Overview
Pain is one of the most common symptoms associated with cancer. Pain is defined by the International Association for the Study of Pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in relation to such damage.1 Cancer pain or cancer-related pain distinguishes pain experienced by patients with cancer from that experienced by patients without malignancies. A meta-analysis revealed that pain was reported in 59% of patients undergoing cancer treatment, in 64% of patients with advanced disease, and in 33% of patients after curative treatment.2 In addition, this is one of the symptoms patients fear most. Unrelieved pain denies patients comfort and greatly affects their activities, motivation, interactions with family and friends, and overall quality of life.3 Evidence is mounting in oncology that quality of life and survival are linked to early and effective palliative care, including pain management.4–9 Although improvements have been observed, undertreatment of pain remains an issue in a significant subset of patients with cancer and this issue may be exacerbated by the inappropriate application of recommendations against the use of opioids to patients with cancer in the setting of the United States opioid epidemic.10,11
Goals of pain management are to optimize pain treatment outcomes in 5 dimensions, frequently referred to as the “5 As” of pain management outcomes (the “4 As” originally proposed by Passik and Weinreb12 were later amended to include “affect”):
Analgesia: optimize analgesia (pain relief)
Activities: optimize activities of daily living (psychosocial functioning)
Adverse effects: minimize adverse events
Aberrant drug taking: avoid aberrant drug taking (addiction-related outcomes)
Affect: relationship between pain and mood
The most widely accepted algorithm for the treatment of cancer pain was developed by the WHO.16,17 It suggests that patients with pain be started on acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). If this is not sufficient, therapy should be escalated to a “weak opioid” such as codeine and subsequently to a “strong opioid” such as morphine. Although this algorithm has served as an excellent teaching tool, the management of cancer pain is considerably more complex than this 3-tiered “cancer pain ladder” suggests.
These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain are unique in several important ways. The NCCN Guidelines identify central principles for assessing and managing cancer pain in adults. First, they list general principles of pain management, followed by guiding principles for assessment, management/intervention, and reassessment. The NCCN Guidelines acknowledge the range of complex decisions faced in the management of these patients. As a result, they provide dosing guidelines for opioids, nonopioid analgesics, and adjuvant analgesics. They also provide specific suggestions for titration and rotation of opioids, escalation of opioid dosage, management of opioid adverse effects, and when and how to proceed to other techniques/interventions for the management of cancer pain.
Management of Adult Cancer Pain
For management of cancer-related pain in adults, the algorithm distinguishes 3 levels of pain intensity based on a 0 to 10 numerical value obtained using a numerical or pictorial rating scale (with 0 being no pain to 10 being the worst pain). The 3 levels of pain intensity referred to in the algorithm are mild pain (1–3); moderate pain (4–7); and severe pain (8–10).
The NCCN panel recommends that providers consider all pain management interventions in the context of patient-specific goals for comfort and function, as well as safety. Individualized pain treatment should also consider the etiology and characteristics of pain and the patient’s clinical condition. Patients presenting with an acute, severe pain or pain crisis may be candidates for hospital admission to achieve patient-specific goals for comfort and function. It is important to separate pain related to an oncologic emergency from pain not related to an oncologic emergency.
In addition, the algorithm distinguishes pain management approaches in patients not chronically taking opioids (opioid naïve) from patients who have previously taken or are chronically taking opioids for cancer pain (opioid tolerant). It also distinguishes circumstances related to anticipated procedure-related pain and anxiety.
Opioid-tolerant patients are those chronically taking opioids for pain, defined by the US FDA as “patients who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid for one week or longer.”18,19 Therefore, patients who do not meet these criteria of opioid tolerance, based on not having had exposure to opioid doses at least as much as those listed for a week or more, are considered to be opioid naïve.
Management of Pain Related to Oncologic Emergency
An oncologic emergency is defined as a life-threatening event directly or indirectly related to a patient's cancer or cancer treatment. Pain related to an oncologic emergency includes pain due to bone fracture or impending fracture of weight-bearing bone; epidural or leptomeningeal metastases seen in patients with advanced cancers; pain related to infection; or obstructed or perforated viscus. Pain associated with oncologic emergency should be treated directly while the treatment of the underlying condition proceeds concurrently.
Management of Pain Not Related to Oncologic Emergency
For all patients experiencing pain, care providers should offer psychosocial support and begin educational activities. Psychosocial support is needed to ensure that patients encountering common barriers to appropriate pain management (eg, fear of addiction or side effects, inability to obtain opioids) or needing assistance in managing additional problems (eg, depression, rapidly declining functional status) receive appropriate aid. The patient and the family/caregiver must be educated regarding pain management and related issues.20,21 Patients should be reevaluated at each contact and as needed to meet their goals for comfort and function.
Although pharmacologic analgesics, including nonopioids (such as NSAIDS or acetaminophen), opioids, and adjuvant analgesics (such as antidepressants, anticonvulsants, topical agents, and corticosteroids) are the cornerstone of cancer pain management, they are not always adequate and are associated with adverse effects. Optimal use of nonpharmacologic integrative interventions (physical, cognitive modalities, and spiritual) may serve as valuable additions to pharmacologic interventions.
When deciding on the most appropriate medication, the patient’s pain diagnosis, comorbid conditions, and potential drug interactions should be considered. Addition of adjuvant analgesics for specific pain syndromes should be considered for all groups of patients. Adjuvant analgesics may be used as the main analgesics (especially for neuropathic pain), or to enhance the effects of opioid- or nonopioid (eg, NSAIDs, acetaminophen) analgesics.22
For opioid-naïve patients (as defined previously) experiencing mild pain intensity (rating of 1–3), treatment with nonopioid analgesics such as NSAIDs or acetaminophen and adjuvant analgesics should be considered before opioid analgesics unless they are contraindicated due to adverse effects or potential drug interactions. Opioid-naïve patients experiencing moderate pain (ie, pain intensity rating, 4–7) should receive nonopioid and adjuvant therapies, as appropriate, with titration of short-acting opioids as needed (see PAIN-3, page 978). Short-acting formulations have the advantage of rapid onset of analgesic effect. The route of administration of opioid is decided (oral vs intravenous) based on what is best suited to the patient’s ongoing analgesic needs.
Opioid-tolerant patients (as defined previously) who are experiencing mild pain (rating, 1–3) should continue to receive nonopioid and adjuvant therapies as appropriate. The need for opioid analgesics should be reevaluated and gradual dose reduction may be initiated, if indicated. Opioid-tolerant patients who are experiencing moderate pain (rating, 4–7) should continue nonopioid and adjuvant therapies, as appropriate, with short-acting opioids, as needed. Short-acting opioids should be titrated with the goal of increasing the daily dose by 30%–50% until pain relief is achieved (see PAIN-4, page 979).
In cases of acute, severe pain or pain crisis, hospital or inpatient hospice admission may be considered to achieve patient-specific goals for comfort and function (see “Management of Pain Crisis” in the complete version of these guidelines, at NCCN.org).
The use of opioid analgesics is potentially associated with substantial adverse effects. The management of common opioid-induced adverse effects should be started simultaneously with the start of opioid therapy. Opioid-induced bowel dysfunction should be anticipated and treated prophylactically with a stimulating laxative to increase bowel motility, as indicated.23
Patients with chronic persistent pain managed by stable doses of short-acting opioids should be provided with round-the-clock extended-release (ER) or long-acting (LA) formulation opioids with provision of a “rescue dose” to manage breakthrough or transient exacerbations of pain. The rescue dose is usually equivalent to 10%–20% of the total opioid daily consumption and may be given every hour as needed during severe exacerbations of pain. Opioids with a rapid onset and short duration are preferred as rescue doses. The repeated need for numerous rescue doses per day may indicate the need to adjust baseline treatment.
Subsequent Management of Cancer Pain
Subsequent treatment is based on the patient’s continued pain rating score and function and evidence of appropriate use of treatments. Approaches for all pain intensity levels must include psychosocial support and education for patients and their families/caregivers. For all levels of pain requiring ongoing use of an opioid, opioid doses should be administered on a routine schedule with rescue doses as needed. Constipation should be routinely evaluated and managed.
