NCCN临床实践指南：成人癌痛（2025.V1）

指南综合与多学科· 未分类与其他 · 2025

NCCN Guidelines Version 1.2025 Adult Cancer Pain

Version 1.2025, 03/12/25 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated. Note: All recommendations are category 2A unless otherwise indicated.

# NCCN Guidelines Index Table of Contents Discussion

NCCN Guidelines Index Table of Contents Discussion

# NCCN Guidelines Index

NCCN Guidelines Index

PAIN

NON-OPIOID ANALGESIC (NONSTEROIDAL ANTI-INFLAMMATORY DRUGS [NSAIDS] AND ACETAMINOPHEN) PRESCRIBING

# NSAIDs and Toxicities

NSAIDs and Toxicities

# PAIN-F 1 OF 2 ADJUVANT ANALGESICS FOR NEUROPATHIC PAIN (ANTIDEPRESSANTS, ANTICONVULSANTS, AND TOPICAL AGENTS)

PAIN-F 1 OF 2 ADJUVANT ANALGESICS FOR NEUROPATHIC PAIN (ANTIDEPRESSANTS, ANTICONVULSANTS, AND TOPICAL AGENTS)

# Examples of Adjuvant Analgesics

Examples of Adjuvant Analgesics

PAIN-G 2 OF 21 OPIOID PRINCIPLES, PRESCRIBING, INITIATION, TITRATION, MAINTENANCE, AND SAFETY

Principles of Maintenance Opioid Therapy • For continuous pain, it is appropriate to give pain medication on a regular schedule with supplemental doses for breakthrough pain.

• Add extended-release or long-acting formulation to provide background analgesia for control of chronic persistent pain controlled on stable doses of short-acting opioids.

Initial range for converting to long-acting opioid would be 50% to 100% of the daily requirement, depending on expected pain trajectory.

If using different forms of long-acting and short-acting opioids, particular care must be taken with conversions and appropriate dosing.

• When using methadone as a long-acting opioid, a short-acting opioid should also be provided for breakthrough pain as needed.

• Increase dose of regularly scheduled opioid if patient persistently needs doses of as-needed opioids or when dose of around-the-clock opioid fails to relieve pain at peak effect or at end of dose. • Breakthrough pain (pain that fails to be controlled or "breaks through" a regimen of regularly scheduled analgesic) may require additional doses of analgesic for pain not relieved by regular schedule of long-acting (eg, extended-release) analgesic. Breakthrough pain may be further evaluated into the following categories, which have direct impact on treatment:

Incident pain: Pain associated with or incident to specific activities or events, potentially managed with short-acting opioid given in anticipation of those events (eg, physical therapy, exercise, routine procedures that may induce pain) End-of-dose failure pain: Pain recurring towards the end of dosing interval for regularly scheduled opioid, potentially managed by increasing the dose or frequency of regularly scheduled opioid Uncontrolled persistent pain: Pain routinely uncontrolled by existing regularly scheduled opioid, potentially managed by adjusting dose of regularly scheduled opioid • Recommend using a single short-acting agent for breakthrough pain.

• Allow rescue doses of short-acting opioids (10%-20% of the 24-hour total of long-acting or regularly scheduled PO opioid dose) up to every 3-4 hours as needed. Titrate rescue dose as needed.

If pain is inadequately controlled, to allow for dose titration, the short-acting opioids could be given as often as once per hour as needed (if hourly dosing is needed for more than 3 cycles, reassessment or other intervention is recommended). Urine drug screen testing costs may not be fully reimbursed by insurers and are sometimes passed on to patients with severe financial impact. Mass spectrometry and or quantitative results may take 1 to 2 weeks, whereas immunoassay results may be available within 24 to 72 hours. • Urine is the preferred route for routine drug testing, but other alternatives do exist such as saliva, blood or plasma, hair, and sweat. These alternatives may be options for patients unable to provide adequate urine samples, but may not provide comparable results.

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Miscellaneous Analgesics (PAIN-G, 19 of 21)

a Codeine, morphine, hydromorphone, hydrocodone, and oxymorphone should be used with caution in patients with fluctuating renal function due to potential accumulation of renally cleared metabolites-monitor for neurologic adverse effects. b Conversion factor listed for chronic dosing. The FDA has limited the amount of acetaminophen in all prescription drug products to no more than 325 mg per dosage unit. Dosage must be monitored for safe limits of acetylsalicylic acid or acetaminophen.

g Codeine has no analgesic effect unless it is metabolized into morphine by hepatic enzyme CYP2D6 and then to its active metabolite morphine-6-glucuronide by phase II metabolic pathways (PAIN-N). h The manufacturer recommends a maximum single dose of tramadol not to exceed 100 mg, with a maximum daily dose of 400 mg for immediate-release formulations (300 mg/ day in older adults, 200 mg/day for renal impairment) or 300 mg/day for extended-release formulations (PAIN-N). i The maximum daily dose for tapentadol extended-release is 500 mg, or 600 mg immediaterelease (lower doses are recommended for moderate hepatic impairment; avoid with severe impairment). j Shorter time generally refers to parenterally administered opioids (except for controlledrelease products, which have some variability); longer time generally applies to PO dosing. k Not recommended for cancer pain management because of central nervous system (CNS) toxic metabolite, normeperidine. l Mixed agonists-antagonists are not recommended for use in cancer pain; however, they can be used to treat opioid-induced pruritus. They should NOT be used in combination with opioid agonist drugs. Converting from an agonist to an agonist-antagonist could precipitate a withdrawal crisis in the opioid-dependent patient.

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PAIN-G 12 OF 21 OPIOID PRINCIPLES, PRESCRIBING, INITIATION, TITRATION, MAINTENANCE, AND SAFETY

References

• When converting from continuous parenteral infusion fentanyl to transdermal fentanyl, a straight 1:1 ratio 20 is appropriate, (ie, the number of mcg of parenteral fentanyl per hour should be approximately equal to the number of mcg of transdermal fentanyl per hour). Decrease basal rate of infusion by 50% at 6 hours after placing fentanyl patch, then stop the basal infusion 12 hours after patch placement.

• When converting from continuous parenteral infusion fentanyl to transdermal fentanyl, a straight 1:1 ratio 20 is appropriate, (ie, the number of mcg of parenteral fentanyl per hour should be approximately equal to the number of mcg of transdermal fentanyl per hour). Decrease basal rate of infusion by 50% at 6 hours after placing fentanyl patch, then stop the basal infusion 12 hours after patch placement.

An alternative method is to stop the basal infusion 6 hours after patch placement. 21 In some patients, additional dose titration of the fentanyl patch may be necessary.

• The fentanyl patch analgesic duration is usually 72 hours, but patients experiencing end-of-dose failure may require fentanyl patch replacement every 48 hours.

TRANSDERMAL FENTANYL

Convert or Rotate From Another Opioid to Transdermal Fentanyl (PAIN-G 13 of 21)

m Opioid-naïve patients are those not chronically receiving opioid analgesic on a daily basis and therefore have not developed significant tolerance. Opioid tolerant includes patients who are chronically receiving opioid analgesic on a daily basis. The FDA identifies tolerance as receiving at least 25 mcg/h fentanyl patch, at least 60 mg of morphine daily, at least 30 mg of PO oxycodone daily, at least 8 mg of PO hydromorphone daily, or an equianalgesic dose of another opioid for a week or longer.

Continued NCCN Guidelines Version 1.2025 Adult Cancer Pain

Note: All recommendations are category 2A unless otherwise indicated.

PAIN-G 13 OF 21

OPIOID PRINCIPLES, PRESCRIBING, INITIATION, TITRATION, MAINTENANCE, AND SAFETY

PAIN-G 14 OF 21

Continued

BUPRENORPHINE Potential Advantages of Buprenorphine:

• Lower misuse potential than other potent opioids. 23 Causes less analgesic tolerance and less constipation when compared to other mu-receptor agonists with no effects on the sphincter of Oddi. 24 Has a ceiling effect for respiratory depression. 25 Can affect QTc interval, although not to the same degree as methadone. 26 May cause less cognitive impairment and has been safely used in older adults. 27 No dose adjustment required for patients with renal failure or renal insufficiency. 28 Less drug dependence and milder withdrawal symptoms. 29 uprenorphine for Cancer Pain: • Buprenorphine is increasingly recognized as an effective analgesic with an improved therapeutic index relative to certain potent opioids; however, it has not been extensively studied in cancer pain. Its use in cancer pain is extrapolated from data on its effectiveness in non-malignant chronic pain. 30 • Buprenorphine transdermal has been suggested to be safe and effective in patients with cancer pain and can be started in opioid-naïve patients as a long-acting opioid. 31, 32 Immediate-release opioid formulations may be used to treat breakthrough pain.

The recommended starting dose of buprenorphine transdermal for opioid-naïve patients is a 5 mcg/hour patch every 7 days or 75 mcg buccal film once or twice a day. Buprenorphine for Chronic Pain: • Buprenorphine is a Schedule III opioid analgesic, considered a partial agonist with very high binding affinity for the mu-opioid receptor, an antagonist with high binding affinity for the delta-and kappa-opioid receptors, and an agonist with low binding affinity for the opioid receptor-like 1 receptor. It has a potential for better tolerability as well as safety advantages compared with full mu-opioid receptor agonists. It can also be used with supplemental dosing. 33 • In selected cases, buprenorphine use may be associated with effective pain control without precipitating opioid withdrawal in patients with pain and on long-term opioid therapy (when using the correct induction method [ie, low-dose]). 34 Buprenorphine for OUD: • It is essential to continue addressing and treating OUD while treating cancer pain. 35, 36 The majority of cancer hospitals do not offer treatment for OUD. 37 atients with OUD may be at higher risk for poorly controlled cancer-associated pain. This is due to higher opioid tolerance and related increased sensitivity to pain. 38, 39 Further, patients with OUD may face challenges accessing clinical support and psychosocial services. 35 linicians treating cancer pain are encouraged to collaborate and coordinate care with local experts in SUD/buprenorphine prescribers already involved in the patient's care. ◊ If a patient with OUD is admitted on buprenorphine, continue buprenorphine unless clinically contraindicated.

◊ If a patient with OUD comes to an outpatient clinic on buprenorphine, ask the buprenorphine prescriber to continue prescribing buprenorphine for OUD and to continue mental health/counseling/support.

-If a local buprenorphine prescriber is not available, consult with your institution's pain, palliative care, or mental health clinicians certified to prescribe buprenorphine for OUD. -Buprenorphine may be considered as a first-line opioid for cancer pain management in patients with OUD.

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OPIOID PRINCIPLES, PRESCRIBING, INITIATION, TITRATION, MAINTENANCE, AND SAFETY BUPRENORPHINE

Regulatory Requirements for Use of Buprenorphine (Note: revised with DEA regulation changes early 2023) 40, 41 • Special training and/or a DEA "X-waiver" is no longer required to prescribe any formulation for pain or OUD (only standard DEA registration is required). • Consultation with a pain or palliative care specialist is recommended. 42 There are no longer any DEA limits or patient caps on the number of patients a prescriber may treat for OUD with buprenorphine.

• State laws or regulations limiting buprenorphine prescription for OUD may still be applicable.

• The FDA strongly encourages health care providers to complete a REMS-compliant education program when prescribing these products.

Adding an Opioid (full mu-agonist) to Treat Pain in a Patient Receiving Buprenorphine for OUD:

• Buprenorphine reduces morbidity and mortality in patients with OUD. 43 Short-acting full opioid agonist may be added if needed for breakthrough pain after initiating buprenorphine.

