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 (QOL). 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, or resembling that associated with, actual or potential tissue damage."[
Pain intensity may be assessed by asking patients to rate their pain on a numeric rating scale (NRS) of 0 to 10, with 0 defined as no pain and 10 defined as the worst pain imaginable. Although highly subjective, this scale may assist practitioners in gauging a patient's pain status.[
Following is a summary of the three steps in the WHO pain ladder for adults:
The results of an open-label randomized trial of low-dose morphine versus weak opioids to treat moderate cancer pain suggested 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 group 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.[
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.[
Pain can be caused by the following:
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 is an expected consequence of surgery. Concerns about the prevalence of opioid misuse have drawn increasing attention to how opioids are prescribed in common settings, including postoperatively. Studies suggest widespread variation in the prescribing patterns of opioids in the postoperative setting.[
The opioid epidemic has also raised questions about whether postoperative use of opioids can lead to misuse. New persistent opioid use develops in 6% to 8% of opioid-naïve patients after noncancer surgery.[
Infusion-related pain syndromes
The infusion of intravenous chemotherapy causes four pain syndromes:[
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.[
White blood cell growth factor–related bone pain
Filgrastim and pegfilgrastim are recombinant granulocyte colony-stimulating factors (G-CSFs) that increase proliferation and differentiation of neutrophil precursors. Ostealgia is a significant adverse effect caused by G-CSFs that can occur in 20% to 71% of patients.[
A second phase II trial randomly assigned patients receiving pegfilgrastim to receive naproxen, loratadine, or no preventative medications.[
Conventional pain medications have also been studied in this area. A phase III, double-blind, placebo-controlled trial of naproxen for the prevention of pegfilgrastim-induced bone pain randomly assigned patients to receive either naproxen 500 mg twice daily for 5 to 8 days after pegfilgrastim administration or placebo.[
Chemotherapy-related musculoskeletal pain
Paclitaxel generates a syndrome of diffuse arthralgias and myalgias in 10% to 20% of patients.[
Dermatologic complications and chemotherapy
EGFR inhibitors cause dermatitis with ensuing pain.[
Supportive care therapies and pain
Supportive care therapies can cause pain, as typified by bisphosphonate-associated osteonecrosis of the jaw.[
Radiation is associated with several distinct pain syndromes. First, patients may experience pain from brachytherapy and from positioning during treatment (i.e., placement on a radiation treatment table). Second, delayed tissue damage such as mucositis, mucosal inflammation in areas receiving radiation, and dermatitis may be painful. Third, a temporary worsening of pain in the treated area (a pain flare) is a potential side effect of radiation treatment for bone metastases.[
Impact on Function and QOL
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.[
In one study, between 20% and 50% of cancer patients continued to experience pain and functional limitations years posttreatment.[
The concept of total pain captures its multidimensional nature by explicitly including the physical, psychological, social, and spiritual components of pain.[
Pain is classified on the basis of the underlying pathophysiologic mechanisms, the duration, or the description of recognizable syndromes associated with pain.[
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).[
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 use disorder.
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.[
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:[
The transition from acute to chronic pain may be understood as a series of relatively discrete changes in the CNS,[
In caring for patients with pain, breakthrough pain is distinguished from background pain.[
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 following:
Multidimensional pain assessment tools such as the McGill Pain Questionnaire, the Brief Pain Inventory,[
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 (PPG).[
Patient-reported symptoms and clinician-assessed pain reporting may not be concordant, and discrepancies in assessment or interpretation of symptoms can be important in making decisions about cancer treatment. In one study, breast cancer patients who were undergoing an exercise intervention and who received four different chemotherapy regimens (e.g., anthracycline- and paclitaxel-based regimens) were assessed for symptoms of chemotherapy-induced peripheral neuropathy (CIPN) by patient self-report (the Patient-Reported Symptom Monitoring form, a five-point symptom scale) and by clinician assessment (the Common Terminology Criteria for Adverse Events form, a five-point adverse event rating scale).[
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.[
Identifying the etiology of pain is important for 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.[
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 pharmacological solutions, is likely to increase the use of pain medication.[
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.[
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.[
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) [
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.[
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.[
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 [
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.[
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.[
These studies describe larger cultural responses to pain that may inform assessments or improve understanding of pain communication by providers. However, in addition to a broad cultural understanding, it should be noted that subcultural differences or individual differences within each ethnic group may affect the experience or expression of pain.