If pain at any time is severe, not improved, or increased, the working diagnosis must be reevaluated and comprehensive pain assessment must be performed. For patients unable to tolerate dose escalation of their current opioid due to adverse effects, an alternate opioid must be considered. Addition of adjuvant analgesics should be reevaluated to either enhance the analgesic effect of the opioids or in some cases to counter the adverse effects associated with the opioids.23 Optimal use of nonpharmacologic integrative interventions (physical, cognitive modalities, and spiritual) may serve as valuable additions to pharmacologic interventions. Given the multifaceted nature of cancer pain, additional interventions for specific cancer pain syndromes and specialty consultation must be considered to provide adequate analgesia. If the patient is experiencing pain of moderate intensity of 4 to 7, with inadequate pain relief on the ongoing opioid regimen, the titration of the opioid may be continued or increased. In addition, as with patients experiencing severe pain, addition of adjuvant analgesics, additional interventions for specific cancer pain syndromes, and specialty consultation must be considered.
For patients experiencing mild pain, if they have adequate analgesia but intolerable or unmanageable adverse effects, the analgesic dose may be reduced by 10% to 25% of the current opioid dose. Addition of adjuvant analgesics may be considered. The need for opioid analgesics should be frequently reassessed and the dose reduced if appropriate.
Pharmacologic Interventions for Cancer Pain Management
Optimal management of cancer pain is often accomplished by using a combination of pharmacologic and nonpharmacologic therapies. Pharmacologic therapies may include nonopioid analgesics (such as acetaminophen or an NSAID), adjuvant analgesics (antidepressants, anticonvulsants, topical agents, and corticosteroids), and/or opioid analgesics.
Nonopioid Analgesics
Acetaminophen
Acetaminophen has analgesic and antipyretic, but not anti-inflammatory properties.24 Recent attention has been drawn toward the relative limited efficacy and significant adverse effects of acetaminophen, particularly hepatic toxicity and possibly renal impairment.25,26 Concerns are compounded by the inclusion of acetaminophen in a variety of prescription opioid preparations (eg, in combination with hydrocodone or codeine), as well as in a wide selection of over-the-counter products. Due to concerns about liver toxicity, the NCCN panel advises that acetaminophen should be used with caution or not used at all with combination opioid-acetaminophen products to prevent excess acetaminophen dosing (see PAIN-K 1 of 2, available online, in these guidelines, at NCCN.org).
The FDA recommends that patients be advised to limit daily acetaminophen intake to a maximum of 4 g, and imposes a limit of 325 mg of acetaminophen per tablet, capsule, or other dosage unit in prescription products to reduce the risk of severe liver injury from acetaminophen overdosing, an adverse event that can lead to liver failure and death.27 The FDA has issued a boxed warning to communicate the risk of severe liver injury associated with acetaminophen to health care professionals. In addition, companies are required to add a new warning about the risk of allergic reactions, including anaphylaxis, to the label of all prescription acetaminophen-containing products.27 Due to concerns of hepatic toxicity, the NCCN panel suggests that providers consider limiting chronic administration of acetaminophen to 3 g or less per day.
NSAIDs
NSAIDs produce analgesia by blocking the biosynthesis of prostaglandins, inflammatory mediators that initiate, cause, intensify, or maintain pain. History of peptic ulcer disease or gastrointestinal bleeding, advanced age (>60 years old), male gender, and concurrent corticosteroid or anticoagulant therapy should be considered before NSAID administration to prevent upper gastrointestinal tract bleeding and perforation. The risk of gastrointestinal bleeding is increased in patients with untreated H. pylori infection and with chronic, rather than short-term, use of NSAIDs. As prophylaxis for NSAID peptic ulceration, consider adding misoprostol or proton pump inhibitors. Well-tolerated proton pump inhibitors are recommended to reduce gastrointestinal adverse effects induced by NSAIDs. The FDA cautions that the concomitant use of an NSAID with aspirin may reduce the cardioprotective efficacy of aspirin,28 and concomitant use of an NSAID and low-dose (or cardioprotective) aspirin may increase the risk of gastrointestinal bleeding.29,30 The NCCN panel recommends avoiding concurrent use or administering these agents separately (see PAIN-K 1 of 2, available online, in these guidelines, at NCCN.org).
NSAIDs should be prescribed with caution in patients older than 60 years of age or in those having compromised fluid status, renal insufficiency, concomitant administration of other nephrotoxic drugs, and renally excreted chemotherapy to prevent renal toxicities. The addition of NSAIDs to opioids has the potential benefit of reducing the opioid dose when sedation, cognitive function, or other central nervous system (CNS) effects of opioid analgesic therapy become burdensome.
In patients at high risk for cardiac toxicities such as those with a history of cardiovascular disease or at risk for cardiovascular disease or complications, NSAIDs should be discontinued if congestive heart failure or hypertension develops or worsens. The FDA has issued a warning that NSAID use may increase the risk of heart attack or stroke.31 This risk is present even with short-term use of NSAIDs and increases with higher doses.32 NSAIDs taken with prescribed anticoagulants, such as warfarin or heparin, may significantly increase the risk of bleeding complications. Oral NSAIDs should be avoided in the setting of prophylactic or therapeutic anticoagulation. Topical NSAIDs such as diclofenac gel or patch may be useful in this population. See “page PAIN-K 2 of 2” in the complete version of these guidelines, at NCCN.org, for more information.
Adjuvant Analgesics
The term adjuvant analgesics refers to medications that are coadministered to enhance opioid analgesia and possibly reduce adverse effects of opioids by allowing the use of lower doses of opioids. These drugs can be helpful for patients whose pain is only partially responsive to opioids. Clinically, adjuvant analgesics consist of a diverse range of drug classes, including anticonvulsants33 (eg, gabapentin, pregabalin), antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs], serotonin–norepinephrine reuptake inhibitors, triglyceride antidepressants [TCAs]), corticosteroids, and local anesthetics/topical agents (eg, topical lidocaine patch). Adjuvant analgesics are commonly used to help manage bone pain, neuropathic pain, and visceral pain and, if desired or indicated, to reduce the opioid requirement. They are particularly important in treating neuropathic pain (see PAIN-D, page 980 and PAIN-G 2 of 2, page 987).34,35
Physicians should check for drug interactions when prescribing antidepressants, paying particular attention to serotonergic medications (eg, SSRIs) due to risk of serotonin syndrome. Several antidepressants are known inhibitors of hepatic drug metabolism via inhibition of cytochrome P450 enzymes, especially CYP2D6. Tamoxifen is an estrogen receptor blocker commonly used in patients with hormone receptor–positive breast cancer. Tamoxifen undergoes extensive hepatic metabolism, and inhibition of CYP2D6 decreases production of tamoxifen active metabolites, potentially limiting tamoxifen efficacy. Although some clinical studies indicate increased risk of breast cancer recurrence in tamoxifen-treated patients with breast cancer also treated with SSRI antidepressants versus those receiving tamoxifen alone,36 other studies have not shown this effect.37,38 If concomitant use of an SSRI is required in a patient receiving tamoxifen, use of a mild CYP2D6 inhibitor (sertraline, citalopram, venlafaxine, escitalopram) may be preferred over a moderate-to-potent inhibitor (paroxetine, fluoxetine, fluvoxamine, bupropion, duloxetine).36
The most commonly used anticonvulsant drugs for the treatment of cancer pain are gabapentin and pregabalin.39 They have been studied primarily in noncancer neuropathy syndromes,40 although data exist supporting their use for treatment of cancer pain in conjunction with opioids.41,42 Gabapentin has been reported to reduce mucositis pain in patients receiving concomitant radiotherapy and chemotherapy.43 When compared in a prospective, randomized, open-label trial, pregabalin relieved neuropathic cancer-related pain more effectively than transdermal fentanyl.44
Corticosteroids have long been used to relieve neuropathic pain syndromes and have also been effective for treating bone pain due to their anti-inflammatory effects and use in relieving malignant intestinal obstruction.22,45 A 2015 Cochrane review summarized the existing data for corticosteroid use in cancer pain.46
Cannabinoids and Medical Marijuana/Cannabis
In the context of shifting legality, many patients with cancer are using cannabinoids or medical marijuana for treatment of cancer- or cancer treatment-related symptoms.47,48 To date, the FDA has approved 3 cannabinoids: dronabinol, nabilone, and cannabidiol.49 Dronabinol and nabilone (both tetrahydrocannabinol [THC] or THC-mimics) have been approved to treat refractory nausea and vomiting associated with cancer treatment, dronabinol has also been approved to treat anorexia and weight loss related to AIDS. Cannabidiol has been approved to treat seizures associated with rare forms of severe epilepsy. Although medical marijuana has been legalized in many states, it has not been FDA-approved for any indication.49 Furthermore, the US Drug Enforcement Administration classifies marijuana as a Schedule I substance, meaning that it has a high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision.50 Regardless, use of medical marijuana is common among patients with cancer, with some recent studies reporting that as many as 24% to 40% of patients with cancer in the United States use marijuana.51,52 Therefore, providers should assess for cannabinoid/medical marijuana use and provide education on state and federal regulations, as appropriate.
