Level of evidence: II] 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 is the concern that this drug may be associated with a prolonged QTc interval and may lead to torsades de pointes and ventricular arrhythmia. A number of studies have raised this concern. A 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.[Level of evidence: III] 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.[34,35] Another study of 100 cancer patients revealed a baseline electrocardiogram in 28%, with only one demonstrating a clinically significant increase in QTc at week 2. Avoidance of concomitant medications that prolong QTc interval  or that share common metabolism pathways with methadone  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.[Level of evidence: II];[Level of evidence: III] One guideline for choosing an appropriate initial dose of methadone based on the oral MEDD of the previous opioid is shown in Table 2. For example, a patient who has been using sustained-release morphine at 80 mg every 8 hours (240 mg/d) would be appropriately switched to methadone at a dose of 10 mg every 8 hours (30 mg/d, an 8:1 conversion ratio). In contrast, a patient who is taking sustained-release morphine at a total daily dose of 60 mg/d might be switched to an oral methadone dose of 5 mg every 8 hours (15 mg/d, a 4:1 conversion ratio).
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 Table 2, several methods of switching to methadone have been proposed.[22,40,41][Level of evidence: III];[42,43][Level of evidence: II]; 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.
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 is 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:
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. When the clinician observes the patient's demand for rescue doses reduces or stabilizes (indicating steady-state being reached), which is usually on day 4 to 7, the daily requirement is recalculated and the dose is given every 8 to 12 hours.
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.
This method is suggested when patients are being switched from high equivalent daily doses of morphine (>600 mg/d orally). 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 on the ability of physicians to prescribe methadone that do not apply to other opioids. 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. It should be noted that ratios are different for switching from methadone to a morphine-like opioid.
Principles of opioid administration
Most patients with cancer pain require fixed-schedule dosing to manage the constant pain and prevent the pain from worsening.[Level of evidence: II] 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.[Level of evidence: II] 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.[Level of evidence: III] Adherence rates are improved when patients are prescribed around-the-clock opioids compared with as-needed prescribing.[Level of evidence: I] 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.[Level of evidence: II]
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.[Level of evidence: I]
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 or when there is metabolite retention in the context of developing and/or worsening renal failure. In situations where interventions achieve complete pain relief, rapid opioid tapering rather than abrupt discontinuation is recommended to avoid opioid withdrawal symptoms.
Different types of opioids
Opioid therapy in special populations
Opioid switching (Opioid rotation)
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.[17,23,70,71,72][Level of evidence: III] 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.[73,74,75][Level of evidence: III];[Level of evidence: II] 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.[Level of evidence: III]
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.[13,78][Level of evidence: IV] 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.[Level of evidence: IV] 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.[Level of evidence: III];[80,81][Level of evidence: II] 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.[Level of evidence: II] 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 Table 3 are NOT recommended starting doses. Opioid doses are highly variable and should be based on the individual's previous responses and overall condition. Important cautions are contained in the footnotes.
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.[83,84] 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.[83,84,85][Level of evidence: IV]
Morphine, as the strong opioid of choice for the management of cancer pain, was used increasingly during the 1970s and 1980s.[Level of evidence: IV] 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.[86,87,88][Level of evidence: IV];[89,90,91][Level of evidence: II];[92,93][Level of evidence: III]
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.[94,95,96,97,98]
Switching from one opioid to another requires familiarity with a range of opioids and the use of opioid dose-conversion tables.[13,78] 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. One review has highlighted some important issues related to these tables. Wide ranges in ratios are noted. In the case of methadone, it is much more potent than previously thought (on average ten times more potent), and its equianalgesic dose-ratio compared to other opioids changes according to the dose of the previous opioid; the higher the dose, the higher the ratio. (Note that potency does not denote more effectiveness but denotes the equivalent dose required to obtain the same effect.)
Route of administration
Oral administration is preferred in patients with intact gastrointestinal tracts because it is convenient and usually inexpensive. When patients cannot take oral medications, other less invasive routes (e.g., rectal or transdermal) should be offered. Parenteral methods should be used only when simpler, less demanding, and less costly methods are inappropriate, ineffective, or unacceptable to the patient. In general, assessing the patient's response to several different oral opioids is advisable before abandoning the oral route in favor of anesthetic, neurosurgical, or other invasive approaches.