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 (refer to Table 1 and Table 3). No single NSAID is preferred over others, and all are better than placebo for analgesia.[
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.[
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.[
|COX-2 = cyclooxygenase-2; GI = gastrointestinal; IM = intramuscular; IV = intravenous; NSAIDs = nonsteroidal anti-inflammatory drugs; PO = by mouth.|
|Acetaminophen||<4,000 mg/d||Dosed every 4 to 8 hours, depending on dose and product used.||[
|Celecoxib||200–400 mg/d||COX-2 specific. Minimal antiplatelet effects compared with nonselective NSAIDs.||[
|Diclofenac||100–200 mg/d||Available as immediate- and delayed/extended–release products.||[
|Ketoprofen||100–300 mg/d||Available as parenteral in some parts of the world, which may be preferred.||[
|Ketorolac||40–60 mg/d, generally dosed every 6 hours||Parenteral (IV, IM) ketorolac is used ≤5 days because of concerns about GI adverse events. May also be given PO.||[
The use of opioids for the relief of moderate to severe cancer pain is considered necessary for most patients.[
In one well-designed review, most individuals with moderate to severe cancer pain obtained significant pain relief from oral morphine.[
The management of acute pain begins with an immediate-release opioid formulation. Once pain is stabilized, opioid consumption is converted to a modified-release or longer-acting opioid on the basis of the patient's previous 24-hour opioid consumption. The Morphine Milligram Equivalent (MME) can then be used to convert to an alternative opioid, if desired. 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.[
During ongoing pain management, the immediate-release opioids inform the titration of long-acting medications. Rapid-acting oral, buccal, sublingual, transmucosal, rectal, and intranasal products are all acceptable for the treatment of breakthrough pain. In people who are unable to take oral medications, a subcutaneous method of delivery is as effective as the intravenous route for morphine and hydromorphone.
|Opioid Drug||Equianalgesic Dosing||Comments||Reference(s)|
|Buprenorphine||No consensus.||Transdermal product and sublingual available. May cause less constipation and nausea than do other opioids.||[
|Codeine||Oral: 200 mg||Maximum of 360 mg/d. Used with or without acetaminophen.||[
|Fentanyl||Transdermal: 12 µg/h × 24 h ~ 25 mg oral morphine/day. Transmucosal: no consensus; varies by product.||Delivered transdermally, transmucosally, or intravenously. Cachectic patients may have decreased absorption from transdermal patch.||[
|Hydrocodone||Immediate release formulation with acetaminophen: 20 mg||Equianalgesic dose calculations for extended-release products vary; refer to prescribing information.||[
|Hydromorphone||Oral: 6-7.5 mg, IV: 1.5 mg||[
|Methadone||Equianalgesic ratio varies widely by dose.||Used primarily for severe pain in non–opioid-naïve patients. Unusual pharmacokinetics require experienced practitioner.||[
|Morphine||Oral: 30 mg, IV: 10 mg||Randomized trials supporting use. First-choice opioid because of familiarity, availability, and cost.||[
|Oxycodone||20 mg||Randomized trials supporting use.||[
|Tapentadol||100 mg||Similar to morphine, 30-40 mg.||[
|Tramadol||150 mg ~ 25 mg oral morphine||Use at <400 mg/d with or without acetaminophen. Used for moderate pain. Inhibits reuptake of norepinephrine and serotonin. Caution with concomitant antidepressant use.||[
|NSAIDs = nonsteroidal anti-inflammatory drugs.|
|Buccal||Fentanyl||Used primarily for breakthrough pain.||[
