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NCCN Overview Pain, defined as “a sensory and emotional experience Adult Cancer Pain associated with actual or potential tissue damage or described in terms of such damage,”1 is one of the Clinical Practice Guidelines in Oncology most common symptoms associated with cancer. Robert Swarm, MD; Amy Pickar Abernethy, MD; Cancer pain or cancer-related pain is distinct from Doralina L. Anghelescu, MD; Costantino Benedetti, MD; pain experienced by patients without malignancies. Craig D. Blinderman, MD, MA; Barry Boston, MD; Pain occurs in approximately one quarter of patients Charles Cleeland, PhD; Nessa Coyle, PhD, NP; with newly diagnosed malignancies, one third of pa- Oscar A. deLeon-Casasola, MD; June G. Eilers, PhD, APRN; Betty Ferrell, RN, PhD; Nora A. Janjan, MD, MPSA, MBA; tients undergoing treatment, and three quarters of 2–4 Sloan Beth Karver, MD; Michael H. Levy, MD, PhD; patients with advanced disease, and is one of the Maureen Lynch, MS, APRN; Natalie Moryl, MD; symptoms patients fear most. Unrelieved pain denies Barbara A. Murphy, MD; Suzanne A. Nesbit, PharmD, BCPS; patients comfort and greatly affects their activities, Linda Oakes, RN, MSN; Eugenie A. Obbens, MD, PhD; motivation, interactions with family and friends, and Judith A. Paice, PhD, RN; Michael W. Rabow, MD; Karen L. Syrjala, PhD; Susan Urba, MD; and overall quality of life. Sharon M. Weinstein, MD The importance of relieving pain and availabili-

NCCN Clinical Practice Guidelines in Please Note Oncology on Adult Cancer Pain The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) are a statement of consensus of the authors regarding their views of currently accepted approach- Key Words es to treatment. Any clinician seeking to apply or consult the NCCN Clinical Practice Guidelines, NCCN Guidelines, cancer, NCCN Guidelines™ is expected to use independent medical pain, malignancy, pain assessment, pain intensity rating (JNCCN 2010;8:1046–1086) judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National NCCN Categories of Evidence and Consensus Comprehensive Cancer Network® (NCCN®) makes no Category 1: The recommendation is based on high-level representation or warranties of any kind regarding their con- evidence (e.g., randomized controlled trials) and there is tent, use, or application and disclaims any responsibility for uniform NCCN consensus. their applications or use in any way. Category 2A: The recommendation is based on lower- © National Comprehensive Cancer Network, Inc. level evidence and there is uniform NCCN consensus. 2010, All rights reserved. The NCCN Guidelines and the Category 2B: The recommendation is based on lower- level evidence and there is nonuniform NCCN consensus illustrations herein may not be reproduced in any form (but no major disagreement). without the express written permission of NCCN. Category 3: The recommendation is based on any level of Disclosures for the NCCN Guidelines evidence but reflects major disagreement. Panel for Adult Cancer Pain

All recommendations are category 2A unless otherwise At the beginning of each NCCN Guidelines panel meeting, panel noted. members disclosed any financial support they have received from industry. Through 2008, this information was published in an Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical aggregate statement in JNCCN and online. Furthering NCCN’s trials is especially encouraged. commitment to public transparency, this disclosure process has now been expanded by listing all potential conflicts of interest respective to each individual expert panel member.

Individual disclosures for the NCCN Guidelines on Adult Cancer Pain panel members can be found on page 1086. (The most recent version of these guidelines and accompanying disclosures, including levels of compensation, are available on the NCCN Web site at www.NCCN.org.)

These guidelines are also available on the Internet. For the latest update, please visit www.NCCN.org.

Journal of the National Comprehensive Cancer Network Adult Cancer Pain ty of effective therapies make it imperative that phy- algorithm has served as an excellent teaching tool, the sicians and nurses caring for these patients be adept management of cancer pain is considerably more com- at the assessment and treatment of cancer pain.5–7 plex than this 3-tiered “cancer pain ladder” suggests. This requires familiarity with the pathogenesis of This guideline is unique in several important cancer pain; pain assessment techniques; common ways. First, it contains several required components: barriers to the delivery of appropriate analgesia; and • Pain intensity must be quantified by the patient (whenever possible), because the algorithm bas- pertinent pharmacologic, anesthetic, neurosurgical, es therapeutic decisions on a numerical value as- and behavioral approaches to the treatment of can- signed to the severity of the pain. cer pain. • A formal comprehensive pain assessment must The most widely accepted algorithm for the treat- be performed. 8,9 ment of cancer pain was developed by the WHO. • Reassessment of pain intensity must be per- It suggests that patients with pain be started on acet- formed at specified intervals to ensure that the aminophen or a nonsteroidal anti-inflammatory drug therapy selected is having the desired effect. (NSAID). If this is not sufficient, patients should be • Psychosocial support must be available. escalated to a weak opioid, such as codeine, and then • Specific educational material must be provided to a strong opioid, such as morphine. Although this to the patient. Text continues on p. 1077

