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Pain is one of the most common symptoms in cancer patients and often has a negative impact on patients' functional status and quality of life. The goal of the following summary is to provide evidence-based, up-to-date, and practical information on the management of cancer pain.
Effective pain management can generally be accomplished by paying attention to the following steps:
Background and Definitions
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." Pain is commonly experienced by cancer patients. Its proper assessment requires measuring pain intensity; clarifying the impact of pain on patients' psychological, social, spiritual, and existential domains; and establishing treatment adherence and responsiveness.
A commonly used approach to pain management employs the World Health Organization (WHO) pain relief ladder, which categorizes pain intensity according to severity and recommends analgesic agents based on their strength. Pain intensity is often assessed using a numeric rating scale (NRS) of 0 to 10. On this scale, 0 indicates no pain, 1 to 3 indicates mild pain, 4 to 6 indicates moderate pain, and 7 to 10 indicates severe pain.
Step 1 on the WHO pain relief ladder treats mild pain. Patients in this category receive nonopioid analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs, or an adjuvant analgesic, if necessary. Step 2 treats patients experiencing mild to moderate pain who are already taking a nonopioid analgesic, with or without an adjuvant analgesic, but who are still experiencing poor analgesia. Step 2 agents include tramadol and acetaminophen products containing hydrocodone, oxycodone, and codeine. Step 3 treats moderate to severe pain with strong analgesics. Step 3 opioids include morphine, hydromorphone, fentanyl, levorphanol, methadone, oxymorphone, and oxycodone. An open-label randomized trial of low-dose morphine versus weak opioids to treat moderate cancer pain suggests that it is acceptable to bypass weak opioids and go directly to strong opioids (step 3 agents) for patients with moderate cancer pain, as patients randomly assigned to the low-dose morphine arm had more frequent and greater reduction in pain intensity with similarly good tolerability and earlier effect.
Familiarity with opioid pharmacokinetics, equianalgesic dosing, and adverse effects is necessary for their safe and effective use. The appropriate use of adjuvant pharmacological and nonpharmacological interventions is needed to optimize pain management.
Pain occurs in 20% to 50% of patients with cancer. Roughly 80% of patients with advanced-stage cancer have moderate to severe pain. One meta-analysis looking at pooled data from 52 studies found that more than half of patients had pain. Younger patients are more likely to experience cancer pain and pain flares than are older patients.
Cancer patients often have multiple sites of pain. Patients rated pain from 4 to 6 (severe) on the NRS, with exacerbations rated as high as 7.
Causes of Cancer Pain: Cancer, Cancer Treatments, and Comorbidities
A study evaluating the characteristics of patients (N = 100) with advanced cancer presenting to a palliative care service found the primary tumor as the chief cause of pain in 68% of patients. Most pain was somatic, and pain was as likely to be continuous as intermittent.
Pain can be caused by cancer therapies, including surgery, radiation therapy, chemotherapy, targeted therapy, supportive care therapies, and/or diagnostic procedures. A systematic review of the literature identified reports of pain occurring in 59% of patients receiving anticancer treatment and in 33% of patients after curative treatments. Pain unrelated to cancer is relatively common in cancer patients, occurring in 16% of patients in one study.
Infusion-related pain syndromes
The infusion of intravenous chemotherapy causes four pain syndromes: venous spasm, chemical phlebitis, vesicant extravasation, and anthracycline-associated flare.[13,14,15] Venous spasm is treated by application of a warm compress or decrease in the infusion rate. Chemical phlebitis may result from chemotherapy or nonchemotherapy infusions such as potassium chloride and hyperosmolar solutions. Vesicant extravasation may cause intense pain followed by desquamation and ulceration. Doxorubicin may result in the venous flare reaction, which includes local urticaria, pain, or stinging. Some chemotherapy agents such as vinorelbine may cause pain at the tumor site.
Severe mucositis often occurs as a consequence of myeloablative chemotherapy and standard-intensity therapy. Cytotoxic agents commonly associated with mucositis are cytarabine, doxorubicin, etoposide, 5-fluorouracil, and methotrexate. Epidermal growth factor receptor (EGFR) inhibitors, multitargeted tyrosine kinase inhibitors, and mammalian target of rapamycin inhibitors also cause mucositis.[18,19] Risk factors for mucositis include preexisting oral pathology, poor dental hygiene, and younger age.
Chemotherapy-related musculoskeletal pain
Paclitaxel generates a syndrome of diffuse arthralgias and myalgias in 10% to 20% of patients. Diffuse pain in joints and muscles appears 1 to 2 days after the infusion and lasts a median of 4 to 5 days. Pain originates in the back, hips, shoulders, thighs, legs, and feet. Weight bearing, walking, or tactile contact exacerbates the pain. Steroids may reduce the tendency to develop myalgia and arthralgias. Among hormonal therapies, aromatase inhibitors cause musculoskeletal symptoms, osteoporotic fractures, arthralgias, and myalgias.
Dermatologic complications and chemotherapy
EGFR inhibitors cause dermatitis with ensuing pain. Acute herpetic neuralgia occurs with a significantly increased incidence among cancer patients, especially those with hematologic malignancies and those receiving immunosuppressive therapies. The pain usually resolves within 2 months but can persist and become postherpetic neuralgia. The palmar-plantar erythrodysesthesia syndrome is observed in association with continuously infused 5-fluorouracil, capecitabine, liposomal doxorubicin, and paclitaxel. Targeted agents such as sorafenib and sunitinib are also associated with hand-foot–like syndrome. Patients develop tingling or burning in their palms and soles, followed by an erythematous rash. Management often requires discontinuing therapy or reducing the treatment dose.
Supportive care therapies and pain
Supportive care therapies can cause pain, as typified by bisphosphonate-associated osteonecrosis of the jaw. Corticosteroid use has also been associated with the development of avascular necrosis.
Radiation causes several pain syndromes, including mucositis, mucosal inflammation in areas receiving radiation, pain flares, and radiation dermatitis. Patients may experience pain from brachytherapy and from positioning during treatment (i.e., placement on a radiation treatment table).
Impact on Function and Quality of Life
Cancer pain is associated with increased emotional distress. Both pain duration and pain severity correlate with risk of developing depression. Cancer patients are disabled an average of 12 to 20 days per month, with 28% to 55% unable to work because of their cancer. Cancer survivors may experience distress when their pain unexpectedly persists after completion of cancer treatments. Survivors also experience loss of support from their previous health care team as oncologists transition their care back to primary care providers.
In one study, between 20% and 50% of cancer patients continued to experience pain and functional limitations years posttreatment. Untreated pain leads to requests for physician-assisted suicide. Untreated pain also leads to unnecessary hospital admissions and visits to emergency departments.
The concept of total pain captures its multidimensional nature by explicitly including the physical, psychological, social, and spiritual components of pain.[1,2,3,4] The immediate implications for the clinician are severalfold:
Pain is classified on the basis of the underlying pathophysiologic mechanisms, the duration, or the description of recognizable syndromes associated with pain. The three mechanisms underlying the pathophysiology of pain are nociceptive, neuropathic, and psychogenic.
Nociceptive pain, which may be either somatic or visceral in nature, originates with a chemical, mechanical, or thermal injury to tissue that stimulates pain receptors that transmit a signal to the central nervous system (CNS), causing the perception of pain. Pain receptors are found in somatic (e.g., cutaneous, bone) and visceral tissues. The amount of visceral sensory innervation and the diffusion of visceral pain signals within the brain explain the difficulty experienced by patients in describing or localizing visceral pain compared with somatic pain. A specific type of visceral pain is referred pain, which is explained by the commingling of nerve fibers from somatic and visceral nociceptors at the level of the spinal cord. Patients mistakenly interpret the pain as originating from the innervated somatic tissue. Visceral pain may be accompanied by autonomic signs such as sweating, pallor, or bradycardia. Somatic pain is more easily localized.
Neuropathic pain is pain caused by damage to the peripheral nervous system or the CNS (spinal cord or brain). Causes of neuropathic pain of particular relevance to cancer include chemotherapy (e.g., vinca alkaloids), infiltration of the nerve roots by tumor, or damage to nerve roots (radiculopathy) or groups of nerve roots (plexopathy) due to tumor masses or treatment complications (e.g., radiation plexopathy). The pain may be evoked by stimuli or spontaneous. Patients who experience pain from nonnoxious stimuli are classified as having allodynia. Hyperalgesia connotes increased sensations of pain out of proportion to what is usually experienced.
Emotional distress may also contribute to the pain experience. Most patients with cancer and pain do not have somatic symptom disorder. However, if pain complaints appear to be disproportionate to the underlying pain stimulus, it is important to evaluate for psychological and existential distress contributing to the pain complaint, chemical coping, and substance abuse.