Parenteral: IV and subcutaneous
Drugs and routes to be avoided
Table 5 and Table 6 present data on drugs and routes of administration not recommended for the management of cancer pain.
Side effects of opioids
Clinicians should anticipate and monitor for side effects. The more common adverse effects include nausea, somnolence, and constipation. These should be discussed with patients before starting opioids. Somnolence and nausea are more often encountered with initiation of opioid treatment but tend to resolve within a few days. Clinicians who follow patients during long-term opioid treatment should watch for potential side effects and manage them as the need arises.
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 cornerstones of effective prophylaxis, therefore, are measures aimed at keeping the patient well hydrated to maintain well-hydrated stool. Unless there are existing alterations in bowel patterns, such as bowel obstruction or diarrhea, all patients using opioids should be started on a laxative bowel regimen and receive education for bowel management. Patients who do not adequately respond to an aggressive regimen with stool softeners may benefit from the addition of mild osmotic agents (e.g., 70% sorbitol solution, lactulose, milk of magnesia), polyethylene glycol, 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.[Level of evidence: I] 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. 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.
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. Reports that fentanyl causes less constipation than oral morphine are interesting but need to be confirmed in further prospective studies.[Level of evidence: III];[Level of evidence: II] One study demonstrated decreased laxative use in patients on transdermal fentanyl as compared with patients receiving oral morphine treatment. One meta-analysis has revealed a significant difference in favor of transdermal fentanyl for constipation, although this included only three randomized controlled clinical trials. 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. Severe opioid-induced constipation may occur. At an extreme it may be present as a severe ileus and pseudo bowel obstruction. 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.[Level of evidence: II];[Level of evidence: I] Although the oral bioavailability of these medications is very limited, opioid withdrawal syndromes have been noted when higher doses have been used. Methylnaltrexone, a quaternary derivative of naltrexone, is an opioid antagonist that does not cross the blood-brain barrier. Preliminary studies suggest that it may be effective when given subcutaneously in the management of opioid-associated constipation without causing opioid withdrawal.[Level of evidence: I];[136,137] (Refer to the PDQ summaries on Gastrointestinal Complications, Nausea and Vomiting, and Nutrition in Cancer Care for more information.)
Nausea and vomiting
Nausea and vomiting (emesis) occur in approximately one-third to two-thirds of patients taking opioids.[Level of evidence: I];[139,140] Nausea and vomiting are common complications of early exposure to opioids and usually disappear within the first week of treatment. Appropriate antiemetic coverage during the opioid-initiation phase is usually effective in limiting these adverse effects. 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 opioid-related nausea and vomiting. The predominant mechanism appears to be stimulation of the chemoreceptor trigger zone, where dopamine is the main neurotransmitter. Another mechanism 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. Metoclopramide or domperidone are generally recommended as first-line agents because they improve gastrointestinal motility and are antidopaminergic.[141,142] 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.[Level of evidence: III]
There appear to be differences between individual patients in the extent to which different opioids cause nausea. These differences form the basis for the strategy of switching from one opioid to another when a particular opioid produces persistent nausea.[145,146] Switching the route, specifically from the oral to the parenteral, has also been suggested, but the study supporting this strategy is small.[Level of evidence: II]
Nausea and vomiting can sometimes persist beyond the opioid-initiation phase or occur de novo in patients on long-term opioid treatment. Nausea and vomiting may become chronic in nature. The multicausal nature of the problem needs to be recognized because management is directed at identifying and addressing the various causes. Constipation is a common contributing cause. Chronic nausea has been associated with the accumulation of active opioid metabolites.[Level of evidence: III] A number of strategies are suggested to manage chronic nausea, including switching the opioid or decreasing the dose when pain is well controlled. (Refer to the PDQ summary on Nausea and Vomiting for more information.)