NCCN Adult Cancer Pain Panel Members Natalie Moryl, MDÞ£ Memorial Sloan-Kettering Cancer Center *Robert Swarm, MD/Chairϕ£ Barbara A. Murphy, MD£† Siteman Cancer Center at Barnes-Jewish Hospital and Vanderbilt-Ingram Cancer Center Washington University School of Medicine Amy Pickar Abernethy, MD†£ Suzanne A. Nesbit, PharmD, BCPS∑ Duke Comprehensive Cancer Center The Sidney Kimmel Comprehensive Cancer Center at Doralina L. Anghelescu, MDϕ Johns Hopkins St. Jude Children’s Research Hospital/ Linda Oakes, RN, MSN# University of Tennessee Cancer Institute St. Jude Children’s Research Hospital/ Costantino Benedetti, MDϕ£ University of Tennessee Cancer Institute The Ohio State University Comprehensive Cancer Center - Eugenie A. Obbens, MD, PhD£Ψ James Cancer Hospital and Solove Research Institute Memorial Sloan-Kettering Cancer Center Craig D. Blinderman, MD, MAÞ£ Judith A. Paice, PhD, RN£# Massachusetts General Hospital Cancer Center Robert H. Lurie Comprehensive Cancer Center of Barry Boston, MD£† Northwestern University St. Jude Children’s Research Hospital/ Michael W. Rabow, MD£ University of Tennessee Cancer Institute UCSF Helen Diller Family Comprehensive Cancer Center Charles Cleeland, PhDθ Karen L. Syrjala, PhDθ The University of Texas MD Anderson Cancer Center Fred Hutchinson Cancer Research Center/ Nessa Coyle, PhD, NP£# Seattle Cancer Care Alliance Memorial Sloan-Kettering Cancer Center Susan Urba, MD£† Oscar A. deLeon-Casasola, MDϕ£ University of Michigan Comprehensive Cancer Center Roswell Park Cancer Institute Sharon M. Weinstein, MD£Ψ June G. Eilers, PhD, APRN# Huntsman Cancer Institute at the University of Utah UNMC Eppley Cancer Center at The Nebraska Medical Center KEY: Betty Ferrell, RN, PhD£# City of Hope Comprehensive Cancer Center Nora A. Janjan, MD, MPSA, MBA§ *Writing Committee Member The University of Texas MD Anderson Cancer Center Sloan Beth Karver, MD£ Specialties: ϕAnesthesiology; £Supportive Care, Including H. Lee Moffitt Cancer Center & Research Institute Palliative, Pain Management, Pastoral Care, and Oncology Michael H. Levy, MD, PhD£† Social Work; †Medical Oncology; ÞInternal Medicine; Fox Chase Cancer Center θPsychiatry, Psychology, Including Health Behavior; #Nursing; Maureen Lynch, MS, APRN£# §Radiotherapy/Radiation Oncology; ∑Pharmacology; Dana-Farber/Brigham and Women’s Cancer Center ΨNeurology/Neuro-Oncology

Adult Cancer Pain Version 1:2010

UNIVERSAL SCREENING ASSESSMENT MANAGEMENT OF PAIN

Opioid-naïve See Management of Pain in patientsa Opioid-Naïve Patients (page 1050)

See Management of Pain in Opioid-Tolerant Patients, pain Pain not related to an Opioid- rating 4 (page 1052) tolerant Quantify pain intensity and Comprehensive pain assessment oncologic emergency or patientsb characterize quality (see pages 1058 and 1059) in order Pain rating 0-3 (see page 1053) ➤ See Pain Intensity Rating (pages to identify pain 1055 and 1056) ➤ Etiology If pain Ask patient to describe characteristics ➤ Pathophysiology present of pain (i.e., aching, burning, etc.) ➤ Specific cancer pain syndrome Severe uncontrolled pain is a medical (see page 1060) ➤ Determine patient goals for emergency and should be responded Anticipated comfort, function to promptly painful events See Procedure-Related Pain and Anxiety (page 1057) and procedures

Screen for pain

Pain related to an oncologic emergency: Rescreen at each If no pain Bone fracture or impending fracture of weight-bearing bone subsequent visit Analgesics as specified by above Brain metastases pathway in addition to specific treatment Epidural metastases for oncologic emergency (e.g., surgery, Leptomeningeal metastases steroids, RT, antibiotics) Pain related to infection Obstructed or perforated viscus (acute abdomen)

Anticipated painful events and See Procedure-Related Pain and Anxiety (page 1057) procedures

aOpioid-naïve patients include those who are not chronically receiving opioid analgesics on a daily basis. bOpioid-tolerant patients include those who are chronically receiving opioid analgesics on a daily basis.

Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are category 2A unless otherwise indicated.

Adult Cancer Pain Version 1:2010

UNIVERSAL SCREENING ASSESSMENT MANAGEMENT OF PAIN

Opioid-naïve See Management of Pain in patientsa Opioid-Naïve Patients (page 1050)

Screen for pain

Anticipated painful events and See Procedure-Related Pain and Anxiety (page 1057) procedures

Version 1.2010, 05-07-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Adult Cancer Pain Version 1:2010

PAIN INTENSITY MANAGEMENT OF PAIN IN OPIOID-NAÏVE PATIENTSa INITIATING SHORT-ACTING OPIOIDS IN OPIOID-NAPÏVE ATIENTSa See Pain Intensity Monitor for acute and chronic adverse effects. (See Management of Opioid Side Effects on pages 1068 and 1069.) Rating (pages 1055 and 1056) Opioid-naïve Initial DoseSubsequent Dose Recognize and treat analgesic side effects (see pages 1068 and 1069) patientsa Consider adding coanalgesics (see page 1070) for specific pain syndrome (see page 1060) ForALL levels Provide psychosocial support (see page 1071) of pain Pain score After 2-3 cycles, Provide patient and family education (see page 1072) Increase dose unchanged consider IV Optimize nonpharmacologic interventions (see page 1073) by 50%-100% or increased titration and/or see page 1053 for Dose 5-15 mg subsequent oral short-acting Reassess management See management for all levels of pain, above Pain score AND Oral (peak morphine sulfate efficacy and Repeat same and treatment decreased Rapidly titrate short-acting opioid, effect 60 min) or equivalent side effects dose Severe to 4-6 see facing page for initiating short-acting opioids and (see pages at 60 min Pain 7-10 see pages 1061-1067 for additional details of opioid principles, 1061-1067) Continue at See Subsequent prescribing, titration, and maintenance current Pain ➤ Begin bowel regimen (see pages 1068 and 1069) Pain score effective Management decreased and Treatment in Pain 4 dose as to 0-3 Opioid-Tolerant See Pain Intensity needed over Patients: Mild Rating (pages initial 24 h Pain 0-3 See management for all levels of pain, above 1055 and 1056) (page 1053) AND or Titrate short-acting opioid, Moderate As indicated for see facing page for initiating short-acting opioids and Pain 4-6 uncontrolled pain see pages 1061-1067 for additional details of opioid principles, (patient goals not prescribing, titration, and maintenance met) ➤ Begin bowel regimen (see pages 1068 and 1069) Pain score Increase dose After 2-3 unchanged by 50%-100% cycles, see or increased page 1053 for See management for all levels of pain, above Intravenousa subsequent AND bolus (peak Reevaluate pain at Dose 2-5 mg management Consider nonsteroidal anti-inflammatory drugs effect 15 min) Reassess each contact and as intravenousc Pain score and treatment Mild (NSAIDs) or acetaminophen without opioid if patient is See Ongoing administered by efficacy and Repeat same needed to meet patient morphine sulfate decreased Pain 1-3 not taking analgesics (see page 1074) Care (page 1054) health care side effects dose goals for comfort and or equivalent to 4-6 or provider or at 15 min function (see pages Consider titrating short-acting opioid (see pages 1061-1067) patient-controlled ➤ 1061-1067) Continue at See Subsequent Begin bowel regimen (see pages 1068 and 1069) analgesia current Pain Pain score effective Management and decreased Treatment in dose as to 0-3 Opioid-Tolerant needed over Patients: Mild initial 24 h Pain 0-3 (page 1053)

aOpioid-naïve patients include those whocare not hronically receiving opioid analgesics on a daily basis. aOpioid-naïve patients include those who are not chronically receiving opioid analgesics on a daily basis. cSubcutaneous can be substituted for intravenous; however, subcutaneous route delays onset of effect by up to 30 min.

Adult Cancer Pain Version 1:2010

MANAGEMENT OF PAIN IN OPIOID-TOLERANTPATIENTSb PAIN INTENSITY SUBSEQUENT PAIN MANAGEMENT ANDTREATMENT GOALS OF See Pain Intensity IN OPIOID-TOLERANTPATIENTSb TREATMENT Monitor for acute and chronic adverse effects. (See Management of Opioid Side Effects on pages 1068 and 1069.) Rating (pages 1055 and 1056) Opioid-tolerant patientsb Initial Dose Subsequent Dose