Acute and Chronic Cancer Pain
Pain is often classified as either acute or chronic or by how it varies over time with terms such as breakthrough, persistent, or incidental. Acute pain is typically induced by tissue injury, begins suddenly with the injury, and diminishes over time with tissue healing. There is no definite length but, in general, acute pain resolves within 3 to 6 months. The treatment of acute pain focuses on blocking nociceptive pathways while the tissue heals.
Chronic pain typically persists even after the injury has healed, although patients with chronic joint disease, for example, may have ongoing tissue damage and therefore experience chronic pain. Pain becomes chronic when it continues for more than 1 month after the healing of precipitating lesions; persists or becomes recurrent over months; or results from lesions unlikely to regress or heal. The transition from acute to chronic pain may be understood as a series of relatively discrete changes in the CNS, but there are also clearly behavioral confounders in the genesis of chronic pain. Chronic pain involves the activation of secondary mechanisms such as the sensitization of second-order neurons by upregulation of N-methyl-D-aspartic acid channels and alteration in microglia cytoarchitecture. Chronic pain, with its multiple factors for perpetuation, often benefits from a multidisciplinary approach to treatment.
In caring for patients with pain, breakthrough pain is distinguished from background pain.[10,11] Breakthrough pain is a transitory increase or flare of pain in the setting of relatively well-controlled acute or chronic pain. Incident pain is a type of breakthrough pain related to certain often-defined activities or factors such as movement increasing vertebral body pain from metastatic disease. It is often difficult to treat such pain effectively because of its episodic nature. In one study, 75% of patients experienced breakthrough pain; 30% of this pain was incidental, 26% was nonincidental, 16% was caused by end-of-dose failure, and the rest had mixed etiologies.
Effective pain treatment begins with screening at every visit and a thorough assessment if pain is present. Patient self-report is the standard of care for evaluating pain.
Many tools have been developed to quantify the intensity of pain. The most commonly used tools include the numerical rating scale (0–10: 0 = no pain, 10 = worst pain imaginable); the categorical scale (none, mild, moderate, severe); and the visual analog scale (0–100 mm: 0 mm = no pain, 100 mm = worst pain imaginable). Multidimensional pain assessment tools such as the McGill Pain Questionnaire, the Brief Pain Inventory, and the PROMIS-PI (Patient-Reported Outcomes Measurement Information System—Pain Interference)  have been developed to evaluate pain and its interference with daily functions. Although these tools are important, they may be best applied in the research setting, given their complexity and significant time requirements.
Pain assessment tools have been developed for special populations such as children and those with cognitive impairment (refer to the Special Considerations section of this summary for more information).
Pain intensity may be assessed for different time frames, such as "now," "last 24 hours," or "last week." In addition to the average pain intensity, the worst or lowest intensity may be assessed. Evaluation of pain intensity at each visit would allow clinicians to monitor for changes and treatment response. Pain intensity scales can also be used to develop a personalized pain goal.
Failure to assess pain adequately leads to undertreatment. Assessment involves both clinician observation and patient report. The goal of the initial pain assessment 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. It is important to recognize that psychosocial issues can either exacerbate or ameliorate the experience of pain. These psychosocial issues cannot be easily treated through pharmacologic approaches; therefore, it is critical that clinicians include these in initial and subsequent examinations of patients with pain to ensure referrals to appropriate treatment resources. Furthermore, distinct cultural components may need to be incorporated into a multidimensional assessment of pain, including how culture influences the pain experience, pain communication, and provider response to pain expression.[6,7,8,9]
Identifying the etiology of pain is important to its management. Clinicians treating patients with cancer need to recognize the common cancer pain syndromes. (Refer to the Approach to Somatic Pain, Approach to Visceral Pain, and Approach to Neuropathic Pain sections of this summary for more information.)
Effective pain management requires close monitoring of patient response after treatment is initiated. In a review of 1,612 patients referred to an outpatient palliative care center, more than half of patients with moderate to severe pain did not show pain relief (a reduction in 2 out of 10 points or a 30% decrease on the pain scale) after the initial palliative care consultation. In addition, one-third of patients with mild pain progressed to moderate to severe pain by the time of their first follow-up visit. The study also identified baseline pain intensity, fatigue, and Edmonton Symptom Assessment System symptom burden as factors predicting response.
Ideally, comprehensive pain assessment includes a discussion about the patient's goals and expectations for pain management. This conversation may lead to a fruitful discussion about balancing pain levels and other patient goals, such as mental alertness. Comprehensive pain assessment also includes pain history, pain intensity, quality of pain, and location of pain. For each pain location, the pattern of pain radiation is assessed. Also important is provider awareness of the patient's current pain management treatment plan and how the patient has responded to treatment; this includes how adequately the current treatment plan addresses any breakthrough or episodic pain. A full assessment also reviews previously attempted pain therapies and reasons for discontinuation; other associated symptoms such as sleep difficulties, fatigue, depression, and anxiety; functional impairment; and any relevant laboratory data and diagnostic imaging. A focused physical examination includes clinical observation of pain behaviors, pain location, and functional limitations.
Psychosocial and existential factors that can affect pain are also assessed and appropriately treated. Depression and anxiety can have a large influence on the pain experience. Across many different types of pain, research has shown the importance of considering a patient's sense of self-efficacy over their pain: low self-efficacy, or focus on solely pharmacologic solutions, is likely to increase the use of pain medication.[11,12] In addition, patients who repeatedly catastrophize pain (e.g., patient reports pain higher than 10 on a 10-point scale) are more likely to require higher doses than are patients who do not catastrophize. Catastrophizing is strongly associated with low self-efficacy and reliance on chemical coping strategies.[13,14,15,16,17] Furthermore, assessing the impact of pain on the individual's life and associated factors that exacerbate or relieve pain can reveal how psychosocial issues are affecting the patient's pain levels.
A pain assessment includes a review of any patient and family history of substance use and the extent of the patient's chemical coping strategies before and since the cancer diagnosis. The extent of chemical coping strategies, including reliance on legal substances (e.g., nicotine, alcohol, and sleeping pills), may indicate a history of reliance on chemicals to alleviate distress. It can also provide the clinician with information about the patient's nicotine use, which may affect how certain opioids may be differentially metabolized and the amount of opioids required to achieve pain control. A remote history of substance abuse can still affect current pain levels and analgesic requirements. Remote substance use may have long-term implications for pain sensitivity, even if the patient has a history of prolonged abstinence from opioid use. Together, personal and family substance use can inform a risk assessment for potential abuse of medications, potential analgesic requirements, and diversion of prescriptions.
Pain Prognostic Scores
A number of pain-related factors and patient-related factors predict response to pain treatment. Specifically, a high baseline pain intensity, neuropathic pain, and incident pain are often more difficult to manage. Furthermore, several patient characteristics such as a personal or family history of illicit drug use, alcoholism ,[21,22] smoking,[23,24,25] somatization, mental health issues such as depression or anxiety, and cognitive dysfunction [28,29,30] are associated with higher pain expression, higher opioid doses, and longer time to achieve pain control.
On the basis of these predictive factors, several risk scores have been developed to assist clinicians in clinical practice, such as the Edmonton Classification System for Cancer Pain (ECS-CP) [20,31] and the Cancer Pain Prognostic Scale (CPPS).
Predictive factors can help to personalize cancer pain management. Especially for patients with a poor pain prognosis, clinicians may consider discussing realistic goals for alleviating pain, focusing on function and use of multimodality interventions. Repeated or frequent escalation of analgesic doses without improvement of pain may trigger clinicians to consider an alternative approach to pain.
Self-report is accepted as the gold standard of pain assessment; however, for certain vulnerable populations, such as children, those with learning disabilities, and those who are cognitively impaired, self-report may not be feasible or reliable.
While adults and children older than 7 years can effectively utilize the numerical rating scale, young children and those with cognitive impairment may benefit from using a pictorial scale such as the Faces Pain Scale. (Refer to the PDQ summary on Pediatric Supportive Care for more information.)
Cognitive impairment may impede a person's ability to describe pain, recall pain events, or understand the tools used to assess pain, leading such patients to receive more or less analgesia.[35,36,37] The American Society for Pain Management Nursing has developed a position statement on pain assessment in the nonverbal patient that includes clinical recommendations. Pain assessment can be evaluated via direct observation, family/caregiver report, and evaluation of response to pain relief interventions. For patients with advanced dementia, tools relying on professional caregiver assessment of pain through the observation of patient behaviors have been developed.[39,40,41] Although the validity and reliability of these tools have been questioned, the tools are often recommended for patients with advanced dementia who cannot report pain and, in combination with self-report by other cognitively impaired groups, as a means to enhance pain assessment and avoid undertreatment of pain.