• Data and consensus statements are lacking in oncology.

In select patients with cancer pain, buprenorphine-naloxone alone may be an effective analgesic. In general, the formulations used for OUD may be used interchangeably. 44 Maintenance doses of buprenorphine as MOUD (medication for treatment of OUD) will not typically be adequate to treat new acute pain, and patients will need an increase in the buprenorphine dosing or an additional full agonist opioid for acute pain. • Continue the patient's home buprenorphine dose perioperatively. 45 atients on buprenorphine perioperatively used significantly less opioids than those whose buprenorphine was stopped. 46 onsult with institutional anesthesiologist, pain, or palliative care providers if the patient is on buprenorphine products for OUD.

• Continuing buprenorphine when admitted to the hospital reduces opioid requirements during the hospital stay. 47 In patients who stopped therapy, 50% relapse into OUD. 48

Pitfalls of Adding

Buprenorphine

Please note: The conversion ratios in Table 2 should NOT be used when converting FROM methadone to other opioids. Methadone conversion can be complex and must be individualized for each patient. Assistance from a practitioner familiar with prescribing methadone or a pain/palliative care specialist is recommended. Note: All recommendations are category 2A unless otherwise indicated.

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METHADONE

PAIN-H 1 OF 3

MANAGEMENT OF OPIOID ADVERSE EFFECTS

Principles of Managing Opioid Adverse Effects

• Adverse effects to opioids are common, should be anticipated, and should be managed aggressively.

• Opioid adverse effects generally improve over time, except with constipation. Maximize non-opioid and nonpharmacologic interventions to limit opioid dose and treat adverse effects. If adverse effects persist, consider opioid rotation. • Patient and family/caregiver education is essential for successful anticipation and management of pain and opioid adverse effects.

• Information from patient and family/caregiver about adverse effects is essential for appropriate opioid dose adjustment and treatment.

• Recognize that pain is rarely treated in isolation in cancer and adverse effects also may be from other treatments or cancer itself.

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Assessment of both pain intensity and impact of pain on daily functions should be considered when establishing patient-specific goals for comfort and function.

An additional assessment tool that has undergone psychometric evaluation is the patient-reported outcomes measurement information system-pain interference (PROMIS-PI) bank; early validation studies suggest the potential utility of this approach to pain assessment as an alternative to standard-of-care assessment methods based on the BPI. 38 dditional studies are needed to assess the application of the PROMIS-PI for assessing cancer pain severity.

Assessing Pain

If the patient has no pain, re-screening should be performed at each subsequent visit or as requested. Identifying the presence of pain through repeated screening is essential to allow implementation of effective pain management as cancer-related pain has been found to be highly dynamic for an individual patient over time. 39 the Pain Rating Scale score is above 0, a comprehensive pain assessment is initiated. The comprehensive pain assessment should focus on the type and quality of pain; pain history (eg, onset, duration, course); pain intensity (ie, pain experienced at rest; with movement); estimated trajectory of pain; location; referral pattern; radiation of pain; impact of pain (ie, interference with activities such as work, sleep, and interpersonal interactions); the associated factors that exacerbate or relieve the pain; current pain management plan; patient's pain experience and response to current therapy; prior pain therapies; breakthrough or episodic pain inadequately managed with existing pain regimen; important psychosocial factors (eg, patient distress, family/caregiver and other support, psychiatric history, risk factors for undertreatment of pain 12 ); and other special issues relating to pain (eg, meaning of pain for patient and family/caregiver including patient experience of medical or other trauma; cultural beliefs toward pain, pain expression, and treatment; spiritual or religious considerations and existential suffering). 40, 41 The patient's goals and expectations of pain management should be discussed, including level of comfort and function, with family/caregivers included.

It is important to keep in mind that due to the biopsychosocial nature of pain, health inequities and disparities influence the pain experience and access to pain evaluation and care. A report from the American Cancer Society's Study of Cancer Survivors-II (SCS-II) concluded that "inequalities in pain management remain a persistent, yet understudied, public health epidemic." The report states that data from multiple sources demonstrate that there are sociodemographic and health-related inequalities that contribute to barriers to cancer pain management. Barriers exist across patient, provider, and system levels and are multifaceted. These findings support the recommendation that providers perform routine assessment of pain using standardized measures, as well as utilize patient education and engagement to promote shared decision making between patients and providers. 42 addition, a thorough physical examination and review of appropriate laboratory and imaging studies are essential for a comprehensive pain assessment. This evaluation should enable caregivers to determine if the pain is related to an underlying cause that requires specific therapy. For example, it is inappropriate to provide only opioids to a patient suffering with pain from impending spinal cord compression. Without glucocorticoids and local radiation therapy, the pain is unlikely to be well-managed, and the patient will remain at high risk for spinal cord injury. Patients with pain that is determined to be unrelated to cancer or cancer treatment should be referred to an appropriate pain provider or program or care should be coordinated as such.

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The NCCN Panel recommends monitoring risk factors for aberrant use or diversion of pain medication, which might be identified at initiation of care using screening tools such as Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), Opioid Risk Tool (ORT), or the Cut Down-Annoyed-Guilty-Eye Opener (CAGE) questionnaire Adapted to Include Drug use tool (CAGE-AID). 43, 44 Although specific screening tools have not been validated in the cancer care setting, their validated efficacy for evaluating risk in patients with non-malignant pain supports their use in this setting. 45 The SOAPP was developed to predict which patients, being considered for long-term opioid therapy, may exhibit aberrant medications behaviors in the future. 46 SOAPP-R is a revised version of the SOAPP. 47 imilar to the SOAPP-R, the ORT assesses the risk of aberrant behaviors when patients are prescribed opioid medication for chronic pain with a high degree of sensitivity and specificity for determining which individuals are at risk for opioid misuse. 48, 49 SOAPP-R and ORT differentiate between patients who are at high risk or low risk for opioid misuse. 50 A high-risk score on the SOAPP-R or ORT correlates with an increased likelihood of drug misuse. 51 The CAGE-AID questionnaire is used to screen patients for the possibility of alcoholism and illicit drug use. It is helpful in screening for maladaptive behavior in patients who present with a seemingly exaggerated need for opioid medication. 44, 52 e endpoint of comprehensive pain assessment is to diagnose the etiology and pathophysiology (somatic, visceral, or neuropathic) of the pain. Treatment must be individualized based on clinical circumstances and patient wishes, with the goal of maximizing function and quality of life. The clinician should also evaluate for factors that could impact equitable access to pain therapies.

Management of Adult Cancer Pain

For management of cancer-related pain in adults, the algorithm distinguishes three levels of pain intensity determined by a numerical or pictorial rating scale used as part of the comprehensive pain assessment. The three levels of pain intensity referred to in the algorithm are mild pain, moderate pain, and severe pain.

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 take into account 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 or are chronically taking opioids for cancer pain (opioid tolerant). It also distinguishes circumstances related to anticipated procedure-related pain and anxiety.

Patients who are opioid-tolerant are those chronically taking opioids for pain, defined by the U.S. Food and Drug Administration (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 1 week or longer." 53 Therefore, patients who do not meet the above criteria of opioid tolerance, based on not having had exposure to opioid doses at least as much as those listed above for ≥1 week, are considered to be opioid naïve.

Management of Pain Related to Oncologic Emergency

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 substance use disorders 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. 54, 55 Patients should be reevaluated at each contact and as needed to meet their goals for comfort and function.

Although pharmacologic analgesics, including non-opioids (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, and spiritual) and multidisciplinary care may serve as valuable additions to pharmacologic interventions.

When deciding upon the most appropriate analgesic regimen, the patient's pain diagnosis, comorbid conditions, safety, potential drug interactions, estimated pain trajectory, medication availability, and expense or financial toxicity 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 non-opioid (eg, NSAIDs, acetaminophen) analgesics. 56 r patients who are opioid-naïve (as defined above) who are experiencing mild pain intensity, treatment with non-opioid analgesics such as NSAIDs or acetaminophen as well as adjuvant analgesics should be considered prior to opioid analgesics unless they are contraindicated due to adverse effects, potential drug interactions, or comorbid conditions. Patients who are opioid-naïve who are experiencing moderate pain should receive non-opioid and adjuvant therapies, as appropriate, with titration of short-acting opioids as needed (see section below on Opioid Prescription, Initiation, Titration, and Maintenance). Short-acting formulations have the advantage of rapid onset of analgesic effect. The route of administration of opioid is decided (oral vs. intravenous [IV]) based on what is best suited to the patient's ongoing analgesic needs. If multiple doses of a short-acting opioid are consistently needed throughout the day, the addition of a long-acting (LA) opioid may be considered.

Patients who are opioid-tolerant (as defined above) who are experiencing mild pain should continue to receive non-opioid and adjuvant therapies, as appropriate. The need for opioid analgesics should be reevaluated and gradual dose reduction may be initiated, if indicated. Patients who are opioid-tolerant who are experiencing moderate pain should continue non-opioid and adjuvant therapies, as appropriate, with short-acting opioids, as needed. Short-acting opioids may be titrated by increasing the daily dose by 30% to 100%, until pain relief is achieved. If multiple doses of a short-acting opioid are consistently needed throughout the day, the addition or increase in dose of a LA opioid may be considered.

In cases of acute, severe pain or pain crisis, hospital or inpatient hospice admission may be considered to rapidly titrate analgesic and quickly 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 initiation of opioid therapy. Opioid-induced bowel dysfunction should be anticipated and treated prophylactically with a stimulating laxative to increase bowel motility, as indicated. 57 tients with chronic persistent pain treated with stable doses of short-acting opioids should be provided with around-the-clock extended-release (ER) or 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% to 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 necessity to adjust the baseline treatment.

Management of Pain Crisis

In order to achieve adequate analgesia, an initial dose of short-acting opioid should be determined and administered in patients who are experiencing severe pain (or uncontrolled pain when goals of pain management and function are not met). 58 For patients who are opioid-naïve, this dose should be 5 to 15 mg oral or 2 to 5 mg IV morphine sulfate or equivalent. A subcutaneous (SC) route of administration can be substituted for IV; however, the time to peak effect is generally longer (~30 minutes). For patients who are opioid-tolerant, a rescue dose equivalent to 10% to 20% of the total opioid taken in the previous 24 hours should be given in supplement to the patient's LA (chronic) opioid dose. However, a retrospective cohort study of 216 patients with cancer who were opioid-tolerant who presented to the emergency department with acute pain found that while 77.4% of those taking < 200 oral morphine equivalent received adequate rescue doses, only 3.2% of those taking > 400 oral morphine equivalent received adequate breakthrough medication. 59 ontinuation of a patient's previous opioid could be considered or upward titration to accommodate dose requirements could be warranted. 60, 61 In patients with risk factors such as decreased renal or hepatic function, chronic lung disease, upper airway compromise, sleep apnea, or poor performance status, the initial dosing and upward titration of opioid analgesia should be approached with caution.

Efficacy and adverse effects should be assessed approximately every 60 minutes for orally administered opioids and every 15 minutes for IV/SC opioids to determine a subsequent dose. Upon assessment, if the pain score remains unchanged or is increased, further increase in opioid rescue dose by 50% to 100% is recommended. If the pain is reduced but still inadequately controlled, the same opioid dose is repeated and reassessment is performed at 60 minutes for orally administered opioids and every 15 minutes for opioids administered by IV/SC. If pain score remains unchanged upon reassessment after 2 to 3 cycles of the opioid, in patients with moderate to severe pain, changing the route of administration from oral to IV/SC or alternate management strategies should be considered. If the pain score decreases to a level where it is adequately controlled, the current effective dose can be continued "as needed" over an initial 24 hours before proceeding to subsequent management strategies.