Pain score Increase dose After 2-3 cycles, unchanged by 50%-100% consider IV ForALL pain Provide psychosocial support (see page 1071) or increased titration and/or levels Provide patient and family education (see page 1072) see facing page for Calculate subsequent previous Reassess management 24-h total oral Pain score Oral (peak efficacy and Repeat same and treatment See management for all levels of pain, above requirement decreased effect 60 min) side effects dose AND and administer to 4-6 at 60 min Reevaluate opioid titration (see pages 1061-1067) 10%-20% (see Severe Reevaluate working diagnosis with a comprehensive pain See Ongoing pages 1061-1067) Continue at See Subsequent assessment (see pages 1058 and 1059) Achieved Pain 7-10 Care (page 1054) current Pain Consider specific pain syndrome problems (see page 1060) Pain score effective Management and Consider pain specialty consultation (see page 1075) decreased Treatment in Pain ≥ 4 dose as Reevaluate coanalgesics as indicated (see page 1070) to 0-3 Opioid-Tolerant See Pain Intensity needed over Patients: Mild Rating (pages initial 24 h Pain 0-3 (facing page) 1055 and 1056) Reevaluate See management for all levels of pain, above patient’s goals of or AND As indicated for comfort and Moderate Continue opioid titration (see pages 1061-1067) uncontrolled pain function at each Pain 4-6 Consider specific pain syndrome problems (see page 1060) (patient goals not Consider pain specialty consultation (see page 1075) contact met) Continue coanalgesic titration (see page 1070) See Universal Pain score Increase dose Screening and unchanged by 50%-100% After 2-3 Assessment or increased cycles, see (pages 1048 and 1049) Calculate facing page for Not achieved Intravenousa See management for all levels of pain, above previous subsequent AND Consider bolus (peak Mild 24 h total management Reassess and modify regimen to minimize side effects Interventional effect 15 min) Reassess Pain 0-3 requirement, Pain score and treatment (see pages 1061-1067, and 1068 and 1069) Strategies administered by efficacy and Repeat same convert to total decreased Coanalgesics as needed (see page 1070) (page 1076) health care side effects dose IV equivalent to 4-6 provider or at 15 min and administer patient-controlled 10%-20% (see Continue at See Subsequent analgesia pages 1061-1067) current Pain Pain score effective Management and decreased Treatment in dose as to 0-3 Opioid-Tolerant needed over Patients: Mild initial 24 h Pain 0-3 (facing page)

bOpioid-tolerant patients include those who are chronically receiving opioid analgesics on a daily basis. c Subcutaneous can be substituted for intravenous; however, subcutaneous route delays onset of effect by up to 30 min. bOpioid-tolerant patients include those whocare hronically receiving opioid analgesics on a daily basis.

Adult Cancer Pain Version 1:2010

ONGOING CARE GOALS OF TREATMENT PAIN INTENSITYRATING (1 of 2)

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, and “worst" and "usual" pain in the past 24 hours. For comprehensive assessment, also Clinician responsibilities include "worst pain in past week", "pain at rest", and "pain with movement". See Comprehensive Pain Assessment (pages 1058 and Convert to oral medications (if feasible) including extended- 1059) for more detail. s release agent with rescue doses (Conversion details, see pages 1061-1067) Table 1: Numerical Rating Scale Routine follow-up Continue routine Achieved Assess pain during each outpatient contact or at least follow-up Numerical rating scale: each day for inpatients or more frequently based on: Patient’s condition Institutional standards • Verbal:“What number describes your worst pain in the past 24 hours from 0 (no pain) to 10 (worst pain you can imagine)?” Regulatory requirements Provide written follow-up pain plan, including prescribed Reevaluate • Written:“Circle the number that describes your worst pain in the past 24 hours.” medications (see page 1072) patient’s goals of Ensure adequate access to prescribed medications, comfort and 0 1 2 3 4 5 6 7 8 9 10 especially during transition between sites of care function at each No pain Worst pain you can imagine Instruct the patient on the importance of the following: contact Follow documented pain plan (see page 1072) Maintain clinic appointments See Universal Contact clinician if pain worsens or side effects Categorical scale: Screening and inadequately controlled Assessment (pages 1048 Process realistic goals, revise, and review and 1049) “What is the worst pain you have had in the past 24 hours?” Address system barriers Not achieved Obtain assistance from social services Consider None (0), Mild (1–3), Moderate (4–6), or Severe (7–10) Maintain communication and coordinate care with pain Interventional specialist and relevant providers Strategies (page 1076) On-call/as-needed availability Table 2: The Faces Pain Rating Scale1

Instructions:“These faces show how much something can hurt. This face (point to the left-most face) shows no pain. Each face shows more and more pain (point to each face from left to right) up to this one (point to the right-most face), which shows very much pain. Point to the face that shows how much you hurt (right now).”

Continued on page 1056

1Ware LJ, Epps CD, Herr K, Packard A. Evaluation of the Revised Faces Pain Scale, Verbal Descriptor Scale, Numeric Rating Scale, and Iowa Pain Thermometer in older minority adults. Pain Manag Nurs 2006;7:117-125.