Cognitive impairment extends beyond patients with a diagnosis of dementia, such as those with brain tumors and delirium, which are common complications of advanced cancer. In such patients, the Faces Pain Scale  and the Coloured Analogue Scale  as well as vertical instead of horizontal orientation of scales may be preferable to the numeric rating scales.
Culture also plays a role in the patient experience of pain and the reporting of pain. For example, among some Asian cultures, patients tend not to report pain. Complaining of pain may be perceived as a sign of weakness. Individuals may hide pain from family members to avoid burdening the family. For some patients, pain may have spiritual value, leading them to accept pain rather than dull the experience with medication. Thus, understanding an individual patient's spiritual and cultural background without making assumptions is important in approaching pain assessment.
In a cross-sectional study, the cancer pain experience of white patients was individual and independent, while that of ethnic minority patients was family oriented. Minority patients received support from their families during the cancer treatment, and they fought cancer for their families. The families were involved deeply in their decision making related to cancer treatment and pain management.
Other studies indicate that Asian patients have greater barriers to pain management and display more fatalism than do Western patients.[8,9]
Acetaminophen and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Often initiated when an individual has mild pain, acetaminophen and NSAIDs are useful in managing moderate and severe pain as adjunct agents to opioids. No single NSAID is preferred over others, and all are better than placebo for analgesia. As opioid adjuncts, acetaminophen and NSAIDs have shown benefit both in improved analgesia and in decreased opioid use. These agents are used with care or perhaps avoided in patients who are elderly or have renal, hepatic, or cardiac disease.
While acetaminophen and NSAIDs provide analgesia on their own, a number of randomized controlled trials have reported that the addition of either agent to opioids may improve pain control and decrease opioid need in cancer patients.[2,3,4] However, these benefits were not consistently observed across trials.[5,6]
High-potency NSAIDs such as ketorolac and diclofenac are more studied and have shown benefit in the management of cancer pain, but there are no comparative data with older agents to show superiority of one product over others. Prominent side effects are gastrointestinal irritation, ulcer formation, and dyspepsia, with other side effects of concern being cardiotoxicity, nephrotoxicity, hepatotoxicity, and hematologic effects.[7,8] Cyclooxygenase-2 (COX-2)–specific agents such as celecoxib may have a more favorable gastrointestinal side effect profile at a higher monetary cost. Long-term safety and efficacy data remain unclear.
The use of opioids for the relief of moderate to severe cancer pain is considered necessary for most patients. For moderate pain, weak opioids (e.g., codeine or tramadol) or lower doses of strong opioids (e.g., morphine, oxycodone, or hydromorphone) are often administered and frequently combined with nonopioid analgesics. For severe pain, strong opioids are routinely used; although no agent has shown itself to be more effective than another, morphine is often considered the opioid of choice because of provider familiarity, broad availability, and lower cost. In one well-designed review, most individuals with moderate to severe cancer pain obtained significant pain relief from oral morphine.
Management of acute pain begins with an immediate-release opioid formulation. Once pain is stabilized, the opioid consumption over the past 24 hours is then converted to a modified-release or longer-acting opioid on the basis of the patient's 24-hour opioid consumption (measured in terms of morphine equivalent daily dose [MEDD]). Randomized controlled trials have shown that long-acting opioids given every 12 hours provide efficacy similar to that of scheduled short-acting opioids given every 4 hours.[12,13] Use of the immediate-release product is continued for management of breakthrough pain. During ongoing pain management, the immediate-release opioids inform the titration of long-acting medication. Rapid-acting oral, buccal, sublingual, transmucosal, rectal, and intranasal products are all acceptable for treatment of breakthrough pain. In people unable to take oral medications, a subcutaneous method of delivery is as effective as the intravenous route for morphine and hydromorphone.
Rapid-onset fentanyl formulations
Rapid-onset opioids are developed to provide fast analgesia without using a parenteral route. Fentanyl, a synthetic opioid 50 to 100 times more potent than morphine, is available in a variety of delivery methods to offer additional options for management of breakthrough pain. Along with rapid onset of action, these products avoid first-pass hepatic metabolism and intestinal digestion.
All rapid-acting fentanyl products are intended for use only in patients already tolerant to opioids and are not initiated in the opioid naïve. However, none are bioequivalent to others, making dose interchange complicated and requiring dose titration of each product individually, without regard to previous doses of another fentanyl product. The dose titration schedule is unique to each product, and it is critical that product information is reviewed individually when each product is used. The risk of addiction with these rapid-onset agents has not been elucidated. In the United States, prescription of these agents requires enrollment in the U.S. Food and Drug Administration's (FDA's) Risk Evaluation and Mitigation Strategies (REMS) program.
Methadone is both a mu-receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist; can be given via multiple routes (oral, intravenous, subcutaneous, and rectal); has a long half-life (13 to 58 hours) and rapid onset of action; and is inexpensive, making it an attractive option for cancer pain control. Because of its NMDA properties, methadone may be particularly useful for the management of opioid-induced neurotoxicity, hyperalgesia, and neuropathic pain, although further studies are needed to confirm these theoretical benefits. Methadone is safer for patients with renal failure, and is preferred for those with known opioid allergies because it is a synthetic opioid. However, methadone also has several distinct disadvantages, including drug interactions, the risk of QT prolongation, and a variable equianalgesic ratio, making rotation more challenging.
Given the complexities related to methadone administration, it is important that this opioid be prescribed by clinicians with experience who are able to provide careful monitoring. Referral to a pain specialist or a palliative care team may be indicated.
Methadone is metabolized by CYP3A4 and CYP2D6. CYP3A4 inducers (e.g., certain anticonvulsants and antiretroviral agents) can potentially reduce its analgesic effect. In contrast, substrates/inhibitors of CYP3A4 may increase methadone's activity, including side effects. For clinicians, the potential for significant drug-drug interactions may mean that some medications need to be replaced and that patients need extra monitoring. Furthermore, because methadone is a substrate of P-glycoprotein, medications that inhibit the activity of this transporter, such as verapamil and quinidine, may increase methadone's bioavailability.
Methadone is associated with QT prolongation. This risk increases in patients receiving high doses (especially >100 mg/day) or with preexisting risk factors, including treatment with some anticancer agents. For patients with risk factors for QT prolongation, it is important to conduct a baseline electrocardiogram (ECG) before treatment with methadone. A follow-up ECG is recommended at 2 to 4 weeks after methadone initiation if the patient has known risk factors, with the occurrence of new risk factor(s) for all patients, and when the doses of methadone reach 30 to 40 mg/day and 100 mg/day for all patients regardless of risk.
One group of investigators reported that the conversion ratio for switching from oral morphine to methadone varied between 2.5 and 14.3, with greater potency as the MEDD increased. In a small retrospective study, other investigators found that the equianalgesic ratio for switching from methadone to oral morphine was 4.7 for oral methadone and 13.5 for intravenous methadone.
A systematic review has highlighted three approaches to methadone conversion in the literature;[30,31] however, the evidence was low, making it difficult to conclude which approach was superior. Rapid titration of methadone may result in delayed respiratory depression because of its long half-life.
Adverse effects from opioids are common and may interfere with achieving adequate pain control. However, not all adverse effects are caused by opioids, and other etiologies also need to be evaluated. Examples of relevant factors include symptoms from disease progression, comorbid health conditions, drug interactions (including adjuvant analgesics), and clinical conditions such as dehydration or malnutrition. In general, options for addressing adverse effects associated with opioids include aggressive management of the adverse effects, opioid rotation, or dose reduction. In most instances, definitive recommendations are not possible.
Central nervous system (CNS) effects
Adverse effects on the CNS may be attributed to opioids' anticholinergic activity or direct effect on neurons.[40,41] Sedation and drowsiness are common but typically transient adverse effects. Patients who have persistent problems may benefit from opioid rotation. Methylphenidate has been proposed as an intervention to reduce opioid-induced sedation.[42,43] The effects of opioids on cognitive or psychomotor functioning are not well established. Given the incidence of sedation, caution is exercised when an opioid is initiated or when dose escalation is required. There is less evidence, however, that patients on chronic stable doses exhibit cognitive or motor impairment.
Delirium is associated with opioids but is typically multifactorial in origin. In one retrospective study, 80% of the delirium cases were not related to opioids. (Refer to the Delirium section in the PDQ summary on Last Days of Life for more information about the management of delirium.)