Cognitive and other neurotoxic side effects of opioids
Opioid-related neurotoxicity may manifest as cognitive impairment, hallucinations, delirium, generalized myoclonus, hyperalgesia and/or allodynia. Patients who have renal impairment or who are taking higher doses of opioids are at greater risk of developing these side effects. The mechanisms underlying these side effects are unclear, but the opioid metabolites are implicated. When patients present with generalized pain of an unknown source and the opioid dose has been recently increased, hyperalgesia should be considered as a possible diagnosis.[149,150] 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.[151,152] In addition to cognitive impairment within the context of delirium, other effects include myoclonus, hyperalgesia, perceptual disturbance, and seizures. 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,[Level of evidence: II] chronic nonmalignant pain,[Level of evidence: I];[Level of evidence: II] and in healthy volunteers.[Level of evidence: I] Collectively, studies of neuropsychological testing have demonstrated somewhat mixed findings, with some detecting opioid-associated impairment in certain aspects of psychomotor or cognitive function [Level of evidence: II] and others detecting minimal or no impairment.[Level of evidence: I]; 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,[Level of evidence: II] thereby allowing patients who are otherwise physically able, and on stable opioid doses, to safely engage in activities such as driving.[154,159]
Decreased brain cholinergic activity is recognized as one of the potential underlying pathophysiological mechanisms of delirium.[160,161][Level of evidence: II] 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.[162,163] 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)  and normorphine-3-glucuronide, and the hydromorphone metabolite, hydromorphone-3-glucuronide.[Level of evidence: II] 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.[Level of evidence: II] 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,[91,98,167][Level of evidence: II];[168,169] and some studies have noted an association with features of neurotoxicity, including cognitive impairment.[152,167][Level of evidence: II] 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.[Level of evidence: II] 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.
Managing cognitive and other neurotoxic effects of opioids
The general management approach to opioid-induced delirium requires a multidimensional assessment to determine the presence of other potentially treatable contributory factors such as dehydration, other centrally acting medications, sepsis, and hypercalcemia.[151,170,171] Clinical experience suggests that the presence of tactile hallucinations and myoclonus, 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 Delirium for more information.) These factors include neuropathic pain, incidental pain, tolerance, somatization of psychological distress, and a positive history of drug or alcohol abuse.[Level of evidence: II]
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, and methotrimeprazine and chlorpromazine are considered useful alternatives,[Level of evidence: I];[Level of evidence: IV] 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.[Level of evidence: III] Typical anxiolytics, including lorazepam, can be used to manage comorbid anxiety; however, they may contribute to the occurrence of delirium, so they should be used sparingly, if at all. 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.[Level of evidence: II]
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.[Level of evidence: II] 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.[85,151,179] This can reflect incomplete cross-tolerance among opioids in relation to analgesic and other effects. It is also possible that switching to a new opioid could allow for the elimination of potentially toxic opioid metabolites.[Level of evidence: III];[151,182] 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,[Level of evidence: II];[181,183] controversy persists over the relative value of opioid switching versus dose reduction.
Cognitive benefit has been reported with the use of methylphenidate in patients receiving a continuous infusion of opioids for cancer pain.[Level of evidence: I] The psychostimulant benefit is likely to relate to mitigation of sedation associated with upward dose titration of opioid.[Level of evidence: II] Although psychostimulants have been advocated for hypoactive delirium,[Level of evidence: IV] 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.[Level of evidence: II]
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.
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.
Perhaps more common than acute respiratory depression, subacute overdose may manifest as slowly progressive (hours to days) somnolence and respiratory depression. Before analgesic doses are reduced, advancing disease must be considered, especially in the dying patient. Generally, withholding one or two doses of an opioid analgesic is adequate to assess whether mental and respiratory depression are opioid related. If symptoms resolve after temporary opioid withdrawal, reduce the scheduled opioid dosage by 25%. If symptoms do not abate, but the patient complains of or exhibits signs of increased pain, or if symptoms referable to opioid withdrawal occur, consider alternative causes for CNS depression and reinstate analgesic treatment. Ongoing assessment is essential to maintain adequate pain relief.
Effects of opioids on sexual function
Reduced libido is a well-known phenomenon for those using heroin or those in a methadone maintenance program; however, clinicians prescribing opioids for pain poorly understand this effect. Early case studies of persons using heroin or methadone described diminished libido, sexual dysfunction, reduced testosterone levels in men, and amenorrhea in women.[190,191,192,193][Level of evidence: II];[194,195] These effects resolve after the opioid has been discontinued. Other case reports of patients receiving opioids for relief of chronic pain suggest these same findings.[196,197][Level of evidence: III] 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.[Level of evidence: III] Patients should be assessed for changes in libido and sexual dysfunction. If these changes are distressing to the patient, serum testosterone levels may be obtained. Should the patient seek improvement in libido and performance, treatment is often empirical, keeping in mind that there are many potential causes of changes in sexual function. Treatment includes using nonopioids for pain, adding adjuvant analgesics in the hope the opioid dose may be reduced, or replacing testosterone through injections or a patch (if not contraindicated). More research is needed to understand the relationship between opioids and sexual function, as well as the most effective treatment strategies. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.)