Adult Cancer Pain Version 1:2010

ONGOING CARE GOALS OF TREATMENT PAIN INTENSITYRATING (1 of 2)

Continued on page 1056

Adult Cancer Pain Version 1:2010

PAIN INTENSITY RATING (2 of 2) PROCEDURE-RELATED PAIN and ANXIETY

Pain Assessment in the Nonverbal Patient1 Events that are expected to cause discomfort to the patient, such as diagnostic and therapeutic procedures (e.g., wound care, IV, • The inability of patients to verbally communicate pain intensity because of cognitive or physiologic issues is a major barrier relating arterial line, central line, injection, manipulation, bone marrow aspiration, lumbar puncture, skin biopsy, bone marrow biopsy), and to pain assessment and management.Therefore, the American Society for Pain Management Nursing (www.aspmn.org) has transportation/change in position for patients with a fracture, should merit pretreatment with an analgesic intervention. Additional developed a position statement and clinical practice recommendations that clinicians may find useful in caring for these patients. analgesics and/or local anesthetics should be available immediately for further titration by the caregiver as needed. • In the absence of self-report, observation of behavior is a valid approach to pain assessment with the understanding that behaviors Consistent adequate analgesia for all pain-related procedures and anxiety is critical. Intervention may be multimodal and include one may also indicate another source of distress, such as emotional distress. Potential causes and the context of the behavior must be or more of the following techniques as appropriate. considered when making pain treatment decisions. • Amultifaceted approach is recommended that combines direct observation, family/caregiver input, and evaluation of response to • Local anesthetics such as: pain medicines or nonpharmacologic interventions. Topical local anesthetics creams (containing lidocaine, prilocaine, tetracaine) applied to intact skin with sufficient time for • For patients with advanced dementia, a comprehensive review of currently published tools is available at effectiveness as per package insert http://prc.coh.org/pain_assessment.asp.These tools are in varying stages of development and validation, and include: Physical approaches (ultrasound, cutaneous warming, laser or jet injection) may accelerate the onset of cutaneous anesthesia The Assessment of Discomfort in Dementia Protocol (ADD)2 Ionophoretic devices to provide lidocaine delivery through the skin without needles in 10-15 min Checklist of Nonverbal Pain Indicators (CNPI)3 Subcutaneous administration of lidocaine with a 27-gauge needle The Pain Assessment in Advanced Dementia Scale (PAINAD)4 • Administration of sedatives/analgesics/general anesthesia by trained personnel • For patients who are intubated and/or are unconscious, pain assessment tools have been tested in specific situations, and include: • Additional nonpharmacologic interventions (see page 1073) Behavioral Pain Scale (BPS);5 tested in adults and intensive care Critical-Care Pain Observation Tool (CPOT);6 tested in adults and intensive care Providing information regarding all of these analgesic techniques before the procedure is ideal because it allows patients and their • Clinicians are encouraged to monitor current research regarding new developments in strategies and tools for assessing pain in families the time they may need to assimilate all of the information, ask questions, and master the techniques while reducing patients who have difficulty with self-report. anticipatory anxiety.

Cultural and Linguistic Assessment7,8 • Health care providers should be aware of the impact that cultural and linguistic diversity may have during universal screening and comprehensive pain assessment.

1Herr K, Coyne P, Key T, et al. Pain assessment in the nonverbal patient: position statement with clinical practice recommendations. Pain Manag Nurs 2006;7:44-52. 2Kovach CR, Noonan PE, Griffie J, et al. The assessment of discomfort in dementia protocol. Pain Manag Nurs 2002;3:16-27. 3Feldt KS. Checklist of nonverbal pain indicators. Pain Manag Nurs 2000;1:13-21. 4Lane P, Kuntupis M, MacDonald S, et al.Apain assessment tool for people with advanced Alzheimer's and other progressive dementias. Home Healthc Nurse 2003;21:32-37. 5Payen JF, Bru O, Bosson JL, et al. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med 2001;29:2258-2263. 6Gélinas C, Johnston C, et al. Pain assessment in the critically ill ventilated adult: validation of the Critical-Care Pain Observation Tool and physiologic indicators. Clin J Pain 2007;23:497-505. 7Al-Atiyyat HN,MohammedN.Cultural diversity and cancer pain. J Hosp Palliat Nurs 2009;11:154-164. 8Ezenwa MO, Ameringer S, Ward SE,SerlinRC. Racial and ethnic disparities in painmanagement in theUnitedStates. JNurs Scholarsh 2006;38:225-233.