Opioid-induced respiratory depression may be caused by a blunting of the chemoreceptive response to carbon dioxide and oxygen levels and altered mechanical function of the lung necessary for efficient ventilation and gas exchange. Opioid-induced respiratory depression may manifest through decreased respiratory rate, hypoxemia, or increases in total exhaled carbon dioxide. The prevalence of respiratory depression is not known but rarely occurs with proper opioid use and titration.[49,50,51,52]
If respiratory depression is thought to be related to opioids (e.g., in conjunction with pinpoint pupils and sedation), naloxone, a nonselective competitive opioid antagonist, may be useful; however, careful titration should be considered because it may compromise pain control, and may precipitate withdrawal in opioid-dependent individuals. Because of methadone's long half-life, naloxone infusion may be required for respiratory depression caused by methadone.
Nausea and vomiting
Opioid-induced nausea occurs in up to two-thirds of patients receiving opioids, and half of those patients will experience vomiting. Opioids cause nausea and vomiting via enhanced vestibular sensitivity, via direct effects on the chemoreceptor trigger zone, and by causing delayed gastric emptying. Antiemetics may be started up front in patients at risk of developing nausea, or instituted once symptoms occur. Tolerance to opioid-induced nausea and vomiting (OINV) may develop, and symptoms should resolve within 1 week. If symptoms persist despite treatment with antiemetics, opioid rotation can be considered, or other causes of nausea can be investigated.
OINV is treated with many of the same antiemetic drugs that are used for chemotherapy-induced nausea and vomiting. Although many antiemetic regimens have been proposed for OINV, there is no current standard. The chemoreceptor trigger zone is stimulated by dopamine, serotonin, and histamine. Metoclopramide may be a particularly attractive option because of its dual antiemetic and prokinetic effects. Other dopamine antagonists such as prochlorperazine, promethazine, and olanzapine have been used to treat OINV. For patients whose nausea worsens with positional changes, a scopolamine patch has been found effective. Serotonin antagonists such as ondansetron may be used; however, they could worsen constipation among patients already taking opioids.
Constipation is the most common adverse effect of opioid treatment, occurring in 40% to 95% of patients. It can develop after a single dose of morphine, and patients generally do not develop tolerance to opioid-induced constipation. Chronic constipation can result in hemorrhoid formation, rectal pain, bowel obstruction, and fecal impaction.
Opioids cause constipation by decreasing peristalsis, which occurs by reducing gastric secretions and relaxing longitudinal muscle contractions, and results in dry, hardened stool. Constipation is exacerbated by dehydration, inactivity, and comorbid conditions such as spinal cord compression. Patients are encouraged to maintain adequate hydration, fiber intake, and regular exercise, in addition to taking laxatives.
A scheduled stimulant laxative is started with opioid initiation. The addition of a stool softener offers no further benefit.[57,58] Laxatives are titrated to a goal of one unforced bowel movement every 1 to 2 days. If constipation persists despite prophylactic measures, then additional assessment of the cause and severity of constipation is performed. After obstruction and impaction are ruled out, other causes of constipation (such as hypercalcemia) are treated.
There is no evidence to recommend one laxative class over another in this setting. Appropriate drugs include bisacodyl, polyethylene glycol, magnesium hydroxide, lactulose, sorbitol, and magnesium citrate. Suppositories are generally avoided in the setting of neutropenia or thrombocytopenia.
Methylnaltrexone and naloxegol are peripherally acting opioid antagonists approved for the treatment of opioid-induced constipation in patients who have had inadequate response to conventional laxative regimens. Laxatives are discontinued before peripherally acting opioid antagonists are initiated. These agents are not used if postoperative ileus or mechanical bowel obstruction is suspected.[59,60]
Defined as "the need for increasingly high levels of opioids to maintain pain inhibition after repeated drug exposure," opioid-induced hyperalgesia (OIH) is a clinical phenomenon that has been differentiated from opioid tolerance in the research literature.[37,61,62,63,64]
The clinical relevance needs to be further studied, and this issue may be underappreciated in clinical practice.
A thorough history and physical are appropriate if OIH is suspected. Changes in pain perception and increasing opioid requirements may be caused by OIH, opioid tolerance, or disease progression. There is no standard recommendation for the diagnosis and treatment of OIH. A trial of incremental opioid dose reductions may lead to an improvement in pain from OIH. However, this may be psychologically distressing to oncology patients who require opioid treatment. Opioid rotation is a strategy frequently employed if opioid tolerance has occurred. Methadone is an ideal opioid to switch to, given its mechanism of action as an opioid receptor agonist and NMDA receptor antagonist. Given the similarities between OIH and neuropathic pain, the addition of an adjunctive medication such as pregabalin has been recommended.
Opioid endocrinopathy (OE) is the effect of opioids on the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis over the long term. Opioids act on opioid receptors in the hypothalamus, decreasing the release of gonadotropin-releasing hormone. This results in a decreased release of luteinizing hormone and follicle-stimulating hormone, and finally a reduction of testosterone and estradiol released from the gonads. These effects occur in both men and women. Patients may present with symptoms of hypogonadism such as decreased libido, erectile dysfunction, amenorrhea or irregular menses, galactorrhea, depression, and hot flashes.
Treatment for OE is not well established. One group of investigators performed a 24-week, open-label pilot study of a testosterone patch in 23 men with opioid-induced androgen deficiency and reported an improvement in androgen deficiency symptoms, sexual function, mood, depression, and hematocrit levels. There was no change in opioid use. Men and women with OE may be offered hormone replacement therapy after a thorough risk-benefit discussion. Testosterone replacement is contraindicated in men with prostate cancer; estrogen replacement therapy may be contraindicated in patients with breast and ovarian cancer and has serious associated health risks.
Opioid-induced immunological changes
Opioids have immunomodulatory effects through neuroendocrine mechanisms and by direct effects on opioid receptors on immune cells. Opioids can alter the development, differentiation, and function of immune cells, causing immunosuppression. Different opioids cause varying effects on the immune system. In mouse and rat models, methadone is less immunosuppressive than morphine. In contrast, tramadol improves natural killer cell activity. Further research is needed to determine the true clinical significance of opioid-induced immunosuppression, such as the risk of infections.
Opioid rotation or switching may be needed when one of the following occurs:[68,69]
The selection of a target opioid depends on the reason for rotation. All strong opioids have similar efficacy and side effect profiles at equianalgesic doses. Because of the lack of predictors for specific opioids, empiric trials are needed to identify the ideal opioid. If opioid-induced neurotoxicity is the reason for switching, it may not matter which opioid is switched to, as long as it is a different agent. Importantly, patient preference, history of opioid use, route of administration, and cost are necessary considerations before the final choice is made.
A study of opioid rotation in the outpatient palliative care setting revealed that approximately one-third of 385 consecutive patients needed an opioid rotation, mostly for uncontrolled pain (83%) and opioid-induced neurotoxicity (12%). The success rate was 65%, with a median pain improvement of two points out of ten (minimal clinically important difference is one point).
Barriers related to opioid use
The barriers to appropriate use of opioids in the treatment of cancer pain include misunderstandings or misapprehensions about opioids by health care providers, patients, and society. One group of investigators surveyed 93 patients with cancer cared for in an academic practice in Australia to understand patient-level barriers to the use of opioids. One-third of the patients reported high levels of pain that adversely affected activity, mood, sleep, and enjoyment of life. High percentages of patients reported concerns about addiction (76%) or side-effects (67%). In addition, patients expressed concerns that the pain represented disease progression (71%), that they were distracting the doctor (49%), or that they would not be seen as a "good patient" (46%). Patients with more severe pain were more likely to express concerns about side effects and were less likely to use unconventional approaches to pain control. Results were similar to those of a survey of American patients from the previous decade.
Physician-perceived barriers to opioid prescribing tend to parallel those of the patient. Physicians and other health care providers have beliefs about addiction, for example, that inhibit prescribing. In addition, there are significant knowledge deficits that lead to inadequate dosing of opioids and unaddressed side effects.
Other barriers to opioid prescribing and compliance are the costs of abuse and misuse of opioids, which are estimated to be in the tens of billions of dollars and include increased mortality rates. As a consequence, many states have developed prescription drug monitoring programs, and the FDA requires REMS for certain opioids (such as rapid-onset fentanyl products), which could serve as an additional barrier to opioid prescribing. Other barriers include poor or limited formulary and reimbursement for opioids.
The liver plays a major role in the metabolism and pharmacokinetics of opioids and most drugs. The liver produces enzymes involved in two forms of metabolism: phase 1 metabolism (modification reactions, CYP) and phase 2 metabolism (conjugation reactions, glucuronidation).