Other opioid side effects
Dry mouth, urinary retention, pruritus, dysphoria, euphoria, sleep disturbances, and inappropriate secretion of antidiuretic hormone are less common.
Adjuvant drugs are valuable during all phases of pain management to enhance analgesic efficacy, treat concurrent symptoms, and provide independent analgesia for specific types of pain.[Level of evidence: IV] Adverse drug reactions are common, however, and there are wide interindividual and ethnic differences in drug metabolism.[Level of evidence: IV] A survey on symptom severity and management in 593 cancer patients treated for an average of 51 days reported that during this time, anticonvulsants were used in 11.8% of patients, antidepressants in 16%, corticosteroids in 28%, and bisphosphonates in 7.3%.[Level of evidence: III] Patients with advanced cancer on palliative medicine services are reported to receive on average five medications for symptom relief, and as a result are at high risk of drug interactions. A further note of caution appears in another study that questioned the concept of opioid-sparing effects of co-analgesics.[Level of evidence: III] Nevertheless, adjuvant analgesics have been extensively studied and reviewed in noncancer settings and are generally endorsed as an important intervention in the provision of adequate pain management (see Table 7).[203,204,205,206][Level of evidence: IV] Few trials compare adjuvant analgesics in the cancer setting. Not all analgesic agents have been shown to provide clinical benefit when used in conjunction with opioids. In a dose escalation, double-blind, randomized placebo-controlled phase III trial of ketamine in patients with uncontrolled pain on opioids, delivered subcutaneously over 3 to 5 days, versus placebo, there was no difference noted in pain response between arms. There was almost twice the incidence of adverse effects in the ketamine group than was in the placebo arm.[Level of evidence: I]
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. 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.[Level of evidence: I];[222,235][Level of evidence: II];[Level of evidence: III];[237,238][Level of evidence: IV] Commonly reported side effects include somnolence, dizziness, ataxia, and fatigue.[206,236] One randomized open-label trial of gabapentin combined with an opioid (n = 38) versus an opioid alone (n = 37) for the management of neuropathic cancer pain suggests that the combination group achieved better relief than those receiving opioid monotherapy.[Level of evidence: I]
Clonazepam is an anticonvulsant from the benzodiazepine class and is commonly used for treating lancinating or paroxysmal neuropathic pain. The patient must be monitored carefully for drowsiness and cognitive impairment.
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.
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.[Level of evidence: I];;[205,206,240,242,243,244,245][Level of evidence: IV]
Radiation therapy (RT) has been established as an effective treatment for pain caused by bony metastases. Local, half-body, or whole-body RT enhances the effectiveness of analgesic drugs and other noninvasive therapies by directly affecting the cause of pain (i.e., reducing primary and metastatic tumor bulk).[Level of evidence: I] RT reduces pain and its interference with function among ambulatory cancer patients with symptomatic bone metastases.
External-beam radiation for bone metastases
External-beam radiation therapy (EBRT) produces significant reduction in bone pain in 50% to 80% of patients, with complete pain relief in 30% to 50% of patients. Dose fractionation schedules utilized for painful bone metastases vary considerably. Common fractionation schemes include 30 Gy in ten fractions, 24 Gy in six fractions, 20 Gy in five fractions, and 8 Gy in one fraction. Single- or multiple-fraction regimens of EBRT are equally effective when RT is administered for pain relief; however, re-treatment is needed more frequently after single-fraction RT.[Level of evidence: I];[2,5][Level of evidence: II] Fractionated RT courses have been associated with a need for re-treatment in 0% to 12% of patients versus a need for re-treatment in 11% to 25% of patients after a single fraction.[3,4,6,7,8,9][Level of evidence: I];[Level of evidence: II]
The dose and fractionation schedule must achieve a balance between the amount of RT required to kill tumor cells and the amount that would adversely affect normal cells or allow repair of damaged tissue. Data from several prospective randomized trials have failed to show any increased rates of long-term toxicity with single-fraction palliative RT compared with multiple-fraction therapy. In addition to pain control considerations, impact on the patient and caregiver related to the number of treatments delivered must be considered, with many patients finding increased convenience with single-fraction treatment. Another consideration is treatment cost, with single-dose fractionation regimens being less costly because of the smaller number of RT treatments delivered.