Management of Procedure-Related Pain and Anxiety

Procedure-related pain represents an acute short-lived experience that may be accompanied by a great deal of anxiety. Procedures reported as painful include bone marrow aspirations; wound care; lumbar puncture; skin and bone marrow biopsies; and injections into or manipulations of an

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IV line, arterial line, or central line. Much of the data available on procedure-related pain come from studies on pediatric patients with cancer, which are then extrapolated to adults.

Interventions to manage procedure-related pain should take into account the type of procedure, the anticipated level of pain, and other individual characteristics of the patient, such as age and physical condition. The interventions may be multimodal and may include pharmacologic and/or nonpharmacologic approaches. Supplemental doses of analgesics should be given in anticipation of procedure-related pain; topical, local, and/or systemic formulations can be considered. Anxiolytics, such as midazolam, lorazepam, or alprazolam, are drugs used for the treatment of anxiety and its related psychologic and physical symptoms. Anxiolytics should be given between 30 and 60 minutes before a procedure to manage procedure-related anxiety when feasible. Patients should be cautioned to avoid driving or operating machinery when taking an anxiolytic.

Local anesthetics can be used to manage procedure-related pain with sufficient time for effectiveness as per package inserts. Examples of local anesthetics include lidocaine, prilocaine, and bupivacaine. Physical approaches such as cutaneous warming, laser or jet injection, and ultrasound (US) may accelerate the onset of cutaneous anesthesia. Sedatives may also be used. However, deep sedation and general anesthesia must be carried out only by trained professionals. In addition, use of nonpharmacologic interventions may be valuable in managing procedure-related pain and anxiety. The major goal of nonpharmacologic interventions that include physical and cognitive modalities is to promote a sense of control, thus increasing hope and reducing helplessness that many patients with pain from cancer experience. Creating a calm, comfortable procedural environment can help achieve this.

Patients usually tolerate procedures better when they know what to expect. Therefore, patients and family members/caregivers should receive written instructions for managing pain. Pre-procedure patient education that includes procedure details and pain management strategies is essential to allow time for assimilating the information, asking questions, and learning self-management techniques to reduce anticipatory anxiety.

Subsequent Management of Cancer Pain

The subsequent treatment is based on the patient's continued pain rating score as well as its function and evidence of appropriate use of prior 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 re-evaluated and comprehensive pain assessment must be carried out. 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 re-evaluated to either enhance the analgesic effect of the opioids or in some cases to counter the adverse effects associated with the opioids. 57 Optimal use of nonpharmacologic integrative interventions (physical, cognitive, 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, 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.

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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.

Ongoing Care

Although pain intensity ratings may be obtained frequently during analgesic titration, formal pain re-evaluation is required at each contact to ensure that pain management therapies are successfully meeting patient-specific goals for comfort, function, and safety.

If an acceptable level of comfort and function has been achieved for the patient, and 24-hour opioid requirement is stable, the NCCN Panel recommends converting to an ER oral medication (if feasible) or other ER formulation (ie, transdermal fentanyl). The subsequent treatment is based on the patient's continued pain rating score. Rescue doses of the short-acting formulation of the same LA opioid may be provided during maintenance therapy for the management of pain in patients with cancer not relieved by ER opioids.

A regular follow-up schedule should be initiated to monitor outcomes of analgesic therapy, including adverse effects. Pain should be assessed during each outpatient contact or at least each day for inpatients depending on patient conditions, institutional standards, and regulatory requirements.

• Chronic opioid therapy may depress hypothalamic-pituitary-adrenal (HPA) axis and cause hypogonadism. Note: All recommendations are category 2A unless otherwise indicated.

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PAIN-I 1 OF 2 1 Stewart M, Brown JB, Donner A, et al. The impact of patient-centered care on outcomes. J Fam Pract 2000;49:797-804.

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Communication with the health care provider is critical for the patient and family/caregiver to assist in meeting goals of care.

• Be certain that patient/family know how to contact physician/hospital.

• Explain that health care providers cannot discern the patient's pain level, and that describing pain is not viewed as "complaining," but rather is an essential source of information to enable the health care provider to adjust treatment. • Explain that health care providers want to know about any problems the patient believes the pain medications may be causing, as there are probably ways to alleviate these issues.

PAIN-J

PROCEDURE-RELATED PAIN AND ANXIETY

•

Major Indication for Referral:

• Pain likely to be relieved or function improved through consultation delivered by a specialty service provider as suggested below.

Note that the specific provider of these services may vary in different treatment settings.

Pain and/or

PAIN-M

1 Patient prognosis should be communicated to interventional pain colleagues as an important consideration when selecting interventional pain therapies. 2 Most of these procedures can be performed in a non-neurodestructive manner as well (eg, a nerve block). 3 Infection, coagulopathy, very short life expectancy, distorted anatomy, patient unwillingness, medications that increase risk for bleeding (eg, anti-angiogenesis agents such as bevacizumab), or technical expertise is not available.

INTERVENTIONAL STRATEGIES

• Commonly used interventional procedures: Note: All recommendations are category 2A unless otherwise indicated.

Regional

PRINCIPLES OF PHARMACOGENETICS

• Patients may respond differently to the same drug given at the same dose for the same indication often as a result of inherent differences in drug disposition due to genetic alterations that impact drug metabolism. These differences may lead to little or no analgesic response or significant adverse effects.

• NCCN Categories of Evidence and Consensus Category 1

Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate. Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate. Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but < 85% support of the Panel) that the intervention is appropriate.

Category 3

Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. All recommendations are category 2A unless otherwise indicated.

MS-2 Overview

Pain is one of the most common symptoms associated with cancer. Pain is defined by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. 1 IASP defines chronic cancer-related pain as chronic pain caused by the primary cancer itself, or metastases (chronic cancer pain) or its treatment (chronic post-cancer treatment pain). 2 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. 3 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. 4 ] [7] [8] [9] [10] Although improvements have been observed, undertreatment of pain remains an issue in a significant subset of patients with cancer. 6] [17] This requires familiarity with the pathogenesis of cancer pain, pain assessment techniques, and common barriers to the delivery of appropriate analgesia. Providers should be familiar with pertinent pharmacologic, anesthetic, neurosurgical, and behavioral interventions for treating cancer pain, as well as complementary approaches such as physical/occupational therapy. Early referral to palliative care may also be helpful in managing cancer pain, as well as other symptoms related to cancer and its treatment.

The most widely accepted algorithm for the treatment of cancer pain was developed by the World Health Organization (WHO). 18, 19 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 three-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 comprehensive care of these patients. As a result, they provide dosing guidelines for opioids, non-opioid 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

Literature Search Criteria

Prior to the update of the NCCN Guidelines ® for Adult Cancer Pain, an electronic search of the PubMed database was performed to obtain key literature in adult cancer pain published since the previous Guidelines update, using the following search terms: cancer pain, oncologic pain, cancer-related pain. The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature. 20 e search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Practice Guideline, Randomized Controlled Trial, Meta-analysis, Multi-center Study, Observational Study, Systematic Reviews, and Validation Studies. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the Panel during the Guidelines update have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the Panel's review of lower-level evidence and expert opinion.

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. 21 NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Pathophysiologic Classification of Cancer Pain Syndromes

Different types of pain occur in patients with cancer. A number of attempts have been made to classify pain according to different criteria. Pain classification includes differentiating between pain associated with tumor, pain associated with treatment, and pain unrelated to either. Acute and chronic pain should also be distinguished from each other when deciding which therapy to use. Therapeutic strategy depends on the pain pathophysiology, which is determined by patient examination and evaluation. There are two predominant mechanisms of pain pathophysiology: nociceptive and neuropathic. 22, 23 ciceptive pain is the result of injury to somatic and visceral structures and the resulting activation of nociceptors. Nociceptors are present in skin, viscera, muscle, and connective tissue. Nociceptive pain can further be divided into somatic pain and visceral pain. 24 Pain described as sharp, well localized, throbbing, and pressure-like is likely to be somatic nociceptive NCCN Guidelines Version 1.2025 Adult Cancer Pain MS-4 pain. It occurs often after surgical procedures or from bone metastasis. Visceral nociceptive pain is often described as more diffuse, aching, and cramping. It is secondary to compression, infiltration, or distension of abdominal or thoracic viscera.

Neuropathic pain results from injury to the peripheral or central nervous system (CNS). This type of pain might be described as burning, sharp, or shooting. Examples of neuropathic pain include pain due to spinal stenosis or diabetic neuropathy, or as an adverse effect of chemotherapy (eg, vincristine), radiation therapy, or following surgical injury to the nerves.

Comprehensive Pain Assessment

A comprehensive evaluation is essential to ensure proper pain management. Inadequate assessment of pain frequently leads to poor pain management. It is therefore important to find the cause of the pain and identify optimal therapies. This algorithm begins with the premise that all patients with cancer should be screened for pain and quality of life during the initial evaluation, at each subsequent contact, and whenever new therapy is initiated. If pain is present on a screening evaluation, the pain intensity must be quantified by the patient (whenever possible). Since pain is inherently subjective, patients' self-reporting of pain is the current standard of care for assessment.

Selecting Tools for Assessing Pain

Various methods and tools exist to assess pain severity. 6] [27] [28] Although pain is commonly assessed using numerical or categorical ratings, some patients may experience difficulty with these scales. The Faces Pain Rating Scale may be successful with patients who have difficulty with other scales, for example, children, older adults, and patients with language or cultural differences or other communication barriers. If the patient is unable to verbally report pain, an alternative method to obtain pain rating and pain assessment must be utilized. In addition to pain intensity, the patient should be asked to describe the characteristics of their pain (ie, aching, burning).

The Brief Pain Inventory (BPI) assesses pain severity in patients with cancer in two important dimensions: intensity of pain and interference of pain with a patient's life. 26, 29, 30 Studies suggest that pain may interfere with daily functions to a different extent in patients with cancer versus those with chronic noncancer pain. 31 As such, pain interference (ie, a measure of the impact of pain on daily functions) is of particular importance when assessing pain in patients with cancer. The BPI quantifies these measures using a 0 to 10 numerical scale. Based on these numerical ratings, cut-points have been established to categorize pain severity as mild, moderate, or severe for the purpose of treatment planning. 26, 29, 30 ecialized assessment tools have been developed for specific cancer pain syndromes. For example, the Oral Mucositis Assessment Scale (OMAS) developed by the Mucositis Study Group 32 and the Patient-Reported Oral Mucositis Symptom (PROMS) scale 33, 34 have been validated in patients with cancer who experienced mucositis as a result of chemotherapy, radiotherapy, or bone marrow transplantation. Several tools have been developed that include assessment for neuropathic pain, including the Neuropathic Pain Scale, Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), and the Neuropathic Pain Questionnaire, among others. 35, 36 A validated clinical assessment tool for bone-related pain and its effect on quality of life is the Functional Assessment of Cancer Therapy -Bone Pain (FACT-BP) Quality of Life Measurement in Patients with Bone Pain. 37 The FACT-BP was developed specifically to assess cancer-related bone pain and reflected clinical change as evidenced by differences in performance status.