Data supporting the use of cannabinoids as adjuvant analgesics for treatment of cancer pain are extremely limited and the results from what little data exist are somewhat conflicting. Although 2 randomized, placebo controlled trials have shown that nabiximols (cannabis extract that contains both THC and cannabidiol; it is not approved for use in the United States) significantly reduced cancer-related pain compared with placebo in patients with inadequate analgesia despite chronic opioid administration,53,54 THC extract alone did not show a significant benefit compared with placebo.53 Another randomized study reported no significant benefit of nabiximols compared with placebo for treatment of chemotherapy-induced neuropathic pain.55 In these studies, the most commonly reported adverse events associated with nabiximols were somnolence, fatigue, dizziness, confusion, nausea, dry mouth, and hypotension, although these were noted to be dose-dependent and generally manageable.53–55 The route of administration can also affect the safety profile of medical marijuana. A recent observational study in a state with legalized marijuana reported that although edible cannabis products accounted for only 0.32% of sales between 2014 and 2016, they accounted for 10.7% of emergency department visits during that time period.56 The adverse effects that prompted the emergency department visits also differed by route of exposure, with cannabinoid hyperemesis syndrome more common for inhaled cannabis and acute psychiatric symptoms, intoxication, and cardiovascular symptoms more common for edible cannabis.56 The authors propose that the delayed onset of effect associated with the edible route may lead users to repeat the dose, potentially resulting in delayed higher plasma concentrations.
Opioids and Miscellaneous Analgesics
While starting therapy, attempts should be made to determine the underlying pain mechanism and diagnose the pain syndrome. Optimal analgesic selection will depend on the patient’s pain intensity, any current analgesic therapy, and concomitant medical illness. An individual approach should be used to determine opioid starting dose, frequency, and titration to achieve a balance between pain relief and medication adverse effects.
Pure agonists (such as morphine, oxycodone, oxymorphone, and fentanyl) are the most commonly used medications in the management of cancer pain. The short half-life opioid agonists (morphine, hydromorphone, fentanyl, and oxycodone) are preferred, because they can be more easily titrated than the long half-life opioids (methadone and levorphanol).57 A randomized trial compared the efficacy of low-dose morphine, a “strong” opioid agonist, to “weak opioids” (ie, codeine, codeine plus acetaminophen, or tramadol) for treating moderate-intensity cancer pain. Among the 240 patients with cancer enrolled in the trial, low-dose morphine had a significantly higher response rate and earlier onset of response compared with weak opioids. Opioid-related adverse effects were comparable across the 2 treatment groups, and overall well-being/symptom burden was rated as significantly better in the low-dose morphine arm.58
Morphine, hydromorphone, hydrocodone, oxymorphone, and codeine should be used with caution in patients with fluctuating renal function due to potential accumulation of renally cleared metabolites that may cause neurologic toxicity.59–61
Morphine
Morphine is a mu-opioid receptor agonist and weak kappa receptor agonist. Morphine is available in a wide range of formulations and routes, including oral, parenteral, and rectal delivery.62 In a patient who has not been exposed to opioids in the past, morphine is generally considered the standard starting drug of choice.63,64 Oral administration is the preferred route. An initial oral dose of 5 to 15 mg of oral short-acting morphine sulfate or equivalent is recommended for opioid-naïve patients. Patients presenting with severe pain needing urgent relief should be treated with parenteral opioids, usually administered by the intravenous or subcutaneous route. If given parenterally, the equivalent dose is one-third of the oral dose.65 An initial dose of 2 to 5 mg of intravenous morphine sulfate or equivalent is recommended for opioid-naïve patients. Morphine-6-glucuronide, an active metabolite of morphine, contributes to analgesia and may worsen adverse effects because it accumulates in patients with renal insufficiency.66,67
Fentanyl
Fentanyl is a highly lipid-soluble mu-opioid receptor agonist that can be administered by the parenteral, spinal, transdermal, transmucosal, buccal, and intranasal routes.68,69 Transdermal fentanyl is not indicated for rapid opioid titration and should be recommended only after pain is adequately managed by other opioids in opioid-tolerant patients.70 It is usually the treatment of choice for patients who are unable to swallow, patients with poor tolerance to morphine, and patients with poor compliance. Findings from a Cochrane Database review support the efficacy of transdermal fentanyl for relieving moderate to severe cancer pain and suggest a reduction in opioid-related constipation compared with oral morphine regimens.71 Another meta-analysis of randomized controlled trials reported similar results, showing similar effectiveness of cancer pain management between transdermal fentanyl and oral morphine, but lower rates of constipation, nausea, vomiting, drowsiness, and urinary retention with transdermal fentanyl.72 Conversion from intravenous fentanyl continuous infusion basal rate via patient-controlled analgesia to transdermal fentanyl can be accomplished effectively using a 1:1 conversion ratio.73 Transmucosal fentanyl may be considered in opioid-tolerant patients for brief episodes of incident pain not attributed to inadequate dosing of an around-the-clock opioid. Data do not support a specific transmucosal fentanyl dose equianalgesic to other opioids or between different transmucosal formulations. There are data showing that transmucosal immediate release fentanyl is effective in treatment of breakthrough pain in patients with cancer.74–76
Hydrocodone
Hydrocodone is a mu- and delta-opioid receptor agonist that may be approximately equipotent with oral morphine; however, its equivalence data are not substantiated.68 Clinical experience suggests use as a mild, initial use opioid, but effective dose may vary. Hydrocodone is available in immediate-release (IR) formulations mixed with acetaminophen or ibuprofen. Hydrocodone ER preparations (without added nonopioid analgesics) are available.
Codeine
Codeine is a weak mu- and delta-opioid receptor agonist with little direct analgesic effect; it is a prodrug that is hepatically metabolized to codeine-6-glucuronide, norcodeine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, and normorphine.68,77 This process is largely through the action of the cytochrome P450 enzyme, CYP2D6. It is important to note that CYP2D6 exhibits polymorphism between various ethnic groups and between individuals. A significant portion of individuals who are poor metabolizers would obtain reduced or no analgesic effects from codeine administration.78 Conversely, rapid metabolizers may experience toxicity after codeine administration from more rapid morphine production.78
Hydromorphone
Hydromorphone is primarily a mu-opioid receptor agonist and weak delta-opioid receptor agonist that has properties similar to morphine and is available in oral tablets, liquids, suppositories, and parenteral formulations.68,79 Some evidence suggests that the metabolite of hydromorphone may lead to opioid neurotoxicity, including myoclonus, hyperalgesia, and seizures.80 This metabolite may be more neurotoxic than the morphine metabolite.81 In a prospective, open-label trial of 879 patients with cancer, hydromorphone effectively reduced pain that was inadequately controlled by other analgesics.82 Additionally, randomized controlled trials (RCTs) have shown the clinical noninferiority of once-daily hydromorphone ER compared with twice-daily oxycodone controlled-release83 and 4 times daily hydromorphone IR compared with 4 times daily oxycodone IR84 for relieving moderate to severe cancer pain. A Cochrane review found evidence that hydromorphone provides similar effect on pain management as reported for oxycodone or morphine.85
Oxycodone and Oxymorphone
Oxycodone is an opioid with agonist activity at the mu-, delta-, and kappa-opioid receptors and is available in IR and ER formulations.86–88 Oxycodone is also available in combination with acetaminophen; therefore, the acetaminophen dose must be monitored for safe limits to avoid potential hepatic toxicity. Recent Cochrane reviews found overall evidence that oxycodone provided similar analgesic and adverse effects to morphine, concluding that these agents could be interchangeable in the front-line treatment setting for cancer-related pain.89,90 Studies of oxycodone/naloxone formulations showed effective analgesia with reduced opioid-induced constipation for long-term use in cancer-related pain.91,92
Oxymorphone is an opioid agonist that acts primarily at the mu-opioid receptor. It is available in an IR formulation.