Stereotactic body RT (SBRT) is used to treat bone metastases by delivering large doses of RT in a highly conformal manner. Most commonly used to treat spinal metastatic disease, SBRT delivers large doses with a steep dose gradient, thereby potentially sparing adjacent neural structures. Most published data on SBRT have come from single-institution, retrospective studies. The complexities of target delineation, total dose, and fractionation have yet to be fully defined. SBRT may also be used when re-treatment is required in previously irradiated areas. Data regarding RT dose or patient selection for the treatment of recurrent, painful spinal bony metastases with SBRT are not yet definitive.
Pain flare, defined as an increase in pain after palliative RT, can occur, although the incidence has not been well documented. A relatively small, prospective, randomized, controlled trial comparing 8 Gy in one fraction with 20 Gy in five fractions reported pain flare in 15 of 44 patients (34%) for a median duration of 3 days. The flare occurred in 10 of 23 patients (44%) in the 8-Gy group and in 5 of 21 patients (24%) in the 20-Gy group.[Level of evidence: I] A multicenter study included three outpatient clinics and 111 patients to determine the incidence of pain flare after palliative RT. Pain flare was defined in this study as an increase in pain severity before achieving pain relief as distinguished from progression of pain by requiring the worst pain score and analgesic intake return to baseline levels after the increase/flare. Most patients received 8 Gy in one fraction (64%) or 20 Gy in five fractions (25%). The overall pain flare incidence was 40% (39% with 8 Gy and 41% with multiple fractions).[Level of evidence: II]
The use of RT with bisphosphonates has been evaluated in several prospective trials. The combination of zoledronic acid with either higher-dose palliative RT (30 Gy in ten fractions) or lower-dose RT (15 Gy in five fractions) for the treatment of single or multiple osteolytic or osteoblastic painful bony metastases in breast cancer patients was evaluated in a phase IV, randomized, controlled trial. Zoledronic acid, 4 mg, was given every 28 days starting with RT. There was no difference in analgesic or pain scores between the two regimens. However, it has not been shown that the combination of these agents with RT is superior to RT alone for pain relief. Additional prospective trials are needed.
Radiopharmaceuticals are also utilized in the palliation of painful bony metastases. Single intravenous injections of beta-emitting agents such as iodine 131, phosphorus-32-orthophosphate, and strontium 89 and newer agents such as rhenium 186 and samarium 153 can relieve pain in widespread bony metastases.[14,15][Level of evidence: II];[16,17] Response rates range from 20% to 85%, depending on the agent used.
These agents have most commonly been used to treat osteoblastic metastases when there are several symptomatic sites and/or when the number of sites exceeds reasonable treatment with EBRT. Small-volume osteolytic metastases may respond to radiopharmaceuticals, but large-volume osteolytic disease usually does not respond. In patients with inadequate pain relief, studies have demonstrated that approximately one-half of patients treated with radiopharmaceuticals respond to a second treatment. A prospective, multicenter, open-label trial of samarium suggested that multiple doses (i.e., more than two doses) may be administered to patients with advanced cancer and painful bone metastases with repeated benefit and adequate safety if there was an initial response to the initial samarium dose.[Level of evidence: II]
Available data do not suggest that these radiopharmaceuticals eliminate the need for palliative EBRT. Limited studies compare the effectiveness of one radiopharmaceutical with another. In a small randomized trial comparing strontium with samarium in patients with painful bony metastases, there was no statistically significant difference in the degree of analgesia seen. Toxicity, primarily hematologic, was likewise similar.