|Epidural||Opioids, local anesthetics||Consider if inadequate analgesia or intolerable side effects with oral or intravenous analgesics.||[
|Intramuscular injection||Opioids, acetaminophen, ketorolac||Typically avoided because of pain from injection.||[
|Intranasal||Fentanyl||Onset faster than that of transmucosal fentanyl or oral morphine. Used for breakthrough pain.||[
|Intrathecal||Opioids||Consider if inadequate analgesia or intolerable side effects with oral or intravenous analgesics.||[
|Intravenous||Most strong opioids (except oxycodone) and some NSAIDs||Availability varies by world region.||[
|Oral||Most opioids except fentanyl and buprenorphine||Most common and preferred method of administration.||[
|Rectal||Morphine, methadone||Onset similar to that of oral; possibly better absorption. May be useful for pediatric and end-of-life patients.||[
|Subcutaneous||Morphine, fentanyl, hydromorphone, ketoprofen, methadone||Benefit similar to that of intravenous; considered an alternative if no oral capacity.||[
|Sublingual||Fentanyl, buprenorphine, concentrated morphine solution, methadone||Used primarily for breakthrough pain.||[
|Topical||Lidocaine||Primarily application of topical anesthetics.||[
|Transdermal||Fentanyl, buprenorphine||Efficacy similar to that of oral agents for moderate to severe pain in opioid-naïve patients.||[
|Transmucosal||Fentanyl||Used primarily for breakthrough pain.||[
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.[
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.
|Drug||Starting Dose (µg)||Tmax(median, minutes)||Comments||Evidence|
|DB = double blinded; PC = placebo controlled; RCT = randomized controlled trial; Tmax = time to maximum blood concentration.|
|Transmucosal fentanyl lozenges (Actiq, generic)||200||20–40||Lozenge on stick, rubbed against cheek. Sugar content may increase dental caries.||Multiple RCTs showing benefit over placebo and oral morphine.|
|Fentanyl buccal tablet (Fentora)||100, 200, or 400||35–45||Absorption may be affected by mucositis. Before use, wet mouth if dry.||RCT showing benefit over placebo, and open-label study showing benefit for pain rescue; more rapid than oxycodone.|
|Fentanyl buccal film (Onsolis)||200||60||Before use, wet mouth if dry.||DB, PC, RCT showing benefit.|
|Fentanyl nasal spray (Lazanda)||100||15–21||Vial contains residual fentanyl when empty, requiring special disposal. Do not use with decongestant sprays.||DB, PC, RCT showed benefit. Open-label RCT showed benefit over transmucosal fentanyl and oral morphine. Most rapid onset.|
|Fentanyl sublingual spray (Subsys)||100||40–75||Contains residual fentanyl when empty, requiring special disposal.||Open-label and PC RCT showing benefit.|
|Fentanyl sublingual tablet (Abstral)||100||30–60||Absorption may be affected by mucositis. Before use, wet mouth if dry.||Multiple PC RCTs showing benefit.|
Given the complexities related to methadone administration, it is important that this opioid be prescribed by experienced clinicians who can provide careful monitoring. Referral to a pain specialist or a palliative care team may be indicated.
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 than other opioids for patients with renal dysfunction, given that it is minimally renally excreted, and is preferred for those with known opioid allergies because it is a synthetic opioid. Additionally, it is long acting, whether given in crushed or liquid form, an important benefit when patients require drug administration via enteral tubes. However, methadone also has several distinct disadvantages, including drug interactions, the risk of QT prolongation, and a variable equianalgesic ratio, making rotation more challenging.