Methadone
Methadone is a mu-opioid receptor agonist and an antagonist at N-methyl-D-aspartate receptors; it is commercially available in multiple strength oral tablets or in an oral or intravenous solution.68 Individual variations in methadone pharmacokinetics (long half-life ranging from 8 to more than 120 hours) make its usage complex in patients with cancer.93 Due to its long half-life, high potency, and interindividual variations in pharmacokinetics, methadone, when indicated, should be started by or in consultation with an experienced pain or palliative care specialist. Although many recommendations for methadone rotation exist, the NCCN panel members find the recommendations on the starting doses of methadone outlined in the “Hospice and Palliative Medicine White Paper” to be the easiest to implement.94 Because the starting dose may need to be titrated up, it is essential to provide the patient with access to adequate, short-acting, breakthrough pain medications during the titration period. The NCCN Guidelines recommend monitoring for drug accumulation and adverse effects, particularly over the first 4 to 7 days, and caution that a steady state may not be reached for several days to 2 weeks. Furthermore, these recommendations should not be applied when converting from methadone to morphine (see PAIN-E 13 of 13, page 986).
Generally, RCT data have demonstrated that appropriately titrated methadone, although harder to manage than morphine, has similar efficacy and tolerability and has a role in treating cancer pain.95 Studies show that outpatient initiation and rotation to methadone can be successfully done in patients with cancer without serious adverse effects.96 Retrospective studies have also reported that low-dose methadone may improve pain control when used as a coanalgesic in patients with cancer-related pain that were receiving a different, regularly scheduled opioid analgesic.97,98
There is evidence suggesting that high doses of methadone (120 mg and above) may lead to QTc prolongation and torsades de pointes, which may lead to sudden cardiac death.99–101 A study conducted in patients with cancer suggests that QT interval changes exist commonly at baseline and are not changed with the addition of methadone.102 The NCCN panel supports the use of baseline and follow-up electrocardiogram for patients treated with methadone as outlined in published recommendations and for patients with cardiac disease, or when methadone is used in patients taking other medications also known to prolong QTc (including TCAs).94,103 electrocardiogram monitoring should be considered within the patient’s goals of care and risk/benefit ratio as discussed with the patient. The following measures may be considered to correct QTc prolongation:
Correction of hypokalemia, hypomagnesemia, or hypocalcemia;
Avoidance of other drugs that can prolong QTc;
Avoidance of other drugs that can inhibit the biotransformation of methadone such as CYP3A4 inhibitors.
Patients and their families may need to be educated about analgesic utility of methadone. Some may only be familiar with methadone use for maintenance of addiction and be unaware of its utility as a potent opioid analgesic. Patients and caregivers should be educated on the signs of delayed sedation and respiratory depression that may occur 4 to 7 days or longer after initiation of methadone or after titrating the dose upwards.
Levorphanol
Levorphanol is a mu-, delta-, and kappa-opioid receptor agonist. Like methadone, levorphanol also acts as an antagonist at N-methyl-D-aspartate receptors, but it has a shorter half-life and more predictable metabolism.104 Similar to methadone, levorphanol varies in its dosing equivalence with morphine. In a case series of 20 patients receiving palliative or hospice care, the morphine to levorphanol conversion factors were listed as 12:1 for morphine doses of less than 100 mg, 15:1 for morphine doses between 100 mg and 299 mg, 20:1 for morphine doses between 300 mg and 599 mg, and 25:1 for morphine doses over 600 mg.104 For certain populations (eg, the elderly), levorphanol may offer similar benefits to methadone but with lessened prescribing complexities and adverse effects.105 One study also demonstrated potential efficacy of levorphanol for treating neuropathic pain.106
Miscellaneous Analgesics and Mixed Mechanism Drugs
Tramadol and tapentadol
Tramadol and tapentadol are atypical opioids with a dual mechanism of action on opioid receptors and neurotransmitter reuptake (eg, norepinephrine, serotonin). Tramadol and tapentadol should be used with caution or avoided in patients taking other serotonergic or monoamine oxidase inhibitors (MAOI)-like medications (eg, TCAs, SSRIs, and MAOIs) due to risk of serotonin syndrome.107 See “Opioid Principles, Prescribing, Titration, Maintenance, and Safety, Miscellaneous Analgesics” (PAIN-E 8 of 13, page 985).
Tramadol is a weak mu-opioid receptor agonist with some norepinephrine and serotonin reuptake inhibition that is indicated for treating moderate to moderately severe pain.108 Tramadol is available as IR and ER formulations. The NCCN panel recommends a maximum daily dose of 400 mg for IR formulations (100 mg 4 times a day), or 300 mg/day for ER formulations, for adults with normal hepatic and renal function. Lower doses are recommended for older adults (75 years and older) and those with hepatic and/or renal dysfunction to reduce the risk of seizures. Tramadol is less potent than other opioids and is considered to be approximately one tenth as potent as morphine.108 One nonrandomized, observational study in patients with cancer found comparable analgesic efficacy of high-dose tramadol (ie, ≥300 mg/d) and low-dose morphine (ie, ≤60 mg/d), but observed higher rates of constipation, neuropsychological symptoms, and pruritus in patients receiving low-dose morphine.109 However, in a double-blind study of patients with cancer, tramadol produced more adverse effects, including vomiting, dizziness, and weakness, than hydrocodone and codeine.110 A Cochrane review of tramadol (with or without acetaminophen) concluded that limited evidence supports the use of tramadol for treatment of cancer pain and that tramadol is likely not as effective as morphine in this setting.111
Tapentadol is an opioid that binds to the mu-opioid receptor and inhibits norepinephrine reuptake.112,113 It is available as ER and IR formulations and is used for treatment of moderate to severe pain as well as for neuropathic pain. Typical doses start at 50 to 100 mg orally every 4 hours as needed, with a maximal daily dose of 500 mg per day (if using the ER) or 600 mg per day (if using the IR only) due to lack of published data regarding higher doses. Lower doses are recommended for patients with moderate hepatic impairment, and tapentadol should be avoided in patients with severe hepatic or renal impairment. In comparative phase 2–3 studies, the efficacy and safety of tapentadol have been shown as compared with placebo and oxycodone for noncancer pain.114–116 Data on tapentadol for treating noncancer pain have also suggested that it may have a lower incidence of gastrointestinal adverse effects than oxycodone.114 Limited data suggest that there may be a roll for tapentadol in the management of cancer pain,117,118 but further clinical trials are needed.
Buprenorphine
Buprenorphine, a partial mu-agonist, has been approved for chronic pain in opioid-naïve or opioid-tolerant patients. Although RCT data on buprenorphine for treating cancer pain are somewhat limited, several case series, prospective uncontrolled studies, and a few randomized trials support its use in cancer-related pain.119–123 Therefore, transdermal buprenorphine may be used at a dose of 5 mcg/hour in opioid-naïve patients requiring initiation of LA opioid therapy. In some instances, transmucosal buprenorphine may be more appropriate given a wider range of available doses, a higher maximum dose, and a lower likelihood of causing skin reactions compared with transdermal buprenorphine.
Based on its pharmacokinetics, buprenorphine may be especially appropriate for treating cancer pain in patients with renal impairment.122 Studies of buprenorphine suggest that, being a partial mu-receptor agonist, it exhibits a ceiling to analgesic efficacy and may precipitate withdrawal symptoms if administered to individuals currently taking a high-dose opioid.124 Although transdermal buprenorphine may have some advantages over methadone in the context of cancer treatments that prolong QT, FDA guidelines recommend limiting dose to a maximum of 20 mcg/hour due to concern for QT prolongation. Because the dose conversion from other opioids to buprenorphine can be complex, the NCCN panel suggests that providers consider a pain specialty consultation for complex cases.
Ketamine
Ketamine is a noncompetitive N-methyl D-aspartate receptor antagonist that blocks glutamate. Low (subanesthetic) doses produce analgesia and may limit central sensitization, hyperalgesia, and opioid tolerance. There are only limited data regarding the use of ketamine as an adjuvant to opioids for management of cancer pain.125 A double-blind, randomized, placebo-controlled trial found no significant difference between the outcomes of patients treated for cancer pain with ketamine versus placebo.126 However, a subsequent systematic review of the evidence on ketamine for treating cancer-related pain concluded that the data, although limited, did suggest modest analgesic potential for ketamine.127 Some data also suggest that ketamine may improve mood in individuals with depressive disorders.128–130
Lidocaine
Although it is most often used as a local analgesic, lidocaine may also be administered intravenously in patients with refractory cancer pain. Although data supporting the use of intravenous lidocaine for treatment of cancer pain are limited, case reports and smaller studies have been published that support its use for opioid-refractory cancer pain or postsurgical pain.131–134 One phase 2, randomized, double-blind crossover study of 50 patients with opioid-refractory cancer pain found that pain relief was better with intravenous lidocaine compared with placebo (P<.001). Additionally, more patients were able to decrease their analgesic requirements after administration of intravenous lidocaine than placebo (P=.0012). Side effects, including tinnitus, perioral numbness, sedation, lightheadedness, and headache, were self-limiting and did not require intervention except for discontinuation of the lidocaine infusion in one patient.131 Intravenous lidocaine may be started as a bolus infusion of 1 to 3 mg/kg over 20 to 30 minutes. If this bolus is tolerated and effective at reducing pain, a continuous infusion of intravenous lidocaine may be started at 0.5 to 2 mg/kg/hr (maximum 100 mg/hour), using the lowest dose that controls the patient’s pain.133 Some reports suggest that intravenous lidocaine may be especially useful for cancer-related neuropathic pain.132–134
Selecting a Route of Administration for Opioid Analgesics and Mixed Mechanism Drugs
The least invasive, easiest, and safest route of opioid administration should be provided to ensure adequate analgesia.