Radiofrequency ablation (RFA) is a relatively new method for treating symptomatic bony metastasis. Through the use of electromagnetic energy, RFA induces thermal energy that damages tissue around the inserted electrode. The destruction of tissue depends on the temperature achieved and the duration of heating. With the use of image guidance, the goal of RFA is to maintain temperatures between 55°C and 100°C for 4 to 6 minutes to achieve cell kill. Because of slow thermal conduction through tissue, treatment time may increase up to 30 minutes. Preliminary results suggest that RFA may achieve palliation in patients with painful bony metastases.[20,21,22,23];[Level of evidence: III]
In a nonconsecutive 27-month period, 43 patients 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 pelvic lesion. Other uncontrolled case reports confirm these findings. Further study is needed to determine potential risks and benefits.
Invasive Palliative Interventions
Less-invasive analgesic approaches should precede invasive palliative approaches; however, for a minority of patients in whom behavioral, physical, and drug therapy do not alleviate pain, invasive therapies are useful.
Control of otherwise intractable pain can be achieved by the application of a local anesthetic or neurolytic agent. Nerve blocks are performed for several reasons:
A single injection of a nondestructive agent such as lidocaine or bupivacaine, alone or in combination with an anti-inflammatory corticosteroid for a longer-lasting effect, can provide local relief from nerve or root compression. Placement of an infusion catheter at a sympathetic ganglion extends the sympathetic blockade from hours to days or weeks. Destructive agents such as ethanol or phenol can be used to effect neurolysis at sites identified by local anesthesia as appropriate for permanent pain relief and may also be used to cause destruction of central nervous system structures. The efficacy of neurolytic sympathetic blocks may vary depending on the underlying pain mechanisms involved. For patients with multiple pain mechanisms, neurolytic sympathetic blocks may serve as adjuvant techniques to analgesic medications.[Level of evidence: II]
Neurosurgery can be performed to implant devices that deliver drugs or electrically stimulate neural structures. Surgical ablation of pain pathways should, like neurolytic blockade, be reserved for situations in which other therapies are ineffective or poorly tolerated. In general, the choice of neurosurgical procedure is based on location and type of pain (somatic, visceral, deafferentation), the patient's general condition and life expectancy, and the expertise and follow-up available.
Management of procedural pain
Many diagnostic and therapeutic procedures are painful to patients. Anticipated procedure-related pain should be treated prophylactically, integrating pharmacologic and nonpharmacologic interventions in a complementary style.
Local anesthetics and short-acting opioids can be used to manage procedure-related pain, when adequate time is allotted 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 may be 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 about what to expect.
Offering the option for a relative or friend to accompany the patient for support can be useful.
Patients should be encouraged to remain active and participate in self-care when possible. Noninvasive physical, integrative (complementary/alternative therapies), cognitive-behavioral, and psychosocial modalities are typically used in conjunction with pharmacotherapy to manage pain during all phases of treatment. These interventions have the potential to enhance pain control directly but also indirectly, by increasing a patient's sense of control over events. 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).[Level of evidence: I]
Generalized weakness, deconditioning, and musculoskeletal pain associated with cancer diagnosis and therapy may be treated by:
Massage, Pressure, and Vibration
Massage therapy is an integrative modality that has been investigated as an adjunct to supportive care interventions in managing cancer-related pain. Preclinical and clinical trials have found that massage reduces pain by reducing cortisol levels, increasing serotonin and dopamine levels, stimulating the release of endorphins, and stimulating blood and lymphatic circulation. Massage may enhance the effects of analgesic medications and decrease inflammation and edema. There is a large body of evidence supporting the role of massage in reducing pain associated with muscle-related conditions such as muscle spasms and tension.[3,4,5,6] Massage may also play a role in the management of procedural pain.
In one of the largest randomized trials, 380 adults with advanced cancer received six sessions of either massage therapy or touch therapy for 30 minutes over a 2-week period. While immediate improvements from massage therapy were significantly greater than those from touch therapy, the benefits were not sustained, according to the Brief Pain Inventory. However, a large number of patients were not included in the assessments of immediate outcomes or sustained outcomes. Data collectors were also not blinded to the study arm, which may have led to overreporting the effects of massage therapy or touch therapy.
A number of reviews exploring the role of massage in the management of cancer pain or other areas of supportive care have been published. In a Cochrane review of the role of massage therapy with or without aromatherapy as a component of supportive care, three studies found a reduction in pain following intervention and reported reductions of 30% to 39% in pain scores after massage therapy, compared to usual care. Another study reported on the role of massage within the context of supportive care in cancer, highlighted pain, and concluded that evidence is encouraging but effect sizes are small. Additional trials are needed.