Methadone is metabolized by CYP2B6, CYP2C19, CYP3A4, and CYP2D6. The principal enzyme responsible for methadone levels and drug clearance is CYP2B6.[
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, if consistent with goals of care.[
Because the equianalgesic ratio between methadone and other opioids is unpredictable, most health care professionals recommend starting at a low dose twice daily, with gradual dose escalation every 3 to 5 days or at longer intervals.[
A systematic review has highlighted three approaches to methadone conversion in the literature;[
Adverse effects from opioids are common and may interfere with achieving adequate pain control (refer to Table 5). However, not all adverse effects are caused by opioids, and other etiologies also need to be evaluated. Examples of relevant factors include the following:[
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.
|Adverse Effect||Relative Prevalenceb||Comments|
|||Acute Usec||Chronic Used|||
|a The reported prevalence may differ on the basis of opioid choice, dose, route, and duration of use.|
|b Relative prevalence: (–) absent; (+) rare; (++) less common; (+++) common.|
|c Acute use defined as use for ≤2 weeks, as-needed use, and upon significant dose increase.|
|d Chronic use defined as consistent use for >2–3 months at stable doses.|
|Hypotension||+||+||Mostly with intravenous opioids.|
|Central nervous system|
|Sedation||+++||+||More common upon opioid initiation and dose increase.[
|Impaired cognitive status||++||+||[
|Nausea||+++||+||Slow upward dose titration reduces risk. Lower rates with hydromorphone vs. morphine.[
|Autonomic nervous system|
|Bladder dysfunction/urinary retention||+||+||[
|Respiratory depression||+||–||Extremely rare if used appropriately.[
|Pruritus||++||–||More common with spinal analgesia.[
|Hyperalgesia||–||+||Observed more commonly with opioid-induced neurotoxicity. May be more common with morphine and hydromorphone.[
|Hypoglycemia||+||+||May be observed among patients on tramadol or methadone. More common among diabetics.|
Opioid-induced neurotoxicity (OIN)
OIN is a broad term used to encompass the neuropsychiatric effects that result from opioid use, including:
The mechanism behind OIN may be attributed to opioids' anticholinergic activity, endocytosis of opioid receptors, and stimulation of N-methyl-D-aspartate receptors.[
Patients who have persistent problems may benefit from opioid rotation. Methylphenidate has been proposed as an intervention to reduce opioid-induced sedation.[
Delirium is associated with opioids but is typically multifactorial in origin.[
In contrast to opioid tolerance, opioid-induced hyperalgesia (OIH) occurs when a patient who has been taking opioids long-term experiences paradoxical pain in regions unaffected by the original pain complaint.[
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-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.[
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. For patients receiving opioids at home, nasal naloxone is indicated, particularly for those at greatest risk of respiratory depression, or if there is a concern about misuse or accidental use by others in the household.
Nausea and vomiting
Opioid-induced nausea occurs in up to two-thirds of patients receiving opioids, and half of those patients will experience vomiting.[
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.[
Constipation is the most common adverse effect of opioid treatment, occurring in 40% to 95% of patients.[
Opioids cause constipation by decreasing peristalsis, which occurs by reducing gastric secretions and relaxing longitudinal muscle contractions, and results in dry, hardened stool.[
A scheduled stimulant laxative, such as senna, is started with opioid initiation. The addition of a stool softener offers no further benefit.[
There is no evidence to recommend one laxative class over another in this setting. Appropriate drugs include the following:
Suppositories and enemas 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.[
Of note, several combination opioid and opioid-antagonist products (e.g., oxycodone-naltrexone) are FDA approved for pain management and have the added benefit of potentially preventing opioid-induced constipation.[
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.[
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.[
Opioid-induced immunological changes
Opioids have immunomodulatory effects through neuroendocrine mechanisms and by direct effects on opioid receptors on immune cells.[
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:[
Methadone and fentanyl are unaffected by liver disease and are drugs of choice in patients with hepatic failure.[
Morphine, oxymorphone, and hydromorphone undergo glucuronidation exclusively. CYP2D6 metabolizes codeine, hydrocodone, and oxycodone; CYP3A4 and CYP2D6 metabolize methadone; and CYP3A4 metabolizes fentanyl.[
In cirrhosis, the elimination half-life and peak concentrations of morphine are increased.[
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, codeine, 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.[
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.[
Opioid rotation or switching may be needed when one of the following situations occurs:[