EN_PAPER

Authors

Keywords

ϕ Anesthesiology Ϋ Complementary and integrative medicine ^ Emergency medicine ‡ Hematology/Hematology oncology Þ Internal medicine ∩ Interventional radiology † Medical oncology # Nursing ¥ Patient advocacy Σ Pharmacology § Radiotherapy/Radiation oncology £ Supportive care including palliative, pain management, pastoral care, & oncology social work * Discussion section writing committee Opioid Dose Reduction

PAIN-G 13 of 21

PAIN-G 15 of 21

Abstract

• Link updated: See transdermal fentanyl package insert FDA website for conversion tables from morphine and other opioids to transdermal fentanyl. PAIN-G 14 of 21 • Buprenorphine for Cancer Pain Sub-bullet removed: Due to its long-duration of effect, it is best used in patients with stable and predictable opioid requirements. Sub-bullet added: The recommended starting dose of buprenorphine transdermal for opioid-naïve patients is a 5 mcg/hour patch every 7 days or 75 mcg buccal film once or twice a day. • Buprenorphine for Chronic Pain Bullet 2 modified: In selected cases, buprenorphine use may be has been associated with effective better pain control without precipitating opioid withdrawal in patients with pain and on long-term opioid therapy (when using the correct induction method [ie, low-dose]). • Buprenorphine for OUD Bullet 2, sub-bullet 1 modified: Patients with OUD may be at higher risk for poorly controlled cancer-associated pain. This is due to higher opioid tolerance and related increased sensitivity to pain.

• Adding an Opioid (full mu-agonist) to Treat Pain in a Patient Receiving Buprenorphine for OUD Bullet 3, sub-bullet 1 modified: In select patients with cancer pain, buprenorphine-naloxone alone may be an effective analgesic. In general, the formulations used for OUD may be used interchangeably. Maintenance doses of buprenorphine as MOUD (medication for treatment of OUD) will not typically be adequate to treat new acute pain, and patients will need an increase in the buprenorphine dosing or an additional full agonist opioid for acute pain. • Pitfalls of Adding Buprenorphine to a Full Opioid Agonist Bullet 3 modified: Discontinue all around-the-clock and long-acting opioids when initiating buprenorphine. For patients who are maintained on full agonist opioids chronically, these patients can be rotated to buprenorphine while maintaining adequate analgesia. Consider consultation with pain management or palliative care specialist with experience in low-dose initiation techniques.

PAIN-4

f Opioid-naïve patients are those not chronically receiving opioid analgesic on a daily basis and therefore have not developed significant tolerance. Opioid tolerant includes patients who are chronically receiving opioid analgesic on a daily basis. The FDA identifies tolerance as receiving at least 25 mcg/h fentanyl patch, at least 60 mg of morphine daily, at least 30 mg of PO oxycodone daily, at least 8 mg of PO hydromorphone daily, or an equianalgesic dose of another opioid for a week or longer. f Opioid-naïve patients are those not chronically receiving opioid analgesic on a daily basis and therefore have not developed significant tolerance. Opioid tolerant includes patients who are chronically receiving opioid analgesic on a daily basis.

PAIN INTENSITY

The FDA identifies tolerance as receiving at least 25 mcg/h fentanyl patch, at least 60 mg of morphine daily, at least 30 mg of PO oxycodone daily, at least 8 mg of PO hydromorphone daily, or an equianalgesic dose of another opioid for a week or longer.

k Preference of PO or IV/SC route of delivery may differ based on the location of care. l Dose and titrate with caution in patients with risk factors such as decreased renal/ hepatic function, chronic lung disease, upper airway compromise, sleep apnea, and poor performance status. Note: All recommendations are category 2A unless otherwise indicated. Note: All recommendations are category 2A unless otherwise indicated. • Verbal: "What number describes your pain from 0 (no pain) to 10 (worst pain you can imagine)?"

• Written: "Circle the number that describes your pain."

Table 1 : Numerical Rating Scale

• Pain intensity rating scales can be used as part of universal screening and comprehensive pain assessment. At minimum, patients should be asked about "current" pain, as well as "worst" pain, "average" pain, and "least" pain in the past 24 hours. For each pain intensity rating, use one of the scales below. • For comprehensive assessment, also include "worst pain in past week," "pain at rest," and "pain with movement." See Comprehensive Pain Assessment (PAIN-B) for more details.

PAIN INTENSITY RATING NCCN Guidelines Version 1.2025 Adult Cancer Pain

PAIN-A 2 OF 2

PAIN INTENSITY RATING

Pain Assessment in the Nonverbal Patient 3 • The inability of patients to verbally communicate pain intensity because of cognitive or physiologic issues is a major barrier relating to pain assessment and management. Therefore, the American Society for Pain Management Nursing (www.aspmn.org) has developed a position statement and clinical practice recommendations clinicians may find useful in caring for such patients. • In the absence of self-report, observation of behavior is a valid approach to pain assessment with the understanding that behaviors may also indicate other sources of distress, such as emotional stress or delirium, which may complicate assessment (NCCN Guidelines for Distress Management). Potential causes and the context of the behavior must be considered when making pain treatment decisions. • A multi-faceted approach is recommended that combines direct observation, family/caregiver input, and evaluation of response to pain medicines or nonpharmacologic interventions. • For patients with advanced dementia, a comprehensive review of currently published tools, including those available at https://www.iasp-pain.org/resources/fact-sheets/pain-assessment-in-dementia/, is recommended. • For patients who are intubated and/or are unconscious, pain assessment tools have been tested in specific situations and include, but are not limited to: Behavioral Pain Scale (BPS) tested in adults in intensive care: http://www.ncbi.nlm.nih.gov/pubmed/11801819 4 Critical-Care Pain Observation Tool (CPOT) tested in adults in intensive care: http://www.ncbi.nlm.nih.gov/pubmed/17575489 5 • Clinicians are encouraged to monitor current research regarding new developments in strategies and tools for assessing pain in patients who have difficulty with self-reporting. • Alternative assessment method and rationale should be documented to facilitate appropriate follow-up and reassessment.

Cultural and Linguistic Assessment 6, 7 • Health care providers should be aware of impact of cultural and linguistic diversity during universal screening and comprehensive pain assessment and respond with trained interpreters and culturally and linguistically appropriate educational materials.

PAIN-B 2 OF 3

Return to Universal Screening (PAIN-2) 1 Moore TM, Jones T, Browder JH, et al. A comparison of common screening methods for predicting aberrant drug-related behavior among patients receiving opioids for chronic pain management. Pain Medicine 2009;10:1426-1433. 2 Smith PC, Schmidt SM, Allensworth-Davies D, Saitz R. A Single-Question Screening Test for Drug Use in Primary Care. Arch Intern Med 2010;170:1155-1160. 3 Butler SF, Fernandez K, Benoit C, et al. Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R). J Pain 2008;9:360-372. 4 Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: Preliminary validation of the Opioid Risk Tool. Pain Med 2005;6:432-442. 5 Keall R, Keall P, Kiani C, et al. A systematic review of assessment approaches to predict opioid misuse in people with cancer. Support Care Cancer 2022;30:5645-5658. 6 Yennurajalingam S, Arthur J, Reddy S, et al. Frequency of and factors associated with nonmedical opioid use behavior among patients with cancer receiving opioids for cancer pain. JAMA Oncol 2021;7:404-411. 7 ◊ Patient, environmental, and social factors as identified by a detailed patient evaluation 1 and/or screening tools at initiation of care (eg, NIDA Single-Question Screening Test, 2 SOAPP-R, 3 ORT, 4 CAGE-AID 5, 6 ) and monitoring of ongoing analgesic use (Specific screening tools have not been validated in the setting of cancer care) 7 (PAIN-G, 6 of 21). These screening tools may help identify risks for SUD but not for risk of diversion.

System-related barriers exist that include cost of analgesics and a lack of access to/availability of analgesics, particularly in low-income neighborhoods or for those who are economically disadvantaged. Studies have documented the inequities that persist since those with financial burdens or from historically marginalized racial and ethnic groups have less access to pain treatment. 41, 62 [65] [66] The patients must be provided with a written follow-up pain plan, including prescribed medications. It is important to ensure that the patient has adequate access to prescribed medications, particularly as research shows that patients with cancer and cancer survivors are having increasing difficulty in accessing their opioid prescriptions. 67 Therefore, the patient should be encouraged to maintain communication and coordination of care with relevant providers, especially during transitions between sites of care. Collaboration with the patient's pharmacist and insurance company is helpful in achieving this. It should be clarified with the patient which clinician will be prescribing their ongoing pain care and confirmed that the patient/caregiver(s) know how to contact the providers and hospital. The use of a pain diary may facilitate communication between the patient and their providers. 68 ually important is monitoring for the use of analgesics as prescribed, especially in patients with risk factors for or history of substance use disorders, diversion, or cognitive dysfunction. Particular attention should be paid to early recognition of ineffective analgesia despite rapid escalation of opioid analgesics, which may indicate opioid misuse. Patients and the family/caregiver should be informed that opioids should only be used to treat pain and are not intended for the treatment of sleep, anxiety, or other mood issues. However, if working closely with health care providers, opioid medications can be used to safely and effectively relieve cancer-related pain.

If an acceptable level of comfort and function has not been achieved for the patients, universal screening and assessment must be carried out and additional strategies for pain relief must be considered. Other sources of distress (eg, psychological, social, spiritual) should also be recognized, documented, and treated as these may contribute to poorly controlled

Pain in Cancer Survivors

Chronic pain in cancer survivors may have a unique etiology and symptomatology compared with pain experienced by patients with cancer. Up to one third of post-treatment cancer survivors experience chronic pain, which can cause psychological distress and impact quality of life. 69, 70 n 2016, ASCO issued a guideline on chronic pain management in adult cancer survivors. 71 A qualitative study demonstrated unmet needs related to cancer survivor and clinician communication about chronic pain. It highlighted that often cancer survivors with chronic pain have challenges in receiving adequate management of their pain due to a lack of clarity about which health care provider's role it is to take on the responsibility of providing long-term pain management. Additionally, it was shown that there is an apparent lack of recognition in clinicians regarding the frequency of chronic pain in cancer survivors. Whether this is due to under-reporting by patients or due to inadequate screening by clinicians was not investigated in this study. 72 For more information on pain in cancer survivors as well as other survivor-related issues, please see the NCCN Guidelines for Survivorship.

Pharmacologic Interventions for Cancer Pain Management

Optimal management of cancer pain is often accomplished by using a combination of pharmacologic and non-pharmacologic 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.

Non-Opioid Analgesics

Acetaminophen

Acetaminophen has analgesic and antipyretic, but not anti-inflammatory properties. 73 Attention has been drawn towards the relative limited efficacy and significant adverse effects of acetaminophen, particularly hepatic toxicity and possibly renal impairment. 74, 75 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. A randomized blinded clinical trial involving hospitalized patients with cancer who were treated with opioids for moderate or severe acute pain, looked to determine if the addition of acetaminophen to their opioid regimen would improve pain control or decrease total opioid use. Among 112 randomized patients, the percentage of patients reporting improvement in pain control after 48 hours was similar between acetaminophen and placebo. The study concluded that addition of acetaminophen to an opioid regimen for cancer-related pain may not improve pain control or decrease total opioid use. 76 e to concerns about liver toxicity, the NCCN Panel Members advise that acetaminophen should be used with caution or not used at all with combination opioid-acetaminophen products to prevent excess acetaminophen dosing.

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. 77 he FDA has issued a boxed warning to communicate the risk of severe liver injury associated with acetaminophen to health care professionals. In addition, the 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. 77 Due to concerns of hepatic toxicity, the NCCN Panel suggests that providers consider limiting chronic administration of acetaminophen or use of acetaminophen in older adults to ≤3 g per day.