Methadone and fentanyl are unaffected by liver disease and are drugs of choice in patients with hepatic failure.[76,77]
Morphine, oxymorphone, and hydromorphone undergo glucuronidation exclusively. CYP2D6 metabolizes codeine, hydrocodone, and oxycodone; CYP3A4 and CYP2D6 metabolize methadone; and CYP3A4 metabolizes fentanyl. Hepatic impairment affects both CYP enzymes and glucuronidation processes. Prescribing information recommends caution when prescribing opioids for patients with hepatic impairment.
In cirrhosis, the elimination half-life and peak concentrations of morphine are increased. Moderate to severe liver disease increases peak levels and the area under the curve (AUC) for both oxycodone and its chief metabolite, noroxycodone. Peak plasma concentrations and AUC of another active metabolite, oxymorphone, are decreased by 30% and 40%, respectively.
Although oxymorphone itself does not undergo CYP-mediated metabolism, a portion of the oxycodone dose is metabolized to oxymorphone by CYP2D6. Failure to convert oxycodone to oxymorphone may result in accumulation of oxycodone and noroxycodone, with an associated increase in adverse events. Hepatic disease increases the bioavailability of oxymorphone as liver function worsens.
Renal insufficiency affects the excretion of morphine, oxycodone, hydromorphone, oxymorphone, and hydrocodone. Methadone and fentanyl are safe to use in patients with renal failure, although there is some evidence that the hepatic extraction of fentanyl is affected by uremia.
When patients with renal insufficiency receive hydromorphone and morphine, both hydromorphone and morphine metabolites accumulate, with the potential to cause neuro-excitatory adverse effects. Morphine, which has a higher risk of drug and metabolite accumulation, may be used in patients with mild renal failure but requires dosing at less-frequent intervals or at a lower daily dose to provide benefit with adequate safety. In patients with stage III to stage IV chronic kidney disease (glomerular filtration rate <59 cc/min), morphine may not be desirable.
There are conflicting reports about the safety of hydromorphone in patients with renal failure. One case series suggests adverse effects increasing when hydromorphone is given by continuous infusion to patients with renal failure. Other series suggest that it is safe to use. Although renal impairment affects oxycodone more than it does morphine, there is no critical accumulation of an active metabolite that produces adverse events.
Opioids and addiction
Most patients begin opioid therapy after an acute event such as a pain crisis from cancer progression. Sometimes cancer treatment and its effects will lead to increased opioid use. All patients taking opioids require assessment for risk of abuse or addiction.
Addiction is defined as continued, compulsive use of a drug despite harm. Many other conditions may be misidentified as addiction, and it is important that clinicians distinguish between the two. These conditions include:[86,87]
The following aberrant behaviors may suggest addiction or abuse; further assessment is required to make the diagnosis:
Risk factors for opioid abuse include smoking, psychiatric disorders, history of childhood sexual abuse, and personal or family history of substance abuse. Screening tools help in risk assessment. Common tools include the Opioid Risk Tool (ORT), the Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R), and the Screening Instrument for Substance Abuse Potential (SISAP).[86,91] The choice of which tool to use depends on the type of practice. The ORT is short and useful for busy practices.
Risk assessment determines the structure of therapy, which can range from minimal structure to more structure. Highly structured opioid therapy requires approaches such as frequent visits, limiting pills per prescription, use of other specialists, and urine drug testing. Opioid agreements outline what is expected of the patient, educate about drug storage, and delineate acceptable and unacceptable behavior. Patients are taught that they must safeguard their medications "like their wallets" to protect against diversion. In addition, state guidelines for chronic opioid use, state prescription monitoring, and the use of pharmacists may reduce the potential for worsening addictive behavior.
Random urine drug testing is used for patients with an inadequate response to opioid therapy and those receiving opioids long term. A urine drug test demonstrating absence of prescribed opioid can be useful because it suggests either diversion or stockpiling; a urine drug test revealing concurrent use of other nonprescribed medications or illicit substances can also be informative. Because many different types of urine drug tests are available, clinicians may want to become familiar with the types and interpretation of tests available locally. A clinician's laboratory can identify the substance in question. Clinicians use urine drug testing differently, with some requiring it at the initiation of therapy, episodically, or at the transition to long-term opioid therapy. Risk assessment helps to determine frequency of urine drug testing.
Pharmacologic deterrence has emerged as another option designed to dissuade misuse and abuse by making it difficult to obtain euphoric effects from opioid use. Creating barriers to increasing the bioavailability of opioids is one method of pharmacologic deterrence. Approaches have included adding an opioid antagonist to the formulation  or adding niacin to create a bad taste in the mouth if too many pills are taken. Embedding opioid into a matrix that cannot be obtained by crushing or chemical extraction is another pharmacologic deterrent.
Gabapentin and Pregabalin
Gabapentin and pregabalin are structurally related to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) but have no effect on GABA binding. Instead, they bind to the alpha2delta-1 subunit of voltage-gated calcium channels, which may result in decreased neuronal excitability in pain-associated sensory neurons. These drugs have been widely studied in the treatment of neuropathic pain syndromes (refer to the Approach to Neuropathic Pain section of this summary for more information) and as adjunctive agents with opioids.
These medications may cause sedation, dizziness, peripheral edema, nausea, ataxia, and dry mouth. Gradual upward titration of gabapentin to a maximum of 3,600 mg per day and pregabalin to 300 mg per day can help with dose-dependent sedation and dizziness. In addition, starting doses of gabapentin may be given at bedtime to assist with tolerating any sedation. Doses of both agents need to be adjusted for patients with renal dysfunction.[10,98]
Venlafaxine and Duloxetine
The antidepressant medications venlafaxine and duloxetine have demonstrated some efficacy in the treatment of neuropathic pain syndromes. Venlafaxine and duloxetine are serotonin and norepinephrine reuptake inhibitors (SNRIs) originally approved for depression; however, both are used off-label for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). Both serotonin and norepinephrine have important roles in analgesia.
Common dosing for duloxetine ranges from 30 mg to 60 mg per day. Side effects include nausea, headache, fatigue, dry mouth, and constipation. Duloxetine is avoided in patients with hepatic impairment and severe renal impairment, and it carries an increased risk of bleeding.
Venlafaxine inhibits serotonin reuptake more intensely at low doses, and norepinephrine more intensely at higher doses; higher doses may be necessary for relief of CIPN.
Venlafaxine can be started at 37.5 mg, with a maximum dose of 225 mg per day. Adverse effects include nausea, vomiting, headache, somnolence, and hypertension at higher doses. These effects decrease with the use of the long-acting formulations. Venlafaxine is used with caution in patients with bipolar disorder or a history of seizures and is dose-adjusted for patients with renal or hepatic insufficiency. If the decision is made to discontinue venlafaxine, a slow tapering course may help to minimize withdrawal symptoms.
Tricyclic Antidepressants (TCAs)
The TCAs amitriptyline, desipramine, and nortriptyline are used to treat many neuropathic pain syndromes. These drugs enhance pain inhibitory pathways by blocking serotonin and norepinephrine reuptake.
TCAs have anticholinergic, antihistaminic, and antiadrenergic effects that result in dry mouth, drowsiness, weight gain, and orthostatic hypotension. Significant drug interactions are a concern, including interactions with anticholinergics, psychoactive medications, class IC antiarrhythmics, and selective serotonin reuptake inhibitors (SSRIs). Because of these adverse effects and drug interactions, TCAs are used with caution in elderly patients, patients with seizure disorders, and those with preexisting cardiac disease.
There is a lack of high-quality data demonstrating the efficacy of corticosteroids in treating cancer pain. A systematic review of the literature resulted in four randomized controlled trials and concluded that there is low-grade evidence to suggest corticosteroids have moderate activity in the treatment of cancer pain. A small but well-designed study showed no benefit to adding corticosteroids to opioid analgesia in the short term (7 days).
Despite the lack of good evidence, corticosteroids are often used in the clinical setting. Corticosteroids (dexamethasone, methylprednisolone, and prednisone) may be used as adjuvant analgesics for cancer pain originating in bone, neuropathy, and malignant intestinal obstruction. Mechanisms of analgesic action include decreased inflammation, decreased peritumoral edema, and modulation of neural activity and plasticity.