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, empirical trials are needed to identify the ideal opioid for a patient. If OIN is the reason for switching, it may not matter which opioid is switched to, as long as it is a different agent. 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 OIN (12%).[
Barriers related to opioid use
The barriers to appropriate use of opioids in the treatment of cancer pain include misunderstanding or misapprehension 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 concerns about the use of opioids.[
Physician-perceived barriers to opioid prescribing tend to parallel those of patients.[
Other barriers to opioid prescribing and compliance are the costs of abuse, which are estimated to be in the tens of billions of dollars, and misuse of opioids, including increased mortality rates.[
Opioids and risk of addiction
In the United States, the number of deaths from opioid overdose in 2019 was nearly 50,000, over six times greater than in 1999.[
Most patients begin opioid therapy after an acute event such as a pain crisis from cancer progression or surgery.[
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.[
The following aberrant behaviors may suggest addiction or abuse; further assessment is required to make the diagnosis:
|a Adapted from DiScala SL, Lesé MD: Chronic pain. In Murphy JE, Lee MW, eds.: Pharmacotherapy Self-Assessment Program. Book 2: CNS/Pharmacy Practice. Lenexa, Kan: American College of Clinical Pharmacy, 2015, p. 102.|
|Current Opioid Misuse Measure (COMM)||17-item self-assessment tool for patients||Identifies aberrant behaviors; for those with chronic pain who are already on opioids.|
|Diagnosis, Intractability, Risk, Efficacy (DIRE)||8-item tool||Determines risk of long-term opioid use in those with chronic pain; evaluates regimen efficacy.|
|Opioid Risk Tool (ORT)||5-item tool||Predicts aberrant or drug-related behaviors.|
|Prescription Drug Use Questionnaire (Self-Report) (PDUQp)||31-item self-assessment tool||Evaluates and predicts opioid misuse in those with chronic pain.|
|Pain Medication Questionnaire (PMQ)||26-item tool||Evaluates risk of opioid misuse in those with chronic pain.|
|Screening Instrument for Substance Abuse Potential (SISAP)||5-item tool||Evaluates those with history of substance use disorder and risk of opioid misuse; used in primary care setting.|
|Screener and Opioid Assessment for Patients with Pain (SOAPP) Version 1.0||24-item self-assessment||Evaluates risk of long-term opioid therapy in those with chronic pain.|
|Screener and Opioid Assessment for Patients with Pain—Revised (SOAPP-R)||24-item self-assessment||Evaluates those already taking opioids, or those about to begin (before initiation of therapy).|
Risk factors for opioid abuse include the following:[
Screening tools help in risk assessment. Common tools include the following:
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.[
Opioid agreements outline what is expected of the patient, educate about drug storage, and delineate acceptable and unacceptable behavior.[
Random urine drug testing is used for patients with an inadequate response to opioid therapy and those receiving opioids long term as part of a risk mitigation strategy.[
Pharmacological deterrence has emerged as another option designed to dissuade misuse and abuse by making it difficult to obtain euphoric effects from opioid use.[
Adjuvant Pain Medications
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 the following symptoms:[
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.[
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). In addition, duloxetine is indicated for musculoskeletal pain. 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 the following:[
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 either venlafaxine or duloxetine, 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 the following:
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.[
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,[
The immediate side effects of corticosteroid use include:
Serious long-term effects—myopathy, peptic ulceration, osteoporosis, and Cushing syndrome—encourage short-term use of corticosteroids. 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.[
A single dose of ibandronate 6 mg was compared with a single fraction of radiation for localized metastatic bone pain in 470 prostate cancer patients.[
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).[
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.[
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
While pharmacological 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.[
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.[
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.[
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.[
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 (QOL) 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:
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.[
Palliative care specialists may also help manage patients with multiple comorbidities, those requiring higher doses of opioids, and those with a history of substance use disorder 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 QOL for both patients and families [