Additionally, data have demonstrated concerns over possible impacts of the efficacy of immunotherapy in the setting of concurrent acetaminophen use. In one study, 600 patients with advanced cancer took acetaminophen prior to the start of immunotherapy and the response of immune checkpoint inhibitors was assessed after initiation of immunotherapy. The response of immune checkpoint inhibitors was significantly reduced, suggesting that acetaminophen has immunosuppressive effects. 78, 79 herefore, the NCCN Panel recommends using acetaminophen with caution in the setting of immunotherapy. There also may be concerns about the risk of masking fever in patients who are immunocompromised.

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 (GI) bleeding, advanced age ( > 60 years old), male sex, and concurrent selective serotonin reuptake inhibitor (SSRI) antidepressants, 80 corticosteroids, or anticoagulant therapy should be considered before NSAID administration to prevent upper GI tract bleeding and perforation. The risk of GI 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 GI adverse effects induced by NSAIDs. The FDA cautions that the concomitant use of an NSAID with aspirin may reduce the cardioprotective efficacy of aspirin, 81 and concomitant use of an NSAID and low-dose (or cardioprotective) aspirin may increase the risk of GI bleeding. 82, 83 The NCCN Panel recommends avoiding concurrent use or administering these agents separately.

NSAIDs should be prescribed with caution in patients > 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. 84 NSAID use should be coordinated with other oncologic therapies. While there is a paucity of high-quality evidence supporting the role of NSAIDs in analgesia of cancer pain, 85, 86 the addition of NSAIDs to opioids has the potential benefit of reducing the opioid dose when sedation, cognitive function, or other 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 develop or worsen. 84 The FDA has issued a warning that NSAID use may increase the risk of heart attack or stroke. 87 This risk is present even with short-term use of NSAIDs and increases with higher doses. 88 NSAIDs taken with prescribed anticoagulants, such as warfarin or heparin, may significantly increase the risk of bleeding complications. Topical NSAIDs such as diclofenac gel or patch may be useful for treatment of peripheral joint pain in this population, due to reduced systemic absorption.

The NSAID and acetaminophen prescribing guidelines are listed in the algorithm under Non-Opioid Analgesic (NSAIDs and Acetaminophen) Prescribing.

Adjuvant Analgesics

The term adjuvant analgesics refers to medications that are coadministered to enhance opioid analgesia and possibly reduce adverse NCCN Guidelines Version 1.2025 Adult Cancer Pain MS-13 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 anticonvulsants 89 (eg, gabapentin, pregabalin), antidepressants (eg, SSRIs, serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic antidepressants [TCAs] ), corticosteroids, and local anesthetics/topical agents (eg, topical lidocaine patch or topical NSAID). 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 Management Strategies for Specific Cancer Pain Syndromes, Neuropathic Pain). 90, 91 ysicians 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 (CYP450) 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. While some clinical studies indicate increased risk of breast cancer recurrence in patients with breast cancer treated with tamoxifen who are also treated with SSRI antidepressants versus those receiving tamoxifen alone, 92 other studies have not shown this effect. 93, 94 If concomitant use of an SSRI is required in a patient receiving tamoxifen, use of a mild CYP2D6 inhibitor (ie, sertraline, citalopram, venlafaxine, escitalopram) may be preferred over a moderate-to-potent inhibitor ie, (paroxetine, fluoxetine, fluvoxamine, bupropion, duloxetine). 92 e most commonly used anticonvulsant drugs for the treatment of cancer pain are gabapentin and pregabalin. 95 They have been studied primarily in noncancer neuropathy syndromes, 96 although there are data supporting their use for treatment of cancer pain in conjunction with opioids. 97, 98 abapentin has been reported to reduce mucositis pain in patients receiving concomitant radiotherapy and chemotherapy. 99 When compared in a prospective, randomized, open-label trial, pregabalin relieved neuropathic cancer-related pain more effectively than transdermal fentanyl. 100 rticosteroids have long been used to relieve neuropathic pain syndromes and have also been effective for treating bone pain due to their anti-inflammatory effects as well as relieving malignant intestinal obstruction. 56, 101 A 2015 Cochrane review summarized the existing data for corticosteroid use in cancer pain. 102

Cannabinoids and Medical Cannabis

In the context of shifting legality, many patients with cancer are using cannabinoids or medical cannabis (also called "medical marijuana") for treatment of cancer-or cancer treatment-related symptoms. 103, 104 Current FDA-approved cannabinoids include dronabinol (THC) and cannabidiol (CBD). 105 At the time of this Discussion update, previously FDA-approved nabilone is no longer available in the United States. 106 onabinol is a synthetic delta-9 tetrahydrocannabinol (THC), which is approved to treat refractory nausea and vomiting associated with cancer treatment and is also approved to treat anorexia and weight loss related to AIDS. CBD has been approved to treat seizures associated with rare forms of severe epilepsy. While medical cannabis has been legalized in many states, it has not been FDA-approved for any indication. 105 urthermore, the U.S. Drug Enforcement Administration (DEA) classifies cannabis as a Schedule I substance, meaning that it has a high potential for misuse, no currently accepted medical use in treatment in the United

MS-14

States, and a lack of accepted safety for use under medical supervision. 107 9] [110] Therefore, providers should assess for cannabinoid/medical cannabis 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. While two randomized, placebo-controlled trials have shown that nabiximols (cannabis extract that contains both THC and CBD-it is not approved for use in the United States) significantly reduced cancer-related pain compared to placebo in patients with inadequate analgesia despite chronic opioid administration, 111, 112 THC extract alone did not show a significant benefit compared to placebo, 111 and another randomized study reported no significant benefit of nabiximols compared to placebo for treatment of chemotherapy-induced neuropathic pain. 113 2] [113] Systematic reviews and meta-analyses of randomized controlled trials (RCTs) have also reported mixed results with some RCTs reporting little or no benefit of cannabinoids for cancer pain, [114] [115] [116] [117] [118] and another RCT reporting that some cannabinoids were able to reduce certain types of cancer pain (notably neuropathic pain) depending on route of administration. 119 e route of administration can also affect the safety profile of medical cannabis. An observational study in a state with legalized cannabis reported that while 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. 120 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. 120 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(es). An individual approach should be used to determine opioid starting dose, frequency, and titration in order 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). 121 A randomized trial compared the efficacy of low-dose morphine, a "strong" opioid agonist, to "weak opioids" (ie, codeine, codeine plus acetaminophen, 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 two treatment groups, and overall well-being/symptom burden was rated as significantly better in the low-dose morphine arm. 122

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[125]

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. 126 In a patient who has not been exposed to opioids in the past, morphine is generally considered the standard starting drug of choice. 127, 128 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 patients who are opioid-naïve with consideration of using a half tablet for lower dose titration in patients who are frail or older. Patients presenting with severe pain needing urgent relief should be treated with parenteral opioids, usually administered by the IV or SC route. If given parenterally, the equivalent dose is one-third of the oral dose. 129 An initial dose of 2 to 5 mg of IV morphine sulfate or equivalent is recommended for patients who are opioid-naïve. Morphine-6-glucuronide, an active metabolite of morphine, contributes to analgesia and may worsen adverse effects as it accumulates in patients with renal insufficiency. 130, 131

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. 132, 133 Transdermal fentanyl is not indicated for rapid opioid titration and should be recommended only after pain is adequately managed by other opioids in patients who are opioid-tolerant. 134 It is usually the treatment of choice for patients who are unable to swallow, patients with poor tolerance to morphine, and patients with poor adherence to treatment. 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. 135 Another meta-analysis of RCTs 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. 136 Conversion from IV fentanyl continuous infusion basal rate via patient-controlled analgesia to transdermal fentanyl can be accomplished effectively using a 1:1 conversion ratio. 137 The basal rate of infusion should be decreased by 50% at 6 hours after placing the fentanyl patch, followed by stopping the basal infusion 12 hours after patch placement. An alternative method is to stop the basal infusion 6 hours after patch placement. 138 Transmucosal fentanyl may be considered in patients who are opioid-tolerant for brief episodes of incident pain not attributed to inadequate dosing of an around-the-clock opioid. [141]

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. 132 Clinical experience suggests use as a mild, initial-use opioid, but effective dose may vary. Hydrocodone is available in IR formulations mixed with acetaminophen or ibuprofen. Hydrocodone ER preparations (without added non-opioid 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. 132, 142 This process is largely through the action of the CYP450 enzyme, CYP2D6. It is important to note NCCN Guidelines Version 1.2025 Adult Cancer Pain MS-16 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. 143 Conversely, rapid metabolizers may experience toxicity after codeine administration from more rapid morphine production. 143

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. 132, 144 There is some evidence suggesting that the metabolite of hydromorphone may lead to opioid neurotoxicity, including myoclonus, hyperalgesia, and seizures. 145 This metabolite may be more neurotoxic than the morphine metabolite. 146 In a prospective, open-label trial of 879 patients with cancer, hydromorphone effectively reduced pain that was inadequately controlled by other analgesics. 147 Additionally, RCTs have demonstrated the clinical noninferiority of once-daily hydromorphone ER compared with twice-daily oxycodone controlled-release 148 and four-times-daily hydromorphone IR compared with four-times-daily oxycodone IR 149 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. 150 Another review of 18 RCTs with 2271 patients concluded that hydromorphone has similar efficacy to morphine and oxycodone in reducing cancer pain intensity, decreasing consumption of additional analgesics, and improving quality of life. Adverse effects were shown to be similar for hydromorphone compared to morphine or oxycodone. 151

Oxycodone and Oxymorphone

] [154] Oxycodone is also available in combination with acetaminophen; therefore, the acetaminophen dose must be monitored for safe limits to avoid potential hepatic toxicity. 6] [157] Studies of oxycodone/naloxone formulations showed effective analgesia with reduced opioid-induced constipation for long-term use in cancer-related pain. 158, 159 ymorphone 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 (NMDA) receptors; it is commercially available in multiple strength oral tablets or in an oral or IV solution. 132 Individual variations in methadone pharmacokinetics (long and variable half-life ranging from 15-120 hours) make its usage complex in patients with cancer. 160 Due to its long half-life, high potency, and inter-individual 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. 161 The evidence is mixed regarding superiority of one method to initiate methadone. Some evidence supports lower adverse events with the 3-day switch method compared to the rapid conversion (stop-and-go) or ad libitum (as often as necessary) methods. In the 3-day switch method for methadone initiation, the original opioid is discontinued gradually by lowering the daily dose by one-third over a 3-day period. Simultaneously, methadone is initiated at one-third of the NCCN Guidelines Version 1.2025 Adult Cancer Pain MS-17 calculated dose and increased by one-third over 3 days to the calculated amount. 162, 163 cause 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 5 to 7 days, and caution that a steady state may not be reached for several days to 2 weeks. Methadone should not be titrated more frequently than every 5 to 7 days or longer. If more rapid titration is desired, consult with a pain or palliative care specialist or experienced methadone prescriber. Any significant sedation or marked improvement in pain prior to the fifth day of methadone may indicate the dose is too high and the patient may be at risk of oversedation or respiratory depression by day 5 to 7 if the dose is not immediately adjusted.

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. 164 Studies show that outpatient initiation and rotation to methadone can be successfully done in patients with cancer without serious adverse effects. 165 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. 166, 167 9] [170] 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. 171 The NCCN Panel supports the use of baseline and follow-up electrocardiogram (ECG) for patients treated with methadone at doses > 30 to 40 mg/day 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). 160, 161 ECG 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:

1) Correction of hypokalemia, hypomagnesemia, or hypocalcemia 2) Avoidance of other drugs that can prolong QTc 3) Avoidance of other drugs that can inhibit the biotransformation of methadone such as CYP3A4 inhibitors Alternate opioids are needed for patients with QTc > 500 msec, and are recommended for those with QTc of 450 to 500 msec, concurrently with interventions to correct any reversible causes of prolonged QTc. 160 The decision must be tailored to the individual clinical situation and goals of care. Good communication among the patient, family, and care providers is a critical component of the decision-making process.