Although there is no established corticosteroid dose in this setting, recommendations range from a trial of low-dose therapy such as dexamethasone 1 mg to 2 mg or prednisone 5 mg to 10 mg once or twice daily, to dexamethasone 10 mg twice daily. Immediate side effects include hyperglycemia, insomnia, immunosuppression, and psychiatric disorders. Serious long-term effects of myopathy, peptic ulceration, osteoporosis, and Cushing syndrome encourage short-term use. If taken for more than 3 weeks, corticosteroids are tapered upon improvement in pain, if possible. If corticosteroids are to be continued long term, anti-infective prophylaxis can be considered. Dexamethasone is preferred because it has reduced mineralocorticoid effects, resulting in reduced fluid retention; however, it does exhibit cytochrome P450–mediated drug interactions.
Bisphosphonates and Denosumab
The bisphosphonate class of drugs inhibits osteoclastic bone resorption, decreasing bone pain and skeletal-related events associated with cancer that has metastasized to the bone. Pamidronate and zoledronic acid decrease cancer-related bone pain, decrease analgesic use, and improve quality of life in patients with bone metastases.[106,107,108,109] American Society of Clinical Oncology (ASCO) guidelines for the use of these bone-modifying agents in patients with breast cancer and myeloma specify they should be used not as monotherapy but as part of a treatment regimen that includes analgesics and nonpharmacologic interventions.[110,111] Bisphosphonates can cause an acute phase reaction characterized by fever, flu-like symptoms, arthralgia, and myalgia that may last for up to 3 days after administration. Additional adverse effects include renal toxicity, electrolyte imbalances, and osteonecrosis of the jaw.[112,113,114] Doses are adjusted for patients with renal dysfunction.
Denosumab is a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL), prevents osteoclast precursor activation, and is primarily used in the treatment of bone metastases. A review of six trials comparing zoledronic acid with denosumab demonstrated a greater delay in time to worsening pain for denosumab (relative risk, 0.84; 95% confidence interval, 0.77–0.91).
Denosumab is avoided in myeloma patients because a subgroup analysis in one trial suggested increased mortality in that patient population. Compared with zoledronic acid, denosumab has similar adverse effects with less nephrotoxicity and increased hypocalcemia. There is no adjustment for renal dysfunction; however, patients with a creatinine clearance lower than 30 mL/min are at a higher risk of developing hypocalcemia. Denosumab may be more convenient than zoledronic acid because it is a subcutaneous injection and not an intravenous infusion; however, it is significantly less cost-effective.
Ketamine is an FDA-approved dissociative general anesthetic that has been used off-label in subanesthetic doses to treat opioid-refractory cancer pain. A 2012 Cochrane review of ketamine used as an adjuvant to opioids in the treatment of cancer pain concluded there is insufficient evidence to evaluate its efficacy in this setting.
Lack of demonstrated clinical benefit, significant adverse events, and CYP3A4-associated drug interactions limit ketamine's utility in the treatment of cancer pain. It is an NMDA receptor antagonist that, at low doses, produces analgesia, modulates central sensitization, and circumvents opioid tolerance. However, a randomized placebo-controlled trial of subcutaneous ketamine in patients with chronic uncontrolled cancer pain failed to show a net clinical benefit when ketamine was added to the patients' opioid regimen. Adverse drug reactions include hypertension, tachycardia, psychotomimetic effects, increased intracranial and intraocular pressure, sedation, delirium, and impaired bladder function.
While pharmacologic therapy using the World Health Organization (WHO) guidelines effectively manages most cancer pain, approximately 10% to 20% of patients will have refractory pain or excessive side effects. For patients with refractory pain or specific regional pain syndromes, an interventional approach to treating pain has been proposed as the fourth step on the WHO pain relief ladder. Some common interventions and their evidence of benefit are discussed below.
The celiac plexus block, used primarily for patients with upper abdominal pain from pancreatic cancer, is the most commonly employed neurolytic blockade of the sympathetic axis, followed by the superior hypogastric plexus block and the ganglion of impar block for patients with lower abdominal or pelvic pain. Traditionally, the autonomic neural blockade was reserved for patients with inadequate response to oral opioids, but some researchers have suggested that the intervention—which is associated with decreased pain, reduced opioid consumption, improved performance status, and few complications—is considered a first-line approach.[2,3]
For patients with regional pain, a peripheral nerve block infusing a local anesthetic can achieve local pain control. This approach can be applied to any peripheral nerve, including the femoral, sciatic, paravertebral, brachial plexus, and interpleural nerves.
Neuroaxial delivery of analgesia
When patients have pain that persists despite high doses of opioids and other analgesics or have intolerable side effects to oral opioids—such as delirium, sedation, or nausea—an alternative route of delivery may be considered. Compared with intravenous administration of opioids, epidural and intrathecal routes of delivery are 10 and 100 times more potent, respectively. Such routes of delivery allow high doses of analgesics to be administered with less systemic absorption and fewer side effects.
One study that randomly assigned patients to receive either an implantable drug delivery system or comprehensive medical management found that patients receiving the analgesic through the implantable pump had less pain, less toxicity, and longer survival at 6 months. While the survival benefit did not persist in other studies, the intrathecal pump may be an option for selected patients with refractory pain and a life expectancy longer than 3 months. However, intrathecal pumps may make it difficult for patients to access hospice care because of care needs and cost issues, and they cannot effectively treat pain that is predominantly related to psychological distress. For patients with shorter life expectancies, placement of an epidural catheter may be a safe and effective technique.
Cordotomy is reserved for pain refractory to other approaches and is done less commonly today. It is most effective in treating unilateral somatic pain from the torso to the lower extremities. The available literature suggests a high rate of efficacy, with 60% to 80% complete pain relief immediately after the procedure, falling to 50% at 12 months. Cordotomy is generally reserved for patients considered to be in the last 2 years of life, with pain refractory to other approaches, and may be done via the open route or the percutaneous route.[9,10,11]
For patients with either regional pain syndromes or pain refractory to escalating systemic medications, the cancer clinician may consult with a pain specialist or neurosurgeon to consider an interventional approach to pain control.
Palliative Care Referral
Palliative care, which is specialized medical care for people with serious illnesses with the goal to maximize quality of life for both patients and families, can provide expert assessment and management of pain and other nonpain symptoms. Palliative care providers work in interdisciplinary teams that include physicians, nurses, mental health specialists, social workers, chaplains, and sometimes pharmacists and dieticians. For patients with refractory pain, prominent nonpain symptoms, or intense psychosocial distress, a referral to palliative care may be appropriate, where available. Many palliative care teams now call themselves supportive care teams because this term is more acceptable to many referring providers and to some patients and families.[12,13]
Palliative care specialists may also help manage patients with multiple comorbidities, those requiring higher doses of opioids, and those with a history of substance abuse or complex psychosocial dynamics that can complicate the management of pain and adherence to recommended medications. Most palliative care specialists have experience using methadone for pain.
The role of specialty palliative care integrated into cancer care has been well studied, with studies showing that early integration of specialty palliative care into cancer care reduces symptom burden and enhances quality of life for both patients and families [14,15,16,17] and may prolong life. (Refer to the PDQ summary on Planning the Transition to End-of-Life Care in Advanced Cancer for more information.)
External-Beam Radiation Therapy
Palliative radiation therapy represents an effective modality for pain related to advanced cancer. Pain related to bone metastases, skin lesions, or isolated tumor lesions may be relieved by a short course of radiation therapy.
For bone metastases, radiation is often delivered as 8 Gy in a single fraction, 20 Gy in five fractions, 24 Gy in six fractions, or 30 Gy in ten fractions. A Cochrane review that included 11 randomized trials consisting of 3,435 patients showed that single-fraction radiation therapy for bone pain provided a similar overall response rate (60% vs. 59%) and complete response rate (34% vs. 32%), compared with multifraction radiation therapy. However, patients who received single-fraction radiation therapy had a higher rate of re-treatment (22% vs. 7%) and a higher rate of pathological fracture (3% vs. 1.6%). This finding was consistent with other systematic reviews. In the Dutch Bone Metastasis Study, the average time to first pain relief was 3 weeks; the peak effect was achieved in 4 to 6 weeks; and the mean duration of response was approximately 30 weeks.[20,21] Single-fraction radiation has several potential advantages: greater convenience, lower cost, and less breakthrough pain associated with transportation to the radiation facility and with getting on and off the radiation table.
Re-irradiation may be considered for selected patients who derive no or partial pain relief with first-time radiation therapy, or who develop worsening pain after an initial response. Re-irradiation typically occurs at least 4 weeks after the first radiation treatment. A systematic review that examined re-irradiation for bone metastases included 15 studies and reported a complete response rate of 20% and a partial response rate of 50%. Re-irradiation was generally well tolerated. Serious adverse effects such as spinal cord compression and pathological fracture were infrequent (<3%). A randomized controlled trial compared a single fraction (8 Gy) with multiple fractions (20 Gy over 5 days) of re-irradiation and found similar response rates at 2 months in an intention-to-treat analysis (28% vs. 32%; P = .02).