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. Patient selection can be important regarding the likelihood of benefit from radiation therapy. In one study, patients with hematologic tumors, a neuropathic component of the index pain, and no previous treatment with opioid analgesics before radiation therapy were more likely to experience pain palliation after 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.[
A study published in 2019 evaluated a higher-dosage (Gy) single-fraction stereotactic body radiation therapy (SBRT) versus multifraction radiation therapy (MFRT), in which patients with primarily nonspine bone metastases received either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for <4-cm lesions) or MFRT to 30 Gy in ten fractions. This randomized phase II trial demonstrated improved pain at 2 weeks, 3 months, and 9 months, without differences in treatment-related toxicity and with no increase with re-treatment rates that had been seen in previous single-fraction studies, done largely with 8 Gy. Patients who received the higher-dose SBRT had improved 1- and 2-year survival rates. The authors concluded that the higher dose of single-fraction SBRT is safe and suggested that this could become the standard of care, if confirmed in phase III studies.[
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%.[
A potential side effect of palliative radiation for painful bone metastases is a temporary increase in pain level, i.e., a pain flare. Pain flares occur in about 40% of patients and may be quite distressing. One study [
In a secondary analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23, the authors investigated pain and QOL at days 10 and 42 after radiation therapy, with the aim of determining whether there are differences in QOL between responders and nonresponders.[
Patients with multiple sites of symptomatic osteoblastic bone metastases may consider radionuclides such as strontium chloride Sr 89 or samarium Sm 153 (153Sm), which are beta-emitters. Two double-blind randomized trials support the superiority of 153Sm over placebo in providing pain control and reducing analgesic use.[
Radium Ra 223-dichloride (223Ra-dichloride) (an alpha-emitter) is approved for use in patients with castration-resistant prostate cancer. A phase III randomized trial compared 223Ra-dichloride with placebo in a 2:1 ratio. Among the 921 symptomatic patients enrolled, those who received 223Ra-dichloride 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.[
Patients with cancer frequently use complementary or alternative medicines or interventions (CAM).[
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 following:
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.[
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.[
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.[
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.[
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.[
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.[
Postmastectomy pain syndrome
Rates of postmastectomy pain range between 25% and 33%,[
A number of small studies have examined the effect of an anesthetic administered intraoperatively or immediately postoperatively, with varying results;[
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.[
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 the following:[
Other agents, including ixabepilone, lenalidomide, and pomalidomide, are common sources of CIPN. With any of these agents, CIPN may limit the dose of chemotherapy delivered, which may affect the outcomes of treatment.[
The effect of a docetaxel regimen and patient characteristics on peripheral neuropathy and quality of life (QOL) was evaluated in a QOL substudy of the NASBP B-30 trial.[
Treatment modalities for CIPN
Studies evaluating treatment for CIPN have been plagued by methodological flaws, such as small size and open-label comparisons. Differences in the defined endpoints have also made the comparison difficult across studies. Duloxetine is the only agent whose efficacy in treating CIPN is supported by data from a large phase III study.[
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.[
Evidence of the efficacy of nortriptyline and amitriptyline in CIPN is limited to small and frequently underpowered trials with mixed results.[
Complementary and integrative therapies
Importantly, a large, randomized, multicenter, double-blind, placebo-controlled trial comparing the use of acetyl-L-carnitine with placebo in 409 women receiving taxane-based chemotherapy for breast cancer showed worsened CIPN. This worsening persisted over 2 years.[
Studies of acupuncture for CIPN have been reported. Refer to the Chemotherapy-induced peripheral neuropathy section in the PDQ summary on Acupuncture for information about these studies.
Scrambler therapy is the application of electrical currents to discrete areas of the body as guided by the patient's report of pain. The therapy is usually applied in ten consecutive sessions, although guidelines permit the skipping of weekend days. The technique is operator dependent, given the importance of identifying the area to treat and the application of the electrical current through five electrodes (referred to as artificial neurons). Furthermore, before daily scrambler therapy sessions, adjustments of the electrode placement and dose, titrated to pain relief, are required. Finally, it has been observed that misapplication of the currents induces worse pain.