Adult Cancer Pain Version 1:2010

PAIN INTENSITY RATING (2 of 2) PROCEDURE-RELATED PAIN and ANXIETY

Adult Cancer Pain Version 1:2010

COMPREHENSIVE PAIN ASSESSMENT IMPACT OF PAIN MEASUREMENT1-3

Mark the number that describes how much, in the past [week/24 hours] pain has interfered with your: Patient’s self-report of pain is the standard of care. If the patient is unable to verbally report pain, an alternative method to obtain pain rating and response should be utilized (see page 1056). 1. General activity 012345678910 • Pain Experience • Psychosocial (see page 1071) Does not Completely Location, referral pattern, radiation of pains Patient distress (see NCCN Clinical Practice Guidelines in Interfere Interferes Intensity (see Pain Intensity Rating, on pages 1055 and 1056) Oncology [NCCN Guidelines] on Distress Management*) Past 24 hours and current pain Family and other support 2. Mood At rest and with movement Psychiatric history including current or prior history of 012345678910 Interference with activities substance abuse Does not Completely See Impact of Pain Measurement (page 1059) Risk factors for aberrant use or diversion of pain Interfere Interferes General activity, mood, relationship with others, sleep, medication appetite Patient, environmental, and social factors 3. Walking ability Timing: onset, duration, course, persistent, or intermittent Risk factors for undertreatment of pain 012345678910 Description or quality Pediatric, geriatric, minorities, female, Does not Completely Aching, stabbing, throbbing, pressure, often associated communication barriers, history of substance abuse, Interfere Interferes with somatic pain in skin, muscle, bone neuropathic pain, and cultural factors 4. Normal work (includes both work outside the home and housework) • Gnawing, cramping, aching, sharp, often associated with Medical history 012345678910 visceral pain in organs or viscera Oncologic treatment including current and prior Does not Completely Sharp, tingling, ringing, shooting, often associated with chemotherapy, radiation therapy, and surgery Interfere Interferes neuropathic pain caused by nerve damage Other significant illnesses, conditions Aggravating and alleviating factors Preexisting chronic pain 5. Relations with other people Other current symptoms • Physical examination 012345678910 Current pain management plan, both pharmacologic and non- • Relevant laboratory and imaging studies to evaluate for Does not Completely pharmacologic. If medications are used, determine: disease progression Interfere Interferes What medications, prescription, and/or over the counter? • The end point of the assessment is to establish the“pain How much? diagnosis” and individualized pain treatment plan based on 6. Sleep How often? mutually developed goals. The“pain diagnosis”includes the 012345678910 Current prescriber? etiology and pathophysiology of pain: Does not Completely Response to current therapy Etiology Interfere Interferes Pain relief Cancer Patient adherence to medication plan Cancer therapy (RT, chemotherapy, surgery) or 7. Enjoyment of life Medication side effects such as constipation, sedation, procedures 012345678910 cognitive slowing, nausea, others Coincidental or noncancer Does not Completely Interfere Interferes Prior pain therapies Pathophysiology Reason for use, length of use, response, reasons for Nociceptive discontinuing Neuropathic Special issues relating to pain Meaning and consequences of pain for patient and family Patient and family knowledge and beliefs surrounding pain and pain medications Cultural beliefs toward pain and pain expression Spiritual, religious considerations, and existential suffering Patient goals and expectations regarding pain management

Return to Initial Screening (pages 1048 and 1049)

1Cleeland CS, NakamuraY, Mendoza TR, et al. Dimensions of the impact of cancer pain in a four country sample: new information from multidimensional *To view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org. scaling. Pain 1996;67:267-273. 2Serlin RC, Mendoza TR, NakamuraY, et al. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain 1995;61:277-284. 3To view the complete Brief Pain Inventory assessment tool, visit mdanderson.org/bpi..

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COMPREHENSIVE PAIN ASSESSMENT IMPACT OF PAIN MEASUREMENT1-3

Return to Initial Screening (pages 1048 and 1049)

Adult Cancer Pain Version 1:2010

ADDITIONAL INTERVENTIONS FOR CANCER PAIN SYNDROMES OPIOID PRINCIPLES, PRESCRIBING,TITRATION,AND MAINTENANCE (1 of 7)