Oral is the preferred route of administration for chronic opioid therapy.135–137 The oral route should be considered first in patients who can take oral medications unless a rapid onset of analgesia is required or the patient experiences adverse effects associated with the oral administration. Continuous parenteral infusion, intravenous or subcutaneous, is recommended for patients who cannot swallow or absorb opioids enterally. Opioids, given parenterally, may produce fast and effective plasma concentrations in comparison with oral or transdermal opioids. Intravenous route is considered for faster analgesia because of the short lag-time between injection and effect (peak 15 minutes) in comparison with oral dosing (peak 60 minutes).138 The subcutaneous route has a slower onset and lower peak (30 minutes) effect when compared with the intravenous route.
Analgesic Agents That Are Not Recommended
The following agents are not recommended for patients with cancer: (1) mixed agonist-antagonists (eg, butorphanol, pentazocine); (2) meperidine; and (3) placebos. Mixed agonist-antagonists should not be used in combination with opioid agonist drugs for cancer pain management. Converting from an agonist to an agonist-antagonist could precipitate abstinence syndrome (a withdrawal crisis) if given to a patient who is physically dependent on a pure opioid agonist. Meperidine is contraindicated for chronic pain, especially in patients with impaired renal function or dehydration, because accumulation of metabolites that are cleared renally may result in neurotoxicity (seizures) or cardiac arrhythmias.135 Use of placebo in the treatment of pain is unethical.
Opioid Prescription, Titration, and Maintenance
The appropriate dose of opioid is based on the patient’s pain intensity and goals, while limiting undesirable and unmanageable adverse drug effects.
The physicians should be aware of potential drug-drug and drug-disease interactions while determining the treatment plan. For a summary of common drug-drug interactions between chemotherapeutics, analgesics, and other commonly prescribed medications, see Table 1 in the complete version of these guidelines, at NCCN.org. The patient’s goals and quality of life should also be considered when modifying the treatment plan.
The following methods of ongoing analgesic administration are widely used in clinical practice: “around the clock,” “as needed,” and “patient-controlled analgesia.” For most patients, long-acting dosing should be used for continuous pain relief. Additional doses of opioid may be required for pain not relieved by a regular schedule of LA (eg, ER) opioid.
The NCCN panel recommends considering opioid rotation if pain is inadequately managed despite adequate dose titration, or if persistent adverse effects from current therapy occur. Other indications for switching to a different opioid include a change in the patient’s condition (dysphagia, NPO [nil per os] status, or initiation of tube feeding), and out-of-pocket costs and limitations based on insurance formularies. See PAIN-E 7 of 13 (page 984) for oral and parenteral opioid equivalences and relative potency of drugs as compared with morphine based on single-dose studies.
For patients who have intermittent pain with pain-free intervals, IR opioids can be administered on an “as needed” basis, with the exception of methadone due to its long duration of effect. The “as needed” method is also used when rapid dose titration is required. The patient-controlled analgesia technique allows a patient to control a device that delivers a bolus of analgesic “on demand” (according to, and limited by, parameters set by a physician).139 However, if the patient persistently requires doses of “as-needed” opioids, or if the “around-the-clock” opioid regimen fails to relieve pain at peak effect or at end of dose, increased dose of ER opioid should be considered.
Breakthrough pain is defined as pain that fails to be adequately managed or “breaks through” a regimen of regularly scheduled opioid and may be further categorized as:
incident pain that is associated with specific activities or events (eg, physical therapy, exercise, or routine procedures that may induce pain), potentially managed with “rescue doses” of short-acting opioid given in anticipation of those events;
end-of-dose failure pain that recurs toward the end of dosing interval for regularly scheduled opioid, potentially managed by increasing the dose or frequency of regularly scheduled opioid; or
persistent pain that is routinely inadequately managed by existing regularly scheduled opioid, potentially managed by adjusting dose of regularly scheduled opioid.
Initiating Short-Acting Opioids in Opioid-Naïve Patients
The route of administration of an opioid (oral or intravenous) must be selected based on the patient’s needs. The NCCN Guidelines for Adult Cancer Pain management provide guidance for initiating short-acting opioids in opioid-naïve and opioid-tolerant patients.
For opioid-naïve patients experiencing pain intensity greater than or equal to 4, or less than 4 but whose goals of pain management and function are not met, an initial dose of 5 to 15 mg of oral morphine sulfate or 2 to 5 mg of intravenous morphine sulfate or equivalent is recommended. Assessment of efficacy and adverse effects should be performed every 60 minutes for orally administered opioids and every 15 minutes for intravenous opioids to determine a subsequent dose. On assessment, if the pain score remains unchanged or is increased, to achieve adequate analgesia, it is recommended that the dose be increased by 50% to 100% of the previous opioid dose. If the pain score decreases to 4 to 6, the same opioid dose is repeated and reassessment is performed at 60 minutes for orally administered opioids and every 15 minutes for opioids administered intraveously. On reassessment after 2 to 3 cycles of the opioid, if inadequate response is seen in patients with moderate to severe pain, changing the route of administration from oral to intravenous or subsequent management strategies can be considered. If the pain score decreases to 0 to 3, the current effective dose of opioid is administered “as needed” over an initial 24 hours before proceeding to subsequent management strategies.
Opioid Dose Reduction
The NCCN panel recommends monitoring patients for situations that may warrant opioid dose reduction. Scenarios where opioid dose reduction may be considered include the patient rarely or never needing breakthrough analgesics, completion of an acute pain event, improvement of pain control through use of nonopioid or interventional pain management therapies, or well-controlled pain in the setting of stable disease. In these situations, the dose of opioid may be reduced by 10% to 20% after which the adequacy of pain control may be reevaluated and further dose reductions may be considered if appropriate. Opioid dose reduction may also be considered when the patient is experiencing unmanageable adverse effects and/or significant safety concerns. For more information on tapering opioids, see PAIN-E 5 of 13 (page 982) and the VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain.145
Preventing Opioid Misuse and Abuse
The NCCN panel recommends monitoring for aberrant medication drug-related behaviors over the course of treatment using tools such as COMM (Current Opioid Misuse Measure). The COMM tool helps clinicians identify whether a patient, currently on long-term opioid therapy, is exhibiting aberrant behaviors associated with misuse of opioid medications.146,147 It examines concurrent misuse; in contrast, SOAPP-R (Screener and Opioid Assessment for Patients with Pain-Revised) or ORT (Opioid Risk Tool) are helpful in predicting which patients being considered for long-term opioid therapy may exhibit aberrant medications behaviors in the future. Potential risk factors for opioid abuse/misuse include the following patient characteristics148:
History of prescription, illicit drug, or alcohol dependence or misuse before cancer diagnosis/treatment
History of binge drinking or peers who binge drink
Family history of substance abuse
History of psychiatric disorder including anxiety, depression, attention-deficit hyperactivity disorder, posttraumatic stress disorder, bipolar disorder, or schizophrenia
History of sexual abuse victimization
Young age (younger than 45 years of age)
History of legal problems or incarceration
History of medication-assisted therapy for substance use disorder
Opioid Adverse Effects
A number of adverse effects are associated with the use of opioid analgesics. Constipation, nausea and vomiting, pruritus, delirium, respiratory depression, motor and cognitive impairment, and sedation are fairly common, especially when multiple agents are used.149–154 Chronic opioid therapy may depress the hypothalamic-pituitary axis and cause hypogonadism.155 Each adverse effect requires a careful assessment and treatment strategy. Management of opioid-induced adverse effects is integral to opioid pain management.149,156–164
The details of prophylactic regimens and other measures to prevent opioid-induced adverse effects are provided in “Management of Opioid Adverse Effects,” available in the complete version of these guidelines, at NCCN.org.