While the benefit of massage therapy on cancer pain may be mixed, existing trials suggest that massage therapy is safe in patients with cancer. However, certain precautions should be taken when providing massage therapy to patients with cancer:
Music Interventions for Pain
There are generally two broad categories of music-based interventions referenced within health care research.
Music therapists use a variety of music-based interventions that include live, interactive music making or carefully selected recorded music. Some examples include music improvisation, song writing and singing, and music relaxation.
A music therapist chooses interventions on the basis of an assessment of a patient's immediate and long-term needs (e.g., pain management, anxiety reduction, coping strategies, and skills).
Music therapy and music medicine interventions have been used to relieve acute and chronic pain related to noxious procedures and treatments and the disease process. Music reduces pain via the mutually inhibitory neuroanatomical pathways that are shared between pain and reward processing. Neuroscience studies are consistent in suggesting that pleasant emotional responses to music activate brain structures related to reward, emotion, and attention and decrease activation in areas associated with aversive events.[12,13,14] Music from an individual's personal collection that elicits a positive emotional response has the most robust effect in increasing pain tolerance, decreasing anxiety, and increasing perceived control.[15,16,17]
Meta-analyses summarizing the effect of music on pain indicate small to moderate benefit, with a high level of heterogeneity. There is preliminary evidence that music interventions delivered by music therapists are more effective than music medicine interventions.[10,18]
Studies reporting rates of 50% pain reduction indicate that participants in music listening had a 70% greater probability of experiencing at least a 50% pain reduction than did controls (n = 4 studies). There is also preliminary evidence that music reduces opioid requirements, but the benefits are small and the clinical importance is unclear. Music-based interventions specifically for cancer patients found a moderate pain-reducing effect of a 0.54 standardized unit difference between music and usual-care groups (5 studies, n = 391).
While initial results are promising, the quality of evidence for music and cancer pain studies is low, often because of wide confidence intervals and high variability in study quality. Common sources of bias and low quality include nonblinding of participant and study personnel, lack of theory guiding music selection and delivery, and incomplete reporting of intervention details.[13,21,22]
Characteristics of music interventions for pain include the following:
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. Other studies suggest that behavioral interventions targeted to specific symptoms, such as pain and fatigue, can significantly reduce symptom burden and improve the quality of life for patients with cancer.[Level of evidence: I] Realistic expectations are needed for delivery of cognitive-behavioral interventions. One study [Level of evidence: I] of cognitive-behavioral interventions for pain management randomly assigned 57 patients (most of whom were women with metastatic breast cancer who were maintained on daily opioid use for pain) to three 20-minute interventions delivered by audiotape (progressive muscle relaxation [PMR], positive mood induction, or a distraction condition) or to a no-intervention control. The patients were provided the audiotapes by a research nurse, given brief instructions, and asked to use the tapes at least five times a week for 2 weeks; more than half of the patients reported complying with these instructions. The relaxation condition and the "distraction" condition (self-selected informational tapes) produced significant immediate effects on pain, but the positive mood induction tapes showed no effects. The effects, however, neither carried over to general symptom management nor affected pain management at other times. One conclusion of this study is that ideally, interventions should be matched to patient preferences; for more extended effects, additional instruction and support may be needed, as suggested by other studies.
Interventions introduced early in the course of illness are more likely to succeed because they can be learned and practiced by patients while they have sufficient strength and energy. Patients and their families should be given information about and encouraged to try several strategies, and to select one or more of these cognitive-behavioral techniques to use regularly:
Relaxation and Imagery
Cognitive Distraction and Reframing
Psychotherapy and Structured Support
Support Groups and Pastoral Counseling
Relaxation Exercises [Note: Adapted and reprinted with permission from McCaffery M, Beebe A: Pain: Clinical Manual for Nursing Practice. St. Louis, Mo: CV Mosby Co, 1989.]
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:
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.
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.
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.
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:
Age and complex medication regimens place them at increased risk for drug-drug and drug-disease interactions.
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.
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.
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.
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.
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.
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.
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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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of pain. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
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Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Pain. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/about-cancer/treatment/side-effects/pain/pain-hp-pdq. Accessed <MM/DD/YYYY>.
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Last Revised: 2015-07-16
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