In general, cancer pain is treated with opioids as indicated on page 1050; these interventions are meant to complement management. • Pain associated with inflammation: GENERALPRINCIPLES Trial of NSAIDs or glucocorticoids • The appropriate dose is the dose that relieves the patient’s pain throughout the dosing interval without causing unmanageable side effects. • Generally, oral route is most common; however, other routes (IV, subcutaneous, rectal, transdermal, transmucosal, buccal) can be • Nerve compression or inflammation: considered as indicated to maximize patient comfort. For intrathecal route administration, see page 1076. Trial of glucocorticoids • Calculate dosage increase based on total opioid dose (around the clock/scheduled and as needed) taken in the previous 24 h. • Increase both around-the-clock and as needed doses.The rapidity of dose escalation should be related to the severity of the • Bone pain without oncologic emergency: symptoms. See Management of Pain in Opioid-Tolerant Patients (page 1052). NSAIDs and titrate analgesic to effect; see Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Acetaminophen • According to FDA guidelines, switch from preparations of opioid combined with other medications (such as aspirin or acetaminophen) to Prescribing (page 1074) pure opioid preparation if opioid dose required would result in excessive (or inadequate) dosing of the non-opioid component of Local bone pain: consider local radiation therapy or nerve block (e.g., rib pain) combination (see page 1074). Diffuse bone pain: consider trial of bisphosphonates, hormonal therapy or chemotherapy, glucocorticoids, and/or • Steady state is achieved in about 5 half-lives. systemic administration of radioisotopes • If patient is experiencing unmanageable side effects and pain is < 4, consider downward dose titration by approximately 25% and Consider physical medicine evaluation; see Pain Specialty Consultations for Improved Pain Management (page 1075) reevaluate. Patient would require close follow-up to make sure pain did not escalate. For resistant pain: consider referral to a pain specialist and/or the use of interventional strategies (see Interventional • Strategies, on page 1076) Consider opioid rotation if pain inadequately controlled or persistent side effects from current therapy. PRINCIPLES OF MAINTENANCE OPIOIDTHERAPY • Bowel obstruction • For continuous pain, it is appropriate to give pain medication on a regular schedule with supplemental doses for breakthrough pain. Bowel rest, nasogastric suction, glucocorticoids, octreotide • 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. • Neuropathic pain: • Provide rescue doses of short-acting opioids for pain not relieved by extended-release opioids including breakthrough pain or acute Trial of antidepressant: start with low dose and increase every 3-5 d if tolerated or lengthen interval up to 14 d exacerbations of pain, activity or position related pain, or pain at the end of dosing interval: (e.g., nortriptyline, 10-150 mg/d; doxepin, 10-150 mg/d; desipramine, 10-150 mg/d; venlafaxine, 37.5-225 mg/d divided When possible, use the same opioid for short-acting and extended release forms. in 2-3 doses; duloxetine, 30-60 mg/d) Allow rescue doses of short-acting opioids of 10%–20% of 24-h oral dose (mg) every 1 h as needed. Ongoing need for and/or repeated rescue doses may indicate a need for adjustment of regularly scheduled opioid dose. Trial of anticonvulsant: start with low dose and increase every 3-5 d if tolerated or lengthen interval up to 14 d (e.g., Consider transmucosal fentanyl (lozenge, tablets, film) only in opioid tolerant patients for brief episodes of acute exacerbation of gabapentin,100-1200 mg 3 times a day; carbamazepine, 100-400 mg 2 times a day; pregabalin 100-600 mg/d divided pain not attributed to inadequate dosing of around the clock opioid. Data do not support a specific transmucosal fentanyl dose in 2-3 doses, or other anticonvulsants) equianalgesic to other opioids. Initiate transmucosal fentanyl with lowest dose (200-mcg lozenge or 100-mcg buccal tablet or and/or 200-mcg buccal soluble film) and titrate to effect. (See specific transmucosal prescribing information for appropriate dosing Consider topical agents, such as local anesthetics including lidocaine patch intervals.) For resistant pain, consider referral to a pain specialist and/or the use of interventional strategies (see Interventional • Increase dose of extended-release opioid if patient persistently needs doses of as-needed opioids or when dose of around the clock Strategies, on page 1076) opioid fails to relieve pain at peak effect or at end of dose.

• Painful lesions that are likely to respond to antineoplastic therapies: Consider trial of radiation, hormones, or chemotherapy

Continued on page 1062 • For severe refractory pain in the imminently dying: See NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Palliative Care*

*To view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org.

Adult Cancer Pain Version 1:2010

ADDITIONAL INTERVENTIONS FOR CANCER PAIN SYNDROMES OPIOID PRINCIPLES, PRESCRIBING,TITRATION,AND MAINTENANCE (1 of 7)

• Painful lesions that are likely to respond to antineoplastic therapies: Consider trial of radiation, hormones, or chemotherapy

Continued on page 1062 • For severe refractory pain in the imminently dying: See NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Palliative Care*

*To view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org.