Patients with multiple sites of symptomatic osteoblastic bone metastases may consider radionuclides such as strontium-89 or samarium-153, which are beta-emitters. Two double-blind randomized trials support the superiority of samarium-153 over placebo in providing pain control and reducing analgesic use.[24,25] The overall response varies between 30% and 80%, with onset of pain relief within the first week; some patients report a long-lasting benefit (up to 18 months). The most common toxicities are pain flare and cytopenias. Pain flare typically occurs in approximately 10% of patients within the first 24 to 48 hours of administration and may be treated with corticosteroids or opioids. Leukopenia and thrombocytopenia are sometimes seen, with a nadir of 4 weeks posttreatment and recovery by 8 weeks. Contraindications to radionuclide therapy include a poor performance status (Karnofsky Performance Status score <50%) and a short life expectancy (<3 months).
Radium-223 (an alpha-emitter) is approved for use in patients with castration-resistant prostate cancer. A phase III randomized trial compared radium-223 with placebo in a 2:1 ratio. Among the 921 symptomatic patients enrolled, those who received radium-223 had a prolonged time to first symptomatic skeletal event (15.6 months vs. 9.8 months, P < .0001), in addition to prolonged overall survival (14.9 months vs. 11.3 months, P < .001).
Physical Medicine and Rehabilitation
Patients with cancer and pain may experience loss of strength, mobility, and, ultimately, functional status secondary to the cause of pain, (e.g., vertebral metastases, incident pain, and chronic nonmalignant pain). Therefore, pain and functional status may improve with physical or occupational therapy, treatments for strengthening and stretching, and the use of assistive devices. Referral to a physiatrist (a physician who specializes in rehabilitation medicine) who could create a comprehensive plan may benefit the patient. In addition, some physiatrists practice interventional pain medicine.
Patients with cancer frequently use complementary or alternative medicines or interventions (CAM). One of the stated benefits of CAM is pain relief. However, a meta-analysis of multi-institutional, randomized, controlled trials for cancer-related pain concluded that methodological flaws hampered interpretation of the few available studies. There were brief positive effects in favor of CAM for acupuncture, support groups, hypnosis, and herbal supplements. (Refer to the PDQ summaries on Complementary and Alternative Medicine for more information.)
Pain management varies widely in complexity. The decision-making process involves a careful consideration of many patient-related and pain-related factors. These may include, but are not limited to, the pain mechanism, pain expression, previous treatments, available options, and prognosis. Recognition of specific pain syndromes can be useful in guiding management.
Approach to Somatic Pain
Damage and/or inflammation involving the muscles, skin, joints, connective tissue, or bones can lead to activation of the nociceptive pathways that result in somatic pain. This type of pain is often well localized; may be described as sharp, achy, throbbing, and/or stabbing in nature; and often worsens with movement. It can often be managed with acetaminophen, anti-inflammatories, and opioids. Bone pain related to metastases is particularly common in cancer patients and is discussed below in more detail.
Bone pain due to metastatic disease is one of the most common causes of pain in cancer patients.[1,2] Bone is highly innervated tissue with receptors sensitive to mechanical damage. The entrapment of nerve fibers in the collapsing bony matrix caused by increased osteoclastic activity and the release of inflammatory cytokines by cancer cells and immune cells are also central to the pathophysiology of bone pain. Patients typically describe the pain as continuous, deep, and throbbing, with brief episodes of more-severe pain often precipitated by movement (i.e., a type of incident pain).
Most patients will require morphine or an equivalent opioid for adequate pain relief, although incident pain is less responsive. Adjunctive agents such as nonsteroidal anti-inflammatory drugs and corticosteroids are often prescribed and appear moderately effective and safe.
In addition to providing analgesia, the clinician introduces treatments designed to prevent further weakening of skeletal integrity, which may lead to loss of functional status or further pain. Bone-targeting agents such as the bisphosphonates (zoledronic acid or pamidronate) or denosumab (refer to the Bisphosphonates and Denosumab section of this summary for more information) have been demonstrated to reduce future skeletal-related events and to reduce the likelihood of increased pain or increased use of opioids in patients with advanced cancer.
Palliative radiation therapy produces complete or partial pain relief in up to 80% of treated patients; the median duration of relief exceeds 6 months. (Refer to the External-Beam Radiation Therapy section of this summary for more information.)
Finally, orthopedic consultation is frequently necessary to determine whether operative intervention is required to prevent and/or treat pathological fractures.
Approach to Visceral Pain
Visceral pain is a type of nociceptive pain that originates in nociceptors innervating visceral organs. Several features of visceral pain inform the therapeutic approach:
Opioids remain the core treatment for severe or distressing visceral pain. Also important are radiographic studies to look for underlying causes that may be amendable to other interventions (e.g., bowel obstruction).
Approach to Neuropathic Pain
Pain with features suggestive of neuropathic pain is common among patients with cancer and can have substantial negative consequences. One study of 1,051 patients with cancer found that 17% had neuropathic pain. These patients reported worse physical, cognitive, and social functioning than did those with nociceptive pain; were on more analgesic medications and higher doses of opioids; and had a worse performance status. Neuropathic pain is considered less responsive to opioids. Multiple therapeutic options instead of or in addition to opioids have been studied. Most of these studies were conducted in patients with nonmalignant sources of neuropathic pain and may not be applicable to patients with cancer with different etiologies for their neuropathic pain.
Gabapentin can be used as monotherapy in the first-line setting for neuropathic pain or in combination therapy if opioids, tricyclic antidepressants (TCAs), or other agents do not provide adequate relief. Gabapentin improved analgesia when added to opioids for uncontrolled cancer-related neuropathic pain.[10,11] When gabapentin was used adjuvantly to an opioid regimen, improvement in pain control was seen within 4 to 8 days. In an open-label trial of pregabalin compared with fentanyl in 120 cancer patients with "definite" neuropathic pain, patients on pregabalin were twice as likely (73.3%) than those on fentanyl (36.7%) to report 30% or more reduction in pain, as measured by a visual analog scale. Compared with monotherapy with amitriptyline, gabapentin, or placebo, pregabalin use resulted in a significant decrease in pain score when studied in neuropathic cancer pain.
Notably, in a systemic review of neuropathic pain that included mostly patients with a nonmalignant source of neuropathic pain, the effect of gabapentin and pregabalin appeared less robust. Data comparing gabapentin or pregabalin directly with TCAs and serotonin–norepinephrine reuptake inhibitors (SNRIs) are limited, especially in patients with cancer. Efficacy of TCAs and SNRIs appears to be comparable and, in some cases, superior to gabapentin or pregabalin (refer to the Chemotherapy-induced peripheral neuropathy (CIPN) section of this summary for more information). Because of concerns about side effects and drug-drug interactions, many practitioners tend to start with gabapentin or pregabalin as first-line treatment for neuropathic pain. However, as noted below, certain neuropathic syndromes may be less responsive to these agents. (Refer to the Postthoracotomy pain syndrome and Chemotherapy-induced peripheral neuropathy (CIPN) sections of this summary for more information.) Studies have also examined the use of lidocaine patches, tramadol, topically applied capsaicin, and botulinum toxin A for use in patients with neuropathic pain  with inconclusive results.
Postmastectomy pain syndrome
Rates of postmastectomy pain range between 25% and 33%,[16,17,18,19] making this a common complication. Women with postmastectomy pain note more role limitations due to physical, emotional, and mental health issues. Associations of postmastectomy pain with extent of surgery, radiation therapy, and chemotherapy are inconsistent across studies. One cross-sectional study found associations between postmastectomy pain and psychosocial factors such as depression, anxiety, somatization, and catastrophizing.[17,19]
A number of small studies have examined the effect of an anesthetic administered intraoperatively or immediately postoperatively, with varying results; one group found a decrease in pain during the infusion but no benefits after the infusion until 12 months.[21,22] The use of venlafaxine or gabapentin for 10 days, starting 1 day before surgery, may decrease postmastectomy pain, but confirmatory studies are needed.
Postthoracotomy pain syndrome
Defined as pain occurring 2 months after thoracotomy, postthoracotomy pain syndrome occurs in approximately 50% of patients and may be underreported and undertreated. The pain is thought to be related to damage to the intercostal nerve during surgery and from postoperative drainage via chest tubes. The pain includes both neuropathic and nonneuropathic components.