Constipation
Constipation can almost always be anticipated with opioid treatment, and patients do not develop tolerance to constipation; therefore, administration of a prophylactic bowel regimen is recommended for nearly all patients taking opioids. However, there is limited evidence on which to base the selection of the most appropriate prophylactic bowel regimen. One study showed that addition of the stool softener, docusate, to the laxative, sennosides, was less effective than administering sennosides alone.165 More recently, an RCT in hospice patients showed that there was no benefit in adding docusate to sennosides compared with sennosides alone.166 Therefore, for prophylaxis, the NCCN Guidelines for Adult Cancer Pain Panel Members recommend a stimulant laxative or a heaping tablespoon (17 g) of polyethylene glycol with 8 oz of water 2 times daily along with maintaining adequate fluid intake. Based on the available literature, docusate has not shown benefit and is, therefore, not recommended. Although maintaining adequate dietary fiber intake is recommended, supplemental medicinal fiber, such as psyllium, is ineffective and may worsen constipation.
Once constipation develops, the cause and severity of constipation must be assessed to rule out obstruction. Laxatives may be titrated as needed with the goal of achieving one non-forced bowel movement every 1 to 2 days. Adjuvant analgesic may be considered to allow reduction of the opioid dose.
If constipation persists, the cause and severity of constipation must be assessed again to rule out bowel obstruction and hypercalcemia. Providers should assess other medications with the potential to cause constipation. Adding stimulant laxatives, such as magnesium-based products, bisacodyl (available in tablets or suppositories), or osmotic laxatives (such as sorbitol, lactulose, and polyethylene glycol) may be helpful. Opioid rotation to fentanyl or methadone may be considered. Enema with sodium phosphate, saline, or tap water may be helpful because it dilates the bowel, stimulates peristalsis, and lubricates the stool to encourage a bowel movement. However, these types of enemas should be used sparingly with awareness of possible electrolyte abnormalities. The use of rectal suppositories or enemas should be avoided in patients with neutropenia or thrombocytopenia. Additionally, oral laxatives or enemas that contain sodium phosphate should be limited to a maximum dose of once daily in patients at risk for renal dysfunction; optimally, alternative agents can be used.
When response to laxative therapy has not been sufficient, peripherally acting mu opioid receptor antagonists such as oral methylnaltrexone,167–172 naloxegol,173 or naldemedine,174 opioid antagonists that work on receptors in the gastrointestinal system, can be used as a rescue when constipation is clearly related to opioid therapy175 (methylnaltrexone is FDA approved for opioid-induced constipation in adults with advanced illness who are receiving palliative care; naloxegol and naldemedine are FDA approved for opioid-induced constipation in adults with chronic noncancer pain, including those with chronic pain related to previous cancer or treatment). Other second-line agents include lubiprostone (FDA approved for opioid-induced constipation in adults with noncancer pain including those with chronic pain related to prior cancer or treatment),176,177 and linaclotide178 (FDA approved for idiopathic constipation). These agents will not be of benefit and should not be used in patients with known or suspected mechanical bowel obstruction. Neuraxial analgesics, neuroablative techniques, or other interventions to decrease pain and/or reduce systemic opioid dose may also be considered to reduce opioid-related adverse effects.
Nausea and Vomiting
For patients with a prior history of opioid-induced nausea, prophylactic treatment with antiemetic agents is highly recommended. If nausea develops, other causes of nausea (eg, constipation, CNS pathology, chemotherapy, radiation therapy, hypercalcemia) must be assessed. Effective agents that may be considered include phenothiazines such as prochlorperazine or thiethylperazine or dopamine receptor antagonists such as metoclopramide or haloperidol.
If nausea persists despite an as-needed regimen, administer antiemetics around the clock for 1 week and then change dosing as needed. When managing opioid-induced persistent nausea, instead of replacing one antiemetic with another, adding therapies that target different mechanisms of action, resulting in a synergistic effect, may be helpful. Adding serotonin receptor antagonists such as granisetron or ondansetron may be helpful and have a lower rate of CNS effects. Alternative agents such as scopolamine, dronabinol, or olanzapine may also be considered for management of nausea. Olanzapine may be especially helpful for patients with bowel obstruction.179,180 Corticosteroids can also be quite beneficial for reducing opioid-induced nausea and vomiting, and in particular have been found to be effective in combination with metoclopramide and ondansetron.181
If nausea persists for longer than a week, the cause of nausea needs to be reassessed and opioid rotation must be considered. If opioid rotation and the previously described measures have been tried and nausea still persists, neuraxial analgesics, neuroablative techniques, and other interventions could be performed to potentially reduce the opioid dose. Cannabinoids that have been FDA-approved for chemotherapy-induced nausea and vomiting (eg, dronabinol, nabilone) may also be considered in this situation.182–185 It should be noted that in the context of shifting legality, many patients with cancer are using medical cannabis for treatment of nausea and other cancer- or cancer treatment-related symptoms.47,48 Although medical cannabis has been legalized in many states, it has not been FDA-approved.48 Education on state and federal regulations for medical cannabis should be provided (see “Adjuvant Analgesics, Cannabinoids and Medical Marijuana”, page 986, for more information).
Pruritus
Pruritus or itchiness is a particularly common and distressing complaint. Pruritus occurs in 10% to 50% of patients receiving opioids. Even in the presence of attentive skin care, opioids can produce recalcitrant pruritus. If pruritus develops, other causes of pruritus such as use of any other medication must first be assessed. Pruritus is more likely to occur early in the course of treatment. If it is persistent despite attempted symptom management, consider changing to another opioid. Careful titration of mixed opioid agonist-antagonists (eg, nalbuphine) or mu-opioid receptor antagonists (eg, naloxone) may help reduce opioid-induced adverse effects while maintaining analgesic efficacy. The mu-receptor antagonists (eg, naloxone) are also used to reverse the effects of opioid-induced adverse effects,186 and careful dose titration can produce relief without reversing analgesic efficacy. A serotonin antagonist such as ondansetron may also be considered. Antihistamines such as cetirizine (nonsedating), diphenhydramine (sedating), or promethazine (sedating) may be beneficial. Hydroxyzine, administered by mouth or intramuscular injection, may also be useful.
Delirium
Delirium is a pathophysiologic condition characterized by altered consciousness and inattention, cognitive dysfunction, and disturbed psychomotor behavior. Delirium may be prevented or decreased with various nonpharmacologic interventions or, when delirium is severe and hyperactive, may be managed with a neuroleptic drug such as haloperidol, olanzapine, or risperidone on an as needed basis or by switching to another opioid.187–190 Studies have shown that stable doses of opioids (>2 weeks) are not likely to interfere with psychomotor and cognitive function, but these functions should be monitored during analgesic administration and titration.191 Patients taking opioids may be screened for driving impairment, if indicated. Driving fitness screens are often performed through occupational therapy.
Sedation
Recognizing the difference between cancer-related fatigue and opioid-induced sedation is critical, because some techniques to manage sedation may not work for fatigue. For more information on managing cancer-related fatigue, see the NCCN Guidelines for Cancer-Related Fatigue (available at NCCN.org). Sedation may hinder the achievement of dose titration of opioids to levels that provide adequate analgesia.23 If opioid-induced sedation develops and persists for more than a week, it may be managed by administration of psychostimulants such as methylphenidate, dextroamphetamine, modafinil, or armodafinil, or by adding caffeine. When using CNS stimulants for sedation, the dosing should be limited to morning and early afternoon to avoid insomnia at night. Sedation often precedes respiratory depression; therefore, progressive sedation should be noted and adjustments in care should be made.
Use caution when combining opioid medications with other medications that have a sedating effect (eg, benzodiazepines). The FDA has issued a black box warning about possible serious effects from this combination, including slowed or difficult breathing and death.192
Respiratory Depression
Respiratory depression is another adverse effect that is a concern for both physicians and patients. Physicians should be aware that patients with limited cardiopulmonary reserve are more susceptible and hypercarbia occurs before hypoxia. Naloxone remains a useful antidote for the reversal of opioid-induced respiratory and CNS depression, but should be administered cautiously so as not to precipitate acute opioid withdrawal syndrome in the opioid-tolerant patient. Abrupt reversal of opioid depression in opioid-tolerant patients may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, and seizures. Pulmonary edema, cardiac arrhythmias, and cardiac arrest have also been associated with naloxone administration.193 Therefore, naloxone should be administered with caution in opioid-tolerant patients. At end-of-life in patients receiving comfort measures only, slowed respiration is expected. Naloxone administration may be inconsistent with goals of care in these patients.