Patients and their families may need to be educated about analgesic utility of methadone. Some may only be familiar with methadone use for maintenance treatment of opioid use disorder (OUD) 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 5 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 NMDA receptors, but it has a shorter half-life and more predictable metabolism. 172 Similar to methadone, levorphanol varies in its dosing equivalence with morphine. In a case series of 20 patients receiving palliative or hospice care, the NCCN Guidelines Version 1.2025 Adult Cancer Pain

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morphine to levorphanol conversion factors were listed as 12:1 for morphine doses of < 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 > 600 mg. 172 For certain populations (eg, patients who are older), levorphanol may offer similar benefits to methadone but with lessened prescribing complexities and adverse effects. 173 One study also demonstrated potential efficacy of levorphanol for treating neuropathic pain. 174

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 inhibitor (MAOI)-like medications (eg, TCAs, SSRIs, SNRIs, and MAOIs) due to risk of serotonin syndrome. 175 Tramadol can also have marked variability in drug metabolism, and should be used with caution for this reason. 176 See Principles of Pharmacogenetics in the algorithm.

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. 177 Tramadol is available as IR and ER formulations. The NCCN Panel recommends a maximum daily dose of 400 mg for IR formulations (100 mg four times a day), or 300 mg/day for ER formulations, for adults with normal hepatic and renal function. Lower doses are recommended for adults aged ≥75 years 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. 177 One nonrandomized, observational study in patients with cancer found comparable analgesic efficacy of high-dose tramadol (ie, ≥300 mg/day) and low-dose morphine (ie, ≤60 mg/day), but observed higher rates of constipation, neuropsychological symptoms, and pruritus in patients receiving low-dose morphine. 178 However, in a double-blind study of patients with cancer, tramadol produced more adverse effects, including vomiting, dizziness, and weakness, than hydrocodone and codeine. 179 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. 180 pentadol is an opioid that binds to the mu-opioid receptor and inhibits norepinephrine reuptake. 181, 182 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 a 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. 4] [185] Data on tapentadol for treating non-cancer pain have also suggested that it may have a lower incidence of GI adverse effects than oxycodone. 183 Limited data suggest that there may be a roll for tapentadol in the management of cancer pain, [186] [187] [188] but further clinical trials are needed. A retrospective study showed that > 90% of patients with moderate-to-severe cancer-related pain (those with neuropathic pain or mixed pain) and all patients with nociceptive pain responded to tapentadol. In this study most patients (93%) achieved clinically relevant pain relief within 4 days. 189 prenorphine Buprenorphine, a partial mu-agonist, has been approved for chronic pain in patients who are opioid-naïve or opioid-tolerant. Special training and/or a DEA "X-Waiver" is no longer required to prescribe any formulation of buprenorphine for pain or OUD. 1] [192] [193] [194] Therefore, transdermal buprenorphine may be used at a dose of 5 mcg/h in patients who are opioid-naïve requiring initiation of LA opioid therapy. Due to its ER formulation, transdermal buprenorphine is best used in patients with predictable and stable opioid requirements. 191, 195 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 to transdermal buprenorphine.

Potential advantages to using buprenorphine over other opioids include its lower potential for misuse, 196 less analgesic tolerance, and less constipation when compared to other mu-receptor agonists with no effects on the sphincter of Oddi. 197 Buprenorphine also has a ceiling effect on respiratory depression and may cause less cognitive impairment, physical dependence, and milder withdraw symptoms. 198, 199 sed on its pharmacokinetics, buprenorphine may be especially appropriate for treating cancer pain in patients with renal impairment. 193 tudies 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. 200 While transdermal buprenorphine may have some advantages over methadone in the context of cancer treatments that prolong QT, FDA guidelines recommend limiting transdermal buprenorphine dose to a maximum of 20 mcg/h due to concern for QT prolongation. Dosing recommendations for transdermal and buccal buprenorphine can be found in the treatment algorithm under Opioid Principles, Prescribing, Initiation, Titration, Maintenance, and Safety -Buprenorphine. 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.

[203] A systematic review and meta-analysis reported the prevalence of OUD in patients with cancer-related chronic pain to be 8% (95% CI, 1-20) and the prevalence of risk factors for OUD was 23.5% (95% CI, 19.5-27.8). 204 It is essential to continue treatment of OUD while still adequately treating cancer pain. Therefore, clinicians are encouraged to collaborate and coordinate care with specialists for substance use disorders and/or buprenorphine prescribers who may already be involved in the patient's care.

Ketamine

Ketamine is a non-competitive N-methyl D-aspartate receptor antagonist that blocks glutamate. Low (sub-anesthetic) 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. 205 A double-blind, randomized, placebo-controlled trial found no significant difference between the outcomes of patients treated for cancer pain with ketamine versus placebo. 206 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. 207 A systemic review and meta-analysis showed that ketamine could significantly reduce pain intensity in patients with cancer-related pain while also reducing adverse side effects typically reported with opioid pain medications. 208 ] [211] NCCN Guidelines Version 1.2025 Adult Cancer Pain

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Lidocaine

While it is most often used as a local analgesic, lidocaine may also be administered intravenously in patients with refractory cancer pain.

3] [214] [215] One phase 2, randomized, double-blind crossover study of 50 patients with opioid-refractory cancer pain found that pain relief was better with IV lidocaine compared to placebo (P < .001). Additionally, more patients were able to decrease their analgesic requirements following administration of IV 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. 212 A meta-analysis of pooled data from RCTs demonstrated a significant reduction in cancer pain with lidocaine infusion compared to placebo in 60 patients. 216 IV 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 IV lidocaine may be started at 0.5 to 2 mg/kg/h (maximum 100 mg/h), using the lowest dose that controls the patient's pain. 214 [215]

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. 60, 217, 218 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, IV or SC, 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. IV 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). 219 he SC route has a slower onset and lower peak (30 minutes) effect when compared with IV 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 the 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. 217 Use of placebo in the treatment of pain is unethical.

Opioid Prescription, Initiation, 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 . The patient's goals and quality of life should also be considered when modifying the treatment plan.

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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, LA 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.

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). 220 However, if the patient persistently requires doses of "as-needed" opioids, or if the "around-the-clock" opioid regimen does not relieve pain at peak effect or at end of dose, increased dose of the regularly scheduled opioid should be considered.

Breakthrough pain is defined as pain that is not adequately managed or "breaks through" a regimen of regularly scheduled analgesic 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.

Breakthrough pain is commonly reported among patients with cancer. In a survey of 1000 oncology patients, 44% reported incident pain, 41.5% reported spontaneous pain, and 14.5% reported both incident-related and spontaneous breakthrough pain. 221 Although the literature on useful therapies for breakthrough cancer pain is relatively small, multiple RCTs suggest that buccal, sublingual, or oral/nasal transmucosal formulations of fentanyl are effective options for managing episodic breakthrough pain. The route of administration of an opioid (oral or IV) 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 patients who are opioid-naïve.

For patients who are opioid-naïve who are experiencing moderate/severe pain, or mild pain when non-opioid therapies are contraindicated, an initial dose of 5 to 7.5 mg of oral morphine sulfate every 3 to 4 hours as needed, or equivalent, is recommended. The algorithm also recommends starting doses for oxycodone immediate release, hydrocodone, and hydromorphone in patients who are opioid-naïve. Pain should be reassessed regularly and the dose titrated further as needed. If ≥4 doses of a short-acting opioid are consistently needed each day, the addition of a long-acting opioid may be considered based on the total daily dose.

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, response to cancer-directed therapies, or improvement of pain control through use of non-opioid or interventional pain management therapies. 226 In these situations, the dose of opioid may be reduced by 5% to 20% after which the adequacy of pain control may be re-evaluated and further dose reductions may be considered if appropriate. Opioid dose reduction may also be considered when the pain is mild and the patient is experiencing unmanageable opioid-related adverse effects and/or rapid clinical deterioration. The expected trajectory of pain and the goals of care and pain management should be carefully reviewed when considering opioid dose reduction. For more information on tapering opioids, see Principles of Opioid Dose Reduction in the algorithm and the VA/DoD Clinical Practice Guideline for the Use of Opioids in the Management of Chronic Pain. 227

Preventing Opioid Misuse

The NCCN Panel recommends monitoring for aberrant medication drug-related behaviors over the course of treatment using tools such as Current Opioid Misuse Measure (COMM). 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. Randomly administered urine drug tests (UDT) and review of prescription drug monitoring programs (PDMPs, also known as PMPs) can be used to monitor for aberrant use or diversion of pain medications. The goal of UDT is to improve patient outcomes and safety. There are limited recommendations regarding use of UDT in patients with cancer-related pain receiving opioid therapy, and as a result UDT appears to be underutilized among this population. 230 Due to the lack of studies in this population, some recommendations are extrapolated from studies done on patients who do not have cancer. It is judicious that the prescriber takes caution in the utilization of UDT to limit bias in test application/interpretation and avoid excessive patient burden and/or negative impacts on patient care. 231 blished studies in patients with cancer found through random UDT that 1 in 4 patients receiving opioids had one or more abnormal results compared to results expected from prescribed therapy. 232 Current data show that UDT ordering is infrequent for patients with cancer on opioid therapy and the majority of ordering is performed by palliative care NCCN Guidelines Version 1.2025 Adult Cancer Pain MS-23 physicians, not oncologists. Furthermore, when definitive UDT results are found to be aberrant, clinicians rarely make prescribing changes reflectively. It is apparent that more definitive guidance related to UDT ordering and opioid management is needed for patients taking opioids for cancer-related pain. 233 e NCCN Panel recommends the consideration of UDT as part of a comprehensive safety monitoring program for patients receiving opioids for subacute and/or chronic cancer pain. This program should also include periodic review of state PDMPs as required by local/state laws, opioid prescribing patient agreement, and informed consent for opioid therapy.

Opioid Adverse Effects

A number of adverse effects are associated with the use of opioid analgesics. 5] [236] [237] [238] [239] Chronic opioid therapy may depress the hypothalamic-pituitary axis and cause hypogonadism. 240 Each adverse effect requires a careful assessment and treatment strategy. [243] [244] [245] [246] [247] [248] [249] The details of prophylactic regimens and other measures to prevent opioid-induced adverse effects are provided in Management of Opioid Adverse Effects in the algorithm.