The proposed mechanism of scrambler therapy begins with the observation that chronic pain may represent dysregulation of the somatosensory nervous system.[
There are two relevant randomized trials of scrambler therapy. One study randomly assigned 52 patients with CIPN to receive either standard guideline–consistent therapy (opioids, gabapentinoids, tricyclic antidepressants) or scrambler therapy.[
A subsequent trial randomly assigned 50 patients to either scrambler therapy or a conventional transcutaneous electrical nerve stimulation (TENS) therapy.[
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%.[
Pharmacological interventions for pain control vary from local anesthesia,[
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.[
Treatment of Pain in Specific Patient Populations
Pediatric cancer patients
Refer to the PDQ summary on Pediatric Supportive Care for more information.
Geriatric cancer patients
Geriatric patients are defined as persons aged 65 years or older, with a significant increase in incidence of comorbidity after age 75 years.[
|Age-Related Physiological Change||Example of Affected Drugs|
|NSAID = nonsteroidal anti-inflammatory drug.|
| a Adapted from American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons,[
|Decreased renal function||Increased accumulation of morphine metabolites|
|Increased risk of NSAID-induced renal dysfunction|
|Increased body fat/decreased body water||Delayed elimination of lipophilic drugs such as methadone|
|Cachexia||Decreased fentanyl absorption from transdermal fentanyl patches[
|Decreased hepatic function||Results in increased oral bioavailability and half-life of opioids|
|– Decrease dose: hydromorphone, oxycodone|
|– Increase dose interval: morphine, oxycodone|
|Reduced protein binding||Increased drug sensitivity/side effects|
|Reduced cytochrome P450 enzyme activity||Increased drug concentrations of fentanyl and methadone|
|Decreased gastrointestinal motility||Increased risk of opioid-induced constipation|
Geriatric patients are also at risk of undertreatment because of underreported pain, difficulty communicating, and physician concerns about adverse effects and aberrant behavior. Persistent, inadequately controlled pain leads to poor outcomes in older patients, including the following:[
Treatment of an underlying depression can help facilitate pain treatment.[
The American Geriatrics Society (AGS) recommends the use of acetaminophen over nonsteroidal anti-inflammatory drugs (NSAIDs), when possible, for the treatment of mild to moderate musculoskeletal pain.[
Strategies to prevent gastrointestinal adverse effects include the following:[
Opioids continue to be the mainstay of treating moderate to severe pain in geriatric patients. Elderly patients may be more sensitive to opioids because of the decreased renal and hepatic clearance of these drugs and their metabolites.[
Adjunct agents are often used with opioids to improve pain control for geriatric patients. Many of these adjunct agents are listed in the AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, to be avoided or used with caution in geriatric patients because of their increased risk of adverse effects [
|CNS = central nervous system; COX-2 = cyclooxygenase-2; NSAIDs = nonsteroidal anti-inflammatory drugs.|
| a Adapted from American Geriatrics Society 2015 Beers Criteria Update Expert Panel.[
|Tricyclic antidepressants||Amitriptyline, clomipramine, imipramine||Anticholinergic effects, sedation, orthostatic hypotension|
|Meperidine||Decreased efficacy, potential neurotoxicity|
|Non–COX-2–selective NSAIDs||Ibuprofen, diclofenac, naproxen||Gastrointestinal bleed risk, increased blood pressure, renal toxicity|
|Skeletal muscle relaxants||Cyclobenzaprine, metaxalone, methocarbamol||Anticholinergic effects, sedation, risk of fracture|
|CNS||Avoid/reduce dose in renal impairment:||CNS adverse effects|
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.
Pharmacological Therapies for Pain Control
Revised text to update the number of deaths from opioid overdose in the United States; in 2019, the number was nearly 50,000, over six times greater than in 1999.
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 in the care of their 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: https://www.cancer.gov/about-cancer/treatment/side-effects/pain/pain-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389387]
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Last Revised: 2022-03-18
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