Naloxone may be made available to caregivers to administer when needed for patients taking opioids who are at high risk for respiratory depression and sedation. Although no RCTs have been published, the results of a nonrandomized intervention study showed that patients receiving long-term opioid analgesia who were coprescribed naloxone had fewer opioid-related emergency department visits compared with those who were not prescribed naloxone.194 Providers should become familiar with state regulations regarding the prescription of naloxone. The availability of needle-free naloxone preparations (eg, nasal spray) may facilitate use of naloxone in the outpatient setting. Importantly, caregivers who are provided naloxone must be educated in the proper indications and usage to prevent inappropriate administration. Naloxone may be available without a prescription in some localities.
Opioid Rotation
No single opioid is optimal for all patients.195 If opioid adverse effects are significant, an improved balance between analgesia and adverse effects might be achieved by changing to an alternative opioid. This approach is known as opioid rotation.149,196,197 Establishing equianalgesic dosing can be challenging; studies have sought to establish safe conversion ratios and methods.198–202 It is important to consider relative effectiveness when switching between oral and parenteral routes to avoid subsequent overdosing or underdosing. Known equianalgesic dose ratios, opioid titration and maintenance, and clinical examples of converting from one opioid to another are listed in “Opioid Principles, Prescribing, Titration, Maintenance, and Safety” (PAIN-E 7 of 13, page 984) as well as in the complete version of these guidelines, at NCCN.org.
Opioids and Risk Evaluation and Mitigation Strategy
Although opioids are the principal analgesics for management of moderate to severe pain in the context of a cancer diagnosis, they pose risks to patients and society. The abuse of opioids is an increasing concern. In 2017, 70,237 drug overdose deaths occurred in the United States, including 47,600 drug overdose deaths involving opioid analgesics.203 Drug poisoning remains the number one cause of injury-related death in the United States.204 Although ensuring that opioids continue to be prescribed for patients for whom they are appropriate is important, it is also essential to ensure that these drugs are prescribed carefully. To reduce addiction, misuse, abuse, overdose, and death, the FDA has established Risk Evaluation and Mitigation Strategy (REMS) programs for opioid products.205 The principal recommendations of opioid REMS programs are educating the provider, patient, and family/caregiver.
The highlights of provider responsibilities included in the REMS are:
Establishing patient-specific goals of opioid analgesic therapy and regularly evaluating therapeutic opioid response to guide further therapy.
Evaluating each patient for risk factors associated with opioid misuse or abuse.
Educating each patient on safe use, storage, and disposal of opioid.
Routinely monitoring patients for opioid misuse, abuse, or diversion.
All prescribers are encouraged to discuss the risks and benefits of opioid products with their patients. A patient counseling document approved with the REMS will be made available by the manufacturers to assist the prescribers in having these discussions. Providers should also routinely screen for signs of opioid misuse, abuse, or diversion. Various screening tools have been described for this purpose, but have not yet been evaluated in patients with cancer.148 One exception is the Opioid Risk Tool, the use of which was evaluated in a retrospective chart review of 114 patients with cancer.209 More research is warranted to determine the best practice for screening methods.
The panel recommends that clinicians use state prescription drug monitoring programs (PDMP, also known as PMP) when available. The National Association of State Controlled Substances Authorities (NASCA) maintains a database of state PMP contacts (available at www.nascsa.org). Written agreements or guidelines may help to clarify expectations and parameters for safe use of opioid analgesics. Although further research is needed to evaluate their utility in patients with cancer, such agreements are consistent with evolving CDC and FDA recommendations and may be required in certain states.
Management Strategies for Specific Cancer Pain Syndromes
Moderate to severe cancer pain is treated with opioids as indicated; however, opioids alone may not provide optimal analgesia. When a specific cancer pain syndrome is suspected or documented, additional interventions may be targeted to that pain syndrome (see “Management Strategies for Specific Cancer Pain Syndromes,” PAIN-D, page 980). Nonopioid analgesics (such as an NSAID), adjuvant analgesics (antidepressants, anticonvulsants, topical agents, and corticosteroids), integrative interventions (psychologic and physical approaches), and/or interventional strategies may be used in conjunction with opioids to help to improve patient outcomes.23
Neuropathic Pain
Cancer-related neuropathic pain is common and can be related to the cancer itself or the acute or chronic effects of cancer treatment.210 Adjuvant analgesics are particularly important in treating neuropathic pain.34,35 The most common adjuvant analgesics used for treating neuropathic cancer pain include anticonvulsants, antidepressants, and topical treatments. See previous section on “Adjuvant Analgesics”(page 985) for more information on these agents, including important cautions for their use. Corticosteroids have also long been used to relieve neuropathic pain syndromes, particularly radiculopathies associated with vertebral body compression fractures.
Although a limited number of RCTs support the role of antidepressants as adjuvant analgesics for neuropathic cancer pain, the effectiveness of TCAs for relief of neuropathic cancer pain may be extrapolated from studies conducted in non-cancer-related neuropathic pain.211–213 Several RCTs have shown that anticonvulsants (pregabalin or gabapentin) provided relief of neuropathic cancer-related pain.44,214 Likewise, some systematic reviews of trials of patients with cancer pain suggest that adjuvant analgesics (antidepressants and antiepileptics) added to opioids provided additional neuropathic pain relief,215 although another concluded that combining opioid analgesia with gabapentinoids did not provide significantly improved pain relief (data on amitriptyline, fluvoxamine, and phenytoin were inconclusive).216 The likelihood of benefit should be balanced with the risk of adverse effects by clinicians considering adjuvant analgesics for neuropathic pain.
Topical local anesthetic agents can be useful in preventing procedural pain and in relieving some types of cancer-related neuropathic pain. They act locally and are also thought to have some central inhibitory effect on pain. They may be used as an analgesic in combination with an opioid, antidepressant, and/or an anticonvulsant. Both the gel and patch forms of lidocaine have been shown to reduce the pain of postherpetic neuropathy and cancer-related pain.217–219
Management of Bone Pain Without an Oncologic Emergency
The clinical complications of bone metastases include debilitating bone pain, which tends to be most prominent with movement, pathologic fractures, spinal cord compression, neurologic complications, and hypercalcemia of malignancy. The term skeletal-related events (SREs) refers to a constellation of skeletal complications including fracture, need for surgery to bone, need for radiation to bone, and spinal cord compression. In some situations, hypercalcemia of malignancy is also included as an SRE. Administration of NSAIDs, acetaminophen, or steroids may improve bone pain control when combined with opioid analgesics.220–222 Topical diclofenac, including gel or patch, may provide relief for pain due to bone metastases with minimal system effects.220
Although bone-modifying agents such as bisphosphonates and RANKL (receptor activator of nuclear factor-kappa-B ligand) inhibitors are primarily used for the reduction of overall SREs, clinical trials have established that these agents can have an analgesic effect on patients with metastatic bone pain from a variety of tumors. Clinical trials have demonstrated the palliative effects of bisphosphonates (eg, zoledronic acid, ibandronate)223–227 and denosumab (a RANKL inhibitor)225,228 on pain related to bone metastases. Randomized trials suggest that, compared with zoledronic acid, denosumab provides comparable palliation of existing bone pain and may be superior for preventing worsening of bone pain,225,228,229 although evidence is insufficient to recommend one of these agents over the others.230 Due to differences in patient populations and the methods for assessing bone pain, direct comparison of bisphosphonates to determine their relative effects on bone pain across studies is difficult. Review of the literature shows that the analgesic effects of bone-modifying agents are modest and, therefore, these agents should not be used as a primary therapy for treatment of bone pain.230
Surgical and radiation treatment of bone metastases is performed to relieve local bone pain, provide stabilization, and prevent impending fracture or spinal cord compression.231 In some situations, interventions such as vertebral augmentation provide a greater likelihood of return to ambulatory status than radiation alone. Plain radiographs may be used to identify impending fractures so that the patient can be referred to an orthopedic specialist for stabilization. Consultation with a pain or palliative care specialist for interventional consultation is recommended to determine optimal management strategy for vertebral augmentation.