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. 250 An RCT in hospice patients showed that there was no benefit in adding docusate to sennosides compared to sennosides alone. 251 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 (PEG) with 8 oz of water one to two times daily along with maintaining adequate fluid intake. Based on the available literature, the stool softener docusate may have limited benefit. While maintaining adequate dietary fiber intake is recommended, supplemental medicinal fiber, such as psyllium, has been shown to be useful in some studies, but may worsen constipation in certain patients. Other dietary modifications such as addition of prunes, prune juice, and/or kiwifruit may improve chronic constipation in some patients, although the studies were not specific to patients using opioids for pain. 252, 253 Patients should be encouraged to stay adequately hydrated and maintain activity (gentle exercise) as tolerated/feasible. 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 analgesics 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 PEG) may be helpful. Opioid rotation to transdermal fentanyl, buprenorphine, or methadone may be considered. These medications may have less risk of constipation. Enema with sodium phosphate, saline, or tap water may be helpful as it NCCN Guidelines Version 1.2025 Adult Cancer Pain MS-24 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 (PAMORAs) that work on receptors in the GI system, such as oral methylnaltrexone, [254] [255] [256] [257] [258] [259] naloxegol, 260 or naldemedine, 261 can be used as a rescue when constipation is clearly related to opioid therapy 262 (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 non-cancer pain, including those with chronic pain related to prior cancer or its treatment). Other second-line agents may be considered, including lubiprostone which is FDA-approved for opioid-induced constipation in adults with non-cancer pain including those with chronic pain related to prior cancer or its treatment. 263, 264 These agents should not be used in patients with known or suspected mechanical bowel obstruction, recent bowel surgery, transmural bowel metastases, or other processes affecting integrity of the GI lumen due to the potential increased risk of perforation. 265 Guidelines from the American Gastroenterological Association Institute for the medical management of opioid-induced constipation may be referenced for more information and recommendations on use of these agents. 266 uraxial 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, bowel obstruction) 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, olanzapine, or mirtazapine may also be considered for management of nausea. Olanzapine may be especially helpful for patients with bowel obstruction. 267, 268 Corticosteroids, such as dexamethasone, 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. 269 nausea persists for > 1 week, the cause of nausea needs to be reassessed and opioid rotation must be considered. 270 If opioid rotation and the above measures have been tried and nausea still persists, neuraxial analgesics, neuroablative techniques, and other interventions could be performed to potentially reduce the opioid dose. Dronabinol, a cannabinoid that has been FDA-approved for chemotherapy-induced nausea and vomiting, may also be considered in this situation. 271, 272 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 NCCN Guidelines Version 1.2025 Adult Cancer Pain MS-25 cancer-or cancer treatment-related symptoms. 103, 104 While medical cannabis has been legalized in many states, it has not been FDA-approved. 104 Education on state and federal regulations for medical cannabis should be provided (see Adjuvant Analgesics and Cannabinoids and Medical Cannabis 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, 273 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 (non-sedating), 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. 5] [276] [277] 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. 278 Quetiapine may be useful, especially in patients with Parkinson's syndrome. 279 Patients taking opioids may be screened for driving impairment, if indicated. Driving fitness screens are often performed through occupational therapy.

Sedation

It is critical to recognize the difference between cancer-related fatigue and opioid-induced sedation, as some techniques to manage sedation may not work for fatigue. The Pasero Opioid-induced Sedation Scale (POSS) has been validated and is recommended for monitoring opioid-induced sedation, particularly for inpatient care and when increasing the dose of opioids. 280, 281 For more information on managing cancer-related fatigue, see the NCCN Guidelines for Cancer-Related Fatigue. Sedation may hinder the achievement of dose titration of opioids to levels that provide adequate analgesia. 57 If opioid-induced sedation develops, 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 typically 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) due to an increased risk for sedation and respiratory depression. The FDA has issued a black box warning about possible serious effects from this combination, including slowed or difficult breathing and death.

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 to respiratory depression and that hypercarbia occurs before hypoxia. Initial steps that may be taken when there is a concern about respiratory depression include reducing the opioid dose, increasing the interval of opioid administration, confirming that the patient does not have any forgotten transdermal opioid patches, and providing close monitoring. If the patient is medically stable, noninvasive respiratory support may be considered and/or additional doses of opioid analgesic may be temporarily halted until the patient's respiratory status improves.

In cases where the patient is unstable or response to the above interventions is inadequate, naloxone remains a useful antidote for the reversal of opioid-induced respiratory and CNS depression. However, naloxone should be administered with caution so as not to precipitate acute opioid withdrawal syndrome in the patient who is opioid-tolerant. Abrupt reversal of opioid depression in patients who are opioid-tolerant 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. 283 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 of patients receiving opioid analgesics to administer in the event of respiratory depression and sedation. While there are no RCTs, the results of a nonrandomized intervention study showed that patients receiving long-term opioid analgesia who were co-prescribed naloxone had fewer opioid-related emergency department visits compared to those who were not prescribed naloxone. 284 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. Caregivers should be instructed to call emergency services (911) if naloxone is administered. Naloxone may be available without a prescription in some localities.

Opioid Rotation

No single opioid is optimal for all patients. 285 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. 234, 286, 287 A post hoc analysis of 498 patients from a randomized phase IV clinical trial found that the opioid was switched in 79 patients, with 51.45% of switches resulting in better pain control and 43.5% resulting in better control of opioid side effects. 288 0] [291] [292] [293] 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, Initiation, Titration, Maintenance, and Safety in the algorithm.

Opioids and Risk Evaluation and Mitigation Strategy

While opioids are the principal analgesics for management of moderate to severe pain in the context of a cancer diagnosis, they pose risks to both individual patients and larger communities. The misuse of opioids is an increasing concern. In 2022, there were 107,941 drug overdose deaths in the United States, including 81,806 deaths due to opioid overdose. 294, 295 rug poisoning remains the number one cause of injury-related death in NCCN Guidelines Version 1.2025 Adult Cancer Pain MS-27 the United States. 296 While it is important to ensure that opioids continue to be prescribed for patients for whom they are appropriate, it is also essential to ensure that these drugs are prescribed carefully and are appropriately managed, especially during prolonged usage. To reduce the risk of substance use disorders, misuse, overdose, and death, the FDA has established Risk Evaluation and Mitigation Strategy (REMS) programs for opioid products. 297 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.

• Educating each patient on safe use, storage, and disposal of opioids.

• Routinely monitoring patients for opioid misuse or diversion.

On September 18, 2018, the FDA approved the Opioid Analgesic REMS program, which covers all opioid analgesics intended for use in an outpatient setting. 298 This program requires that training be made available to all health care providers who are involved in the comprehensive care of patients with pain (eg, nurses, pharmacists) and requires that education cover broader information about pain management, including non-opioid analgesics and non-pharmacologic interventions. 299 The complete list of currently approved REMS programs is available on the FDA website. 300 l 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 or diversion. Various screening tools have been described for this purpose, but have not yet been evaluated in patients with cancer. 45 One exception is the ORT, the use of which was evaluated in a retrospective chart review of 114 patients with cancer. 301 ore research is warranted to determine the best practice for screening methods. If signs of aberrant drug use are observed, patient counseling, UDT, and limiting or restricting use accordingly is strongly encouraged. However, UDT results can be challenging to interpret and are susceptible to false positives and negatives; therefore, unexpected results should be followed up with confirmatory testing and/or input from a certified laboratory professional or toxicologist. 230 e Panel recommends that clinicians utilize state PDMPs. The National Association of State Controlled Substances Authorities (NASCA) maintains a database of state PMP contacts (see NASCA's website). Written agreements or guidelines may help to clarify expectations and parameters for safe use of opioid analgesics. While 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. Nonopioid analgesics (such as an NSAIDs), 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 improve patient outcomes. 57

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. 302, 303 CCN Guidelines Version 1.2025 Adult Cancer Pain

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Adjuvant analgesics are particularly important in treating neuropathic pain. 90, 91 The most common adjuvant analgesics used for treating neuropathic cancer pain include anticonvulsants, antidepressants, and topical treatments. See Adjuvant Analgesics 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.

5] [306] Several RCTs have shown that anticonvulsants (pregabalin or gabapentin) provided relief of neuropathic cancer-related pain. 100, 307, 308 ikewise, 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, 309 although another concluded that combining opioid analgesia with gabapentinoids did not provide significantly improved pain relief (data on amitriptyline, fluvoxamine, and phenytoin were inconclusive). 310 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. [313]

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. 5] [316] Topical diclofenac, including gel or patch, may provide relief for pain due to bone metastases with minimal system effects. 314 though bone-modifying agents such as bisphosphonates and receptor activator of nuclear factor-kappa-B ligand (RANKL) 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) 317- 321 and denosumab (a RANKL inhibitor) 319, 322 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, 319, 322, 323 although evidence is insufficient to recommend one of these agents over the others. 324 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. Surgical and radiation treatment for bone metastases is performed to relieve local bone pain, provide stabilization, and prevent impending fracture or spinal cord compression. 325 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 and/or an interventional therapist is recommended to determine optimal management strategy for vertebral augmentation.

Ablative strategies such as image-guided ablation may also be performed to reduce pain and prevent SREs. [335]

Management of Pain from Mucositis

Certain treatments for cancer-including systemic therapy, head and neck radiation, or hematopoietic cell transplant-can cause pain in the mouth, pharynx, and esophagus. 336 Resources and guidelines from the Oncology Nursing Society (ONS), 337 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO), 338 and European Society for Medical Oncology (ESMO) 339 detail strategies for prevention and management of oral and GI mucositis.

To prevent oral mucositis, cryotherapy may be performed by having the patient suck on ice chips or hold ice water in their mouth 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. 340, 341 Gabapentin may be used in combination with opioid or non-opioid analgesics for treatment of mucositis, although studies on the effectiveness of this approach have reported mixed results. 99, 342 al care protocols, consisting of good oral hygiene and prophylactic mouth rinses, may be used for prevention of mucositis. 343 Prophylactic mouth rinses (also called "magic mouthwash") compositions vary significantly, including ingredients such as antibiotics, antihistamines, antifungals, corticosteroids, and antacids. 344, 345 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. 336 The NSAID benzydamine also has some data supporting its use in an oral rinse for the prevention and treatment of mucositis. 346, 347 Local anesthetics (eg, lidocaine) may be used to treat mucositis either as a component of a mouth rinse or separately, in a liquid or gel formulation.

Pharmacogenetic Considerations

Pharmacogenetics can be defined as the study of how genetic differences may determine drug metabolism, and therefore response to analgesics. On the other hand, pharmacogenomics generally refers to a broader understanding of how all the genes in the genome relate to pain perception and response to analgesic drugs. There is considerable overlap in these terms, however, and they are often used interchangeably. 348 For the purposes of this Guideline, the term pharmacogenetics will be used as it is referring to detection of specific allelic variants, rather than the entire genome. This terminology is in agreement with that which is used in the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines. 349, 350 CCN Guidelines Version 1.2025 Adult Cancer Pain

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Several classes of analgesic drugs have pharmacogenetic implications that may lead to little or no analgesic response or significant adverse effects. Notable among these are opioids, 176 TCAs, 351, 352 and NSAIDs, 353 which are all metabolized by the CYP450s, a family of enzymes that represent the major system for oxidative metabolism of drugs. In humans, there are at least 57 documented CYP genes across 18 different families and 44 subfamilies. CYP families 1-3 are most relevant to the pharmacogenetics of drug metabolism. 354 CYP enzymes are named with the letters "CYP" followed by a numeral designating the family, then a letter designating the sub-family, and finally another numeral that represents the individual gene or isoform. Evidence also supports the roles of OPRM1 (mu receptor) and Catechol-O-methyltransferase (COMT) in response to opioids, although current implications for clinical practice are unclear. 176 e FDA has published a table of pharmacogenetic associations that it believes have sufficient evidence to suggest that subgroups of patients with certain genetic variants have altered drug metabolism and/or therapeutic effects. 355 Of note for this guideline, codeine (CYP2D6), tramadol (CYP2D6), amitriptyline (CYP2D6), doxepin (CYP2D6, CYP2C19), celecoxib (CYP2C9), and meloxicam (CYP2C9) are included on this list. See Table 1 for potential drug-drug interactions of commonly prescribed medications and Table 2 for a more complete list of CYP450 opioid metabolic pathways and related drug-to-drug interactions. FDA-approved pharmacogenetic tests for CYP2D6, CYP2C19, and CYP2C9 are currently available. However, insurance reimbursement, availability of pharmacogenetic tests, and other implementation barriers may limit their use in clinical practice. 356, 357 See Principles of Pharmacogenetics in the algorithm for recommendations on how to adjust drug dosages or selection based on the results of specific pharmacogenetic tests.