Opioid and nonopioid analgesics are part of the standard approach to treatment. Several approaches in the immediate postoperative period are being investigated. An open-label noncontrolled study of 5% lidocaine patches showed improvement in pain scores 1 month postoperatively. A small randomized trial of transcutaneous electrical nerve stimulation demonstrated decreased pain and reduced use of morphine and nonopioid analgesia in the immediate postoperative period. Patients randomly assigned to receive intraoperative cryoanalgesia versus placebo were found to have less pain at time points up to 60 days postoperatively and reduced analgesic use in the first 3 days. Further work is needed to confirm these results. In a randomized, double-blinded, placebo-controlled study of gabapentin started preoperatively and titrated over 5 days postoperatively, gabapentin failed to show benefit.
Chemotherapy-induced peripheral neuropathy (CIPN)
Peripheral neuropathy is a common toxic effect of chemotherapy and is predominantly a sensory neuropathy. Patients report numbness and tingling in a "stocking-and-glove" distribution. CIPN is most commonly associated with platinum compounds (e.g., oxaliplatin, cisplatin, and carboplatin, in descending order of severity), taxanes (e.g., paclitaxel, docetaxel), thalidomide, and vinca alkaloids. Among newer agents, ixabepilone, lenalidomide, pomalidomide, and bortezomib are common sources. With these agents, CIPN limits the dose of chemotherapy delivered, which may affect the outcomes of treatment. In one series of women treated with taxanes, approximately one in four reported CIPN. Although CIPN often improves after discontinuation or completion of chemotherapy, symptoms can linger for a year or longer for some patients, especially those treated with taxanes.
Studies evaluating treatment for CIPN have been plagued by methodologic flaws such as small size and open-label comparisons. Differences in the defined endpoints have also made it difficult to compare across studies. Duloxetine is the only agent whose efficacy in treating CIPN is supported by data from a large phase III study. One group of investigators found an average decrease of 0.73 in the pain scores of patients who titrated up to 60 mg of duloxetine daily, when compared with placebo. Patients also had improvements in daily functioning and quality of life. Some argue that, while statistically significant, the difference of less than 1 (0.73) on a pain scale of 0 to 10 may not be clinically important. Gabapentin failed to provide a benefit in CIPN when used as monotherapy in a randomized, double-blind, placebo-controlled trial.[32,33]
Investigators studied the use of venlafaxine for prevention and relief of oxaliplatin-induced acute neuropathy and found both a significant decrease in acute neuropathy and an increased relief at 3 months after treatment. There is hesitation to use venlafaxine preventively because its antioxidative effects may decrease the efficacy of oxaliplatin. American Society of Clinical Oncology (ASCO) CIPN guidelines do not recommend routine use of venlafaxine for CIPN because of a lack in strength of the existing data.
Evidence of the efficacy of nortriptyline and amitriptyline in CIPN is limited to small and frequently underpowered trials with mixed results.[36,37,38] ASCO guidelines  recommend against the use of many commonly prescribed agents for the treatment of existing CIPN and do not recommend any agent for CIPN prevention. For treatment, the guidelines suggest that the best current evidence supports the use of duloxetine, on the basis of the randomized controlled trial mentioned above. Despite inconclusive trials, the authors suggest that a trial of TCAs, gabapentin, and topical baclofen/amitriptyline/ketamine may be reasonable in light of evidence supporting the benefit of these agents in other types of neuropathy and the relative lack of effective alternatives in this setting.
Approach to Acute Procedural Pain
Bone marrow biopsy and aspiration
Bone marrow biopsy and aspiration cause pain in 84% of patients, with intensity reported as severe in 8% to 35%. Factors associated with greater pain are the duration of the procedure (taking longer than 10 minutes), younger age, higher body mass index, female sex, anxiety, site of examination (sternum being the most painful), inadequate information given before procedure, and lack of physician experience. Pharmacologic interventions for pain control vary from local anesthesia, to intravenous sedation with benzodiazepines and/or opioids, to the use of inhaled nitrous oxide, to premedication with opioids. Addressing anxiety is an important nonpharmacologic intervention.
Lumbar puncture is a diagnostic and staging tool for hematologic malignancies and solid tumors involving the central nervous system. Patients can develop post–lumbar puncture headache. Headaches usually develop hours to days after the procedure and are caused by leakage of cerebrospinal fluid, possible compensatory intracranial vessel dilatation, or increased tension on brain and meninges. The use of an atraumatic small-bore needle has been found to reduce to incidence of post–lumbar puncture headaches.[46,47] A Cochrane review that included 13 small randomized trials mostly in noncancer patients reported some evidence to support the use of caffeine, gabapentin, hydrocortisone, and theophylline to treat post–lumbar puncture headache, and a lack of efficacy for sumatriptan, adrenocorticotropic hormone, pregabalin, and cosyntropin.
Approach to Special Populations
Refer to the PDQ summary on Pediatric Supportive Care for more information.
For geriatric patients, analgesic medications need to be started at low doses and titrated up gradually. The reasons behind this approach include higher pain thresholds, differences in pain expression, and greater effects on physical and psychosocial function in this patient population. (Refer to the Pain Assessment section of this summary for more information.) Polypharmacy is common among the geriatric population. The Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommended against the use of some pain medications in geriatric patients, including nonsteroidal anti-inflammatory drugs, meperidine, and tricyclic antidepressants.
Geriatric patients may need less opioid because they achieve greater analgesia from opioids. Opioids may have a heightened effect in older people because of higher levels of morphine and its metabolites.[53,54] One retrospective study of opioid consumption in geriatric patients found that they need less opioid with acute and chronic pain therapy; they require less opioid regardless of route of administration; and incidental pain and/or neuropathic pain did not confound the correlation between age and opioid consumption but was associated with higher doses of opioids.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Cancer Pain
Revised text to state that determining whether the pain requires pharmacologic and/or other modalities of treatment is one step in effective pain management.
Revised text to include patient prognosis, predictive factors for pain control (e.g., psychological distress), and impact on function as issues to be considered when determining the most appropriate treatment.
Added text to state that patients and family caregivers should be educated about the safe storage, use, and disposal of opioids; and that one study demonstrated that improper use, storage, and disposal are common among cancer outpatients (cited Reddy et al. as reference 2).
Added text to state that an open-label randomized trial of low-dose morphine versus weak opioids to treat moderate cancer pain suggests that it is acceptable to bypass weak opioids and go directly to strong opioids (step 3 agents) for patients with moderate cancer pain, as patients randomly assigned to the low-dose morphine arm had more frequent and greater reduction in pain intensity with similarly good tolerability and earlier effect (cited Bandieri et al. as reference 6).
Added text about how emotional distress may also contribute to the pain experience.
Added Portenoy et al. and Narayana et al. as references 10 and 11, respectively.
Revised text to state that psychosocial and existential factors that can affect pain are also assessed and appropriately treated.
Pharmacologic Therapies for Pain Control
Revised Table 2 to note that for fentanyl, cachectic patients have decreased absorption from the transdermal patch (cited Heiskanen et al. as reference 20).
Revised Table 3 to note that intramuscular injection of opioids, acetaminophen, and ketorolac is typically avoided because of pain from the injection. Also added fentanyl as a subcutaneous agent (cited Oosten et al. as reference 24).
Added text to state that rapid titration of methadone may result in delayed respiratory depression because of its long half-life (cited Modesto-Lowe et al. as reference 32).
Revised text to state that careful titration of naloxone should be considered because it may compromise pain control, and may precipitate withdrawal in opioid-dependent individuals. Also added text to state that because of methadone's long half-life, naloxone infusion may be required for respiratory depression caused by methadone.
Modalities for Pain Control: Other Approaches
Revised text to state that intrathecal pumps may make it difficult for patients to access hospice care because of care needs and cost issues.
Revised text to state that cordotomy is generally reserved for patients considered to be in the last 2 years of life, with pain refractory to other approaches, and may be done via the open route or the percutaneous route.
Added text to include social workers as part of palliative care interdisciplinary teams. Also added text to state that many palliative care teams now call themselves supportive care teams because this term is more acceptable to many referring providers and to some patients and families (cited Fadul et al. and Dalal et al. as references 12 and 13, respectively).
Added text to state that single-fraction radiation has several potential advantages: greater convenience, lower cost, and less breakthrough pain associated with transportation to the radiation facility and with getting on and off the radiation table.
General Approaches to Pain Treatment
Revised text to state that orthopedic consultation is frequently necessary to determine whether operative intervention is required to prevent and/or treat pathological fractures.
This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of pain. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Cancer Pain are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Supportive and Palliative Care Editorial Board. PDQ Cancer Pain. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: http://www.cancer.gov/about-cancer/treatment/side-effects/pain/pain-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389387]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Last Revised: 2016-03-10
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