Ablative strategies such as radiofrequency (RF) ablation or ultrasound ablation may also be performed to reduce pain and prevent SREs. RF ablation of bone lesions has proven successful in pain management, especially for those who do not attain adequate analgesia without intolerable effects.232–235 Several small studies have also demonstrated the palliative effects of high-intensity focused ultrasound (HIFU) treatment of bone lesions.236–238
Physical and occupational therapy may also be beneficial in the prevention of complications associated with SREs.239–241
Management of Pain From Mucositis, Pharyngitis, and Esophagitis
Certain treatments for cancer–including systemic therapy, head and neck radiation, or hematopoietic stem cell transplant; can cause pain in the mouth, pharynx, and esophagus.242 To prevent mucositis, cryotherapy may be performed by having the patient suck on ice chips or hold ice water in their mouths before, during, and/or after rapid infusions of systemic therapies that are associated with mucositis. Studies have shown this approach to be effective in patients receiving melphalan for multiple myeloma and 5-fluorouracil for solid tumors.243,244 Gabapentin may be used in combination with opioid or nonopioid analgesics for treatment of mucositis, although studies on the effectiveness of this approach have reported mixed results.43,245
Oral care protocols, consisting of good oral hygiene and prophylactic mouth rinses may be used for prevention of mucositis.246 Prophylactic mouth rinses (also called “magic mouthwash”) compositions vary significantly, including ingredients such as antibiotics, antihistamines, antifungals, corticosteroids, and antacids.247,248 The effectiveness of these ingredients for preventing or treating mucositis and the evidence supporting their use varies. Because of this, bland mouth rinses using ingredients such as sodium bicarbonate are often recommended.242 The NSAID benzydamine also has some data supporting its use in an oral rinse for the prevention and treatment of mucositis.249,250 Local anesthetics (eg, lidocaine) may be used to treat mucositis either as component of a mouth rinse or separately, in a liquid or gel formulation.
Management of Pain Due to Bowel Obstruction
Malignant bowel obstruction is a common complication in patients with abdominal or pelvic cancers. The initial management of patients presenting with bowel obstruction includes evaluation of the etiology of the obstruction. If the obstruction is resulting from cancer, surgical intervention should be considered. Patients with advanced disease or poor general condition who are unfit for surgery may require other palliative measures to relieve distressing symptoms. These measures include bowel rest, nasogastric suction, venting gastrostomy, corticosteroids, anticholinergic agents (eg, scopolamine, hyoscyamine, glycopyrrolate), and/or octreotide (see the NCCN Guidelines for Palliative Care). Although metoclopramide should not be used in the setting of full bowel obstruction, it may be considered for partial obstructions. Although evidence supporting the use of H2 blockers for malignant bowel obstruction is lacking,251 H2 blockers are a reasonable consideration for reducing gastric secretions in this setting. Use of opioid analgesics to help manage pain related to malignant bowel obstruction is appropriate.
Nonpharmacologic Interventions for Cancer Pain Management
Integrative Interventions
Since pain encompasses physical, psychosocial, and spiritual dimensions, the treatment of cancer pain inherently requires integration of therapies inclusive of nonpharmacologic interventions. A growing body of evidence suggests that the use of nonpharmacologic interventions (physical, cognitive, psychosocial, and spiritual) may serve as valuable additions to pharmacologic interventions.252–254 The integration of physical, cognitive, psychosocial, and spiritual modalities should be based on assessment of cultural and financial considerations, and are best presented as part of joint and informed decision making (see PAIN-J, page 988).
Physical Interventions
Physical interventions include, but are not limited to, therapeutic or conditioning exercise, physical or occupational therapy, massage, use of heat and/or cold, acupuncture, and acupressure.255–258
Cognitive-behavioral Interventions
Cognitive interventions are aimed at enhancing a sense of control over the pain or underlying disease. Mindfulness-based stress reduction, breathing exercises, relaxation, imagery, hypnosis, biofeedback, music, and other behavioral therapies can be very useful.259–264 Patient-based educational interventions have a significant impact in providing pain relief.265 Skills training helps modify the patient’s experience of pain and helps patients acquire techniques of pain management such as deep muscle relaxation. Patients who may benefit from skills training may be referred to a licensed mental health professional trained in cognitive behavioral therapy, hypnosis, biofeedback, or mindfulness-based stress reduction. Education provides patients and family/caregivers with the knowledge to use analgesics correctly and to address side effects or unrelieved pain.
Psychosocial interventions
Attention should focus on psychosocial support and providing education to patients and families.266,267 Psychosocial support can greatly enhance patients’ sense of control as well as greatly reduce the family/caregivers’ feeling of helplessness.263 A meta-analysis of the effect of psychosocial interventions on cancer pain highlights the importance of a multimodal approach to the management of cancer pain.268
Spiritual Interventions
In cancer care, there is growing interest in attention to spiritual needs and the existential concerns often associated with pain. Many patients hold cultural beliefs about such treatments, and home remedies, rituals, prayer, and other spiritual practices may be most helpful in relieving or coping with pain. Involvement of spiritual care providers from a range of culturally appropriate spiritual backgrounds is essential.269 Spiritual needs should be routinely assessed and spiritual care should be incorporated as a component of comprehensive pain management.
Interventional Strategies
Some patients experience inadequate pain management despite pharmacologic therapy or may not tolerate an opioid titration program because of side effects. Some patients may prefer interventional therapies instead of a chronic medication regimen. Interventional techniques have been shown, in some cases, to eliminate or significantly reduce the level of pain, and they may allow a significant decrease in systemic analgesics (see PAIN-M, page 989). Interventional therapies that can be useful in the relief of cancer pain include nerve blocks, vertebral augmentation, regional infusion of analgesics, RF ablation, and other techniques.23,234,235,270–274
The major indications for referral for interventional therapies include a patient suffering from pain that is likely to be relieved with nerve block (eg, pancreas/upper abdomen with celiac plexus block, lower abdomen with superior hypogastric plexus block, intercostal nerve, peripheral/plexus nerve) and/or patients unable to achieve adequate analgesia and/or the presence of intolerable side effects. For example, a patient with pancreatic cancer who was not tolerating opioids or not receiving adequate analgesia could be offered a neurolytic celiac plexus block. Neurolytic celiac plexus block may offer some improvement in pain management over systemic analgesics, but it is generally associated with a reduction in adverse effects.275,276
Regional infusion of analgesics (epidural, intrathecal, and regional plexus) minimizes the distribution of drugs to receptors in the brain, potentially avoiding adverse effects of systemic administration. The intrathecal route of opioid administration should be considered in patients with intolerable sedation, confusion, and/or inadequate pain management with systemic opioid administration.277 This approach is a valuable tool to improve analgesia for patients who have pain from a variety of anatomic locations (eg, head and neck, upper and lower extremities, trunk).278–281 However, due to the risk of catheter migration and infection risk, consider limiting the duration of use to several days.
Percutaneous vertebral augmentation might be useful for the treatment of lytic osteoclastic spinal metastases or in cases of vertebral compression fractures or spinal instability for which surgery is not feasible or indicated. Vertebral augmentation helps restore mechanical stability while reducing pain and neurologic symptoms.282–287 Ablation techniques may also be helpful for pain management in patients who receive inadequate relief from pharmacologic therapy. Additionally, these approaches could be considered for patients who do not prefer or are not indicated for receiving additional pharmacologic interventions or radiation therapy. Neurodestructive procedures may be used for well-localized pain syndromes (eg, back pain due to facet or sacroiliac joint arthropathy; visceral pain due to abdominal or pelvic malignancy). Ablation therapy (eg, RF ablation, ultrasound ablation) for bone lesions can also be helpful in reducing pain.232–238 See “Management Strategies for Specific Cancer Pain Syndromes, Bone Pain Without an Oncologic Emergency” (PAIN-D, page 980) for more information.
Neurostimulation procedures have been suggested as useful for painful chemotherapy-induced peripheral neuropathies, neuralgias, and complex regional pain syndrome.288
The interventional strategies listed previously are not appropriate if patients are unwilling or in patients with infections, coagulopathy, or with very short life expectancies. Also, experts performing the interventions must be made aware of any medications that the patient is taking that might increase bleeding risk (ie, anticoagulants [warfarin, heparin], antiplatelet agents [clopidogrel, dipyridamole], antiangiogenesis agents [bevacizumab]). The patient may need to stop taking the medication for an appropriate amount of time before the pain intervention and may need to continue to stay off the medication for a specified amount of time after the procedure. Interventions are not appropriate if technical expertise is not available. Additionally, if interventional treatment is undertaken and successfully improves pain control, significant opioid dose reduction may be required.
Summary
In most patients, cancer pain can be successfully managed with appropriate techniques and safe drugs. The overall approach to pain management encompassed in these guidelines is multimodal and comprehensive. It is based on routine pain assessments, uses both pharmacologic and nonpharmacologic interventions, and requires ongoing reevaluation of the patient. The NCCN Adult Cancer Pain Guidelines Panel advises that cancer pain can be well managed in the vast majority of patients if the algorithms presented are systematically applied, carefully monitored, and tailored to the needs of the individual patient.
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