The NCCN Panel recommends that pharmacogenetic testing may be considered either prior to initiation of therapy or when concerns of toxicity or lack of analgesic response arise during analgesic treatment. Consultation with a clinical pharmacist or clinical pharmacogenomics/pharmacogenetics specialist may be helpful in the interpretation of pharmacogenetic test results and to aid in drug selection and/or dose adjustments, when necessary.

Specialty Consultations

Continued pain assessments should be obtained and documented in the medical record to ensure that the patient's pain remains well-managed and goals of treatment are achieved. Specialty consultations can be helpful in providing interventions to assist with difficult cancer pain problems. The major indication for referral to a specialty service provider is if the pain is likely to be relieved or will help patients become functional in their daily activities. These modalities are delivered by a specialty service provider, and pain management is accomplished by establishing individualized goals and then providing specific treatment and education for patients. The specialties include physical/occupational therapy; integrative medicine; mental health support services (including psychiatric consultation, psychology consultation, and/or substance use disorders consultation, as needed); pain and palliative care services; depression/distress consultation; spiritual care consultation; or social work services. Consultation with a specialist in the treatment of substance use disorders may be helpful for managing aberrant drug behavior in patients with a history of or risk factors for misuse of pain medication.

Non-Pharmacologic 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 NCCN Guidelines Version 1.2025 Adult Cancer Pain MS-31 inclusive of non-pharmacologic interventions. 9] [360] 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. ASCO has published a guideline on Integrative Medicine for Pain Management in Oncology, which provides evidence-based recommendations to health care providers on integrative approaches to managing pain in patients with cancer. 361

Physical Interventions

Cognitive-Behavioral Interventions

Cognitive interventions are aimed at enhancing a sense of control over the pain or underlying disease. 1] [372] [373] [374] [375] [376] Patient-based educational interventions have a significant impact in providing pain relief. 377 Skills training helps modify the patient's experience of pain and helps patients acquire techniques of pain management such as deep muscle relaxation. 378 Patients who may benefit from skills training may be referred to a licensed mental health professional trained in CBT, hypnosis, biofeedback, or MBSR. 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. 379, 380 Psychosocial support can greatly enhance patients' sense of control as well as greatly reduce the family/caregivers' feeling of helplessness. 374 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. 381

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 helpful in relieving or coping with pain. Involvement of spiritual care providers from a range of culturally appropriate spiritual backgrounds is essential. 382 Spiritual needs should be routinely assessed and spiritual care should be incorporated as a component of comprehensive pain management.

Nutritional Interventions

Consultation with a nutritional care provider experienced in nutritional counseling of patients with cancer may be helpful in providing dietary recommendations to help patients maintain a healthy body weight and avoid malnutrition. Some studies have reported malnutrition in approximately 30% to 40% of patients with cancer 383, 384 and malnutrition can increase treatment toxicities, diminish quality of life, and increase cancer mortality. A nutritional care provider can also help to assess and educate on herbal, botanical, and dietary supplements a patient may be taking and their potential impact on treatment effectiveness and side effects.

Interventional Strategies

Some patients experience inadequate pain management despite pharmacologic therapy or may not tolerate an opioid titration program NCCN Guidelines Version 1.2025 Adult Cancer Pain MS-32 because of side effects. Some patients may prefer interventional therapies instead of a chronic medication regimen. Interventional techniques have been demonstrated, in some cases, to eliminate or significantly reduce the level of pain, and/or may allow a significant decrease in systemic analgesics. 385 [388] [389] [390] [391] 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 abdominal pain with celiac plexus block, lower abdominal pain with superior hypogastric plexus block, chest pain with intercostal nerve block, 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 is generally associated with a reduction in adverse effects. 392, 393 gional analgesics techniques potentially allow for targeted delivery of local anesthetics when pain control is required for specific (limited) areas of pain which can be addressed by neural blockade of appropriate peripheral nerves or nerve plexus. 5] [396] [397] [398] [399] Nerve blockade techniques may be especially important in patients with intolerable sedation, confusion, constipation, and/or inadequate pain control from systemic analgesics. Percutaneous catheters with external infusion pumps may be used for prolonged administration (days to a few weeks) for selected peripheral nerve/regional plexus blocks as well as epidural/intrathecal analgesics administration. For clinical settings requiring longer-term administration of epidural/intrathecal analgesics, implanted spinal pump systems are typically used to minimize the concern of catheter migration (displacement) and the risk of infection.

Percutaneous vertebral augmentation and/or cementoplasty 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. 1] [402] [403] [404] [405] Ablation techniques may also be helpful for pain management in patients who receive inadequate relief from pharmacologic therapy. 7] [408] [409] [410] [411] [412] [413] [414] [415] Non-ionizing thermal ablative techniques may serve as an alternative and/or adjunct to radiation therapy or be offered in patients who refuse or cannot receive radiation therapy. Early data suggest a synergistic effect with radiation therapy and these different treatment modalities may prove to be complementary. 416, 417 imilarly, vertebral augmentation/cementoplasty provides pain relief with the additional benefit of improved stabilization, which may prevent or halt pathologic fracture. 418 urodestructive 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). 7] [328] [329] [330] [331] [332] *Denotes moderate inhibitors ( > 2 to < 5-fold increase in exposure, or 50% to 80% decrease in clearance of substrate).

β Tapentadol is not extensively metabolized via CYP450 enzymes; therefore, clinically relevant interactions mediated by this metabolic pathway are unlikely to occur.

Ω Denotes strong inducer ( > 80% reduction in AUC of substrate).

||INITIAL DOSE (PAIN-G) l|SUBSEQUENT DOSE l| |---|---|---|

||• Opioid-naïve patients f||

||Dose 5-15 mg||

||PO short-acting||

||morphine sulfate or||

|PO analgesics -IR (|equivalent • Opioid-tolerant patients f Administer PO||

|Severe Pain/ Pain Crisis (Pain Intensity Rating|opioid dose equivalent to 10%-20% of total opioid taken in the previous 24 h||

|[PAIN-A])|||

|or|||

|As indicated|||

|for|||

|uncontrolled|||

|pain (patient|||

|goals not|||

|met)|||

|• Cognitive Modalities| |---|

|Cognitive behavioral therapy (CBT), cognitive restructuring|

|Mindfulness-based stress reduction (MBSR)|

|Imagery|

|Hypnosis|

|Biofeedback|

|Acceptance-based training|

|Distraction training|

|Relaxation training|

|Active coping training|

|Graded task assignments,|

|Table of Contents| |---|

|Discussion|

|Cardiac Toxicities •|

|PAIN-E 2 OF 2|

||Table of Contents| |---|---|

||Discussion|

|OPIOID PRINCIPLES, PRESCRIBING, INITIATION, TITRATION, MAINTENANCE, AND SAFETY||

|• General Principles|PAIN-G|

||PAIN-G|

|NCCN Guidelines Index| |---|

|Table of Contents|

|Response to cancer-directed treatment (including extended|Unstable or clinical cancer-related disease progression| |---|---|

|stable disease)||

|Completion of acute pain event|End-of-life or hospice eligible|

|Minimal utilization of breakthrough opioid|Patient resistance to dose changes|

|Response to non-opioid and/or non-pharmacologic analgesics Failure of alternative analgesics|Response to non-opioid and/or non-pharmacologic analgesics Failure of alternative analgesics|

|Patient preference||

|Aberrant behavior||

|Intolerable side effects||

|Codeine|Morphine (active), norcodeine, hydromorphone, norhydrocodone,|1-4|Morphine is the active/major metabolite of codeine metabolism| |---|---|---|---|

||hydrocodone, dihydrocodeine, codeine-6-glucuronide|||

||(inactive), hydromorphone, codeine**|||

|(Diacetylmorphine)|codeine**||hydrolyzed to morphine. Due to the rapid elimination of 6-MAM, morphine is|

||||commonly reported|

|Hydrocodone|Hydromorphone (active), dihydrocodeine, norhydrocodone|1-4||

|Hydromorphone|Hydromorphone-3-glucuronide|1-4||

|Oxymorphone|Noroxymorphone, oxymorphone 3-glucuronide, 6-hydroxy|1-4||

||oxymorphone|||

|Fentanyl|Norfentanyl|1-3||

||||and dextrorphan (metabolite of dextromethorphan); additional confirmatory|

||||testing may be needed|

|Methadone|EDDP (2-ethylene-1,5-dimethyl-3-3-diphenylpyrrolidine)|1-14||

|Meperidine|Normeperidine, meperidinic and normeperidinic acid|1-2||

|Tapentadol|Tapentadol-o-sulfate, nortapentadol (N-desmethyltapentadol)|1-3||

||hydroxyl-tapentadol|||

|Tramadol|O-desmethyl tramadol (active), N-desmethyl tramadol|1-4||

|Green (naturally occurring opioids, including diacetylmorphine), Yellow (semi-synthetic opioids), Blue (synthetic opioids)| |---|

|Note: Not all metabolites listed above may be reported, but if no metabolites or high concentrations of parent drug alone are found, this may indicate tampering or spiking|

|(adding drug to urine sample). Immunoassay, or point-of-care testing, cannot identify metabolites or detect spiking. Patients taking opioids as needed may have negative|

|results based on infrequent patterns of use (outside of the detection window) or recent drug initiation.|

|Alcohol (ethanol)|< 1| |---|---|

|Amphetamine/Dextroamphetamine|1-5|

|Barbiturates|1-10|

|Benzodiazepines|1-10|

|Cathinones (Bath Salts)|1-5|

|Cocaine|1-5|

|PAIN-H 2 OF 3|

|Buprenorphine CYP3A4|Carbamazepine Ω|Rifampin Ω|Adagrasib Ceritinib|Telaprevir** Nelfinavir**|| |---|---|---|---|---|---|

|Oxycodone|CYP2D6, CYP3A4|||Ritonavir** Saquinavir**|Tucatinib|

|Tapentadol|CYP2C9, CYP2C19 CYP2D6 β|CYP 2D6 Inducers 420|CYP 2D6 Inhibitors 420|||

Discussion

1.2025, 03/12/25 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

The PO conversion ratio of methadone varies. PRACTITIONERS ARE ADVISED TO CONSULT WITH A PAIN OR PALLIATIVE CARE SPECIALIST IF THEY ARE UNFAMILIAR WITH METHADONE PRESCRIBING (see special notes regarding oral methadone, PAIN-G, 17 of 21).

45 8,229It examines concurrent misuse; in contrast, SOAPP-R, ORT, or CAGE-AID 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 misuse of prescribed analgesics include the following patient characteristics:45

, 420, 423 CYP

be useful for painful chemotherapy-induced peripheral neuropathies, neuralgias, and complex regional pain syndrome. 419 terventional strategies listed above are not appropriate if patients are unwilling or in patients with infections, coagulopathy, or with very short life expectancies. Also, the 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] , anti-angiogenesis agents [bevacizumab]). If this occurs, the patient may have to be off the medication for an appropriate amount of time prior to 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, utilizes both pharmacologic and nonpharmacologic interventions, and requires ongoing re-evaluation 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.

References

引用 / 出处

NCCN临床实践指南：成人癌痛（2025.V1）. 2025.