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Table 1: Oral and Parenteral Opioid Equivalences and Relative Potency of Drugs Compared with CONVERTOR ROTATE FROM ONE OPIOID TO ANOTHER OPIOID Morphine Based on Single-Dose Studies • To convert or rotate from one opioid to another opioid: Factor Duration of 1. Determine the amount of current opioid(s) taken in a 24-h period that effectively controls pain. Opioid Agonists Parenteral Dose Oral Dose (IV to PO) Action9 2. Calculate the equianalgesic dose of the new opioid. See(Table 1 previous page). Codeine1,2 130 mg 200 mg 1.5 3-4 h 3. If pain was effectively controlled, reduce the dose by 25%-50% to allow for incomplete cross-tolerance between different opioids. During the first 24 h, titrate liberally and rapidly to analgesic effect. If previous dose was ineffective, may begin with 100% of Fentanyl3 100 mcg -- -- 1-3 h equianalgesic dose or increase that by 25%. Hydrocodone4 -- 30-45 mg -- 3-5 h 4. Lastly, for oral opioids divide the total daily dose of new opioid needed by the number of doses per day to determine the individual dose (e.g., 6 doses for regular PO morphine every 4 h; 2 doses for extended-release morphine every 12 h). Hydromorphone 1.5 mg 7.5 mg 5 2-3 h Case example of converting IV morphine to IV hydromorphone Levorphanol5 2 mg 4 mg 2 3-6 h A patient is taking IV morphine at 8 mg/h and must be converted to IV hydromorphone. Methadone5,6 ------1. Determine the total amount of current IV morphine in a 24-h period for this patient Morphine2,7 10 mg 30 mg 3 3-4 h (8 mg/h x 24 h =192 mg/d) 1 (total amount of IV morphine this patient is taking is 192 mg/d) Oxycodone -- 15-20 mg -- 3-5 h Oxymorphone 1 mg 10 mg 10 3-6 h 2. From Table 1 on previous page, calculate the equianalgesic dose of IV hydromorphone 8 (10 mg IV morphine = 1.5 mg IV hydromorphone therefore, Tramadol -- 50-100 mg -- 3-7 h 192 mg/d IV morphine = 28.8 mg/d IV hydromorphone = 1.2 mg/h IV hydromorphone)

NOT RECOMMENDED Special Note: Mixed agonists-antagonists have limited 3. If patient was effectively controlled with IV morphine (192 mg/d) reduce the dose of hydromorphone by 25%-50% usefulness in cancer pain. They should NOT be used in (28.8 mg/d reduced by 25% = 21.6 mg/d IV hydromorphone = 0.9 mg/h IV hydromorphone) Meperidine10 combination with opioid agonist drugs. Converting from an (28.8 mg/d reduced by 50% = 14.4 mg/d IV hydromorphone= 0.6 mg/h IV hydromorphone) If dose of IV morphine was ineffective in controlling pain, may begin with 100% of equianalgesic hydromorphone dose Propoxyphene10 agonist to an agonist-antagonist could precipitate a withdrawal crisis in opioid-dependent patients. (28.8 mg/d IV hydromorphone = 1.2 mg/h IV hydromorphone) Mixed agonist-antagonists (pentazocine, or increase that by 25% nalbuphine, butorphanol, dezocine) (36 mg/d IV hydromorphone = 1.5 mg/h IV hydromorphone)

Continued on page 1064

1Dosage must be monitored for safe limits as it may be available in 6The oral conversion ratio of methadone varies. PRACTITIONERS ARE combination with acetylsalicylic acid (ASA) or acetaminophen. Dose listed ADVISED TO CONSULTWITHAPAIN OR PALLIATIVE CARE refers only to opioid portion. SPECIALIST IF THEY ARE UNFAMILIAR WITH METHADONE 2Avoid using codeine or morphine in patients with renal failure from PRESCRIBING. (See Converting from Oral Morphine to Oral Methadone, accumulation of renally cleared metabolites. page 1066). 3The equianalgesic dose listed only applies to IV fentanyl compared with 7Conversion factor listed for chronic dosing. other IV opioids. For transdermal fentanyl conversions, see page 1064. 8Weak opioid receptor agonist with some antidepressant activity. For mild to 4Equivalence data not substantiated. Clinical experience suggests use as a moderate pain. Recommended dose of 100 mg 4 times a day mild, initial use opioid but effective dose may vary. Usually combined with (maximum daily dose, 400 mg) to avoid CNS toxicity. Even at maximum ASA or acetaminophen in doses from 325 to 750 mg. Dosage must be dose of 100 mg 4 times a day, tramadol is less potent than other opioid monitored for safe limits of ASA or acetaminophen. Dose listed refers only analgesics, such as morphine. to opioid portion. 9Shorter time generally refers to parenterally administered opioids (except 5Long half-life, observe for drug accumulation and side effects after 2-5 d. for controlled-release products, which have some variability); longer time May need to be dosed every 4 h initially then changed to every 6-8 h after generally applies to oral dosing. steady state achieved (1-2 wk). 10Not recommended for cancer pain management because of CNS toxic metabolites (normeperidine, norpropoxyphene).

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CONVERT OR ROTATE FROM ANOTHER OPIOID TO TRANSDERMAL FENTANYL CONVERTOR ROTATE FROM ANOTHER OPIOID TO TRANSDERMALFENTANYL (continued) • To convert or rotate from another opioid to transdermal fentanyl: Example of opioid using Table 2 directly: 1. Determine the 24-h analgesic requirement of current opioid. Table 2 (below) can be used directly for patients on oxycodone, hydromorphone, and codeine. If not one of these opioids, convert to equianalgesic dose of morphine requirement. Case example of converting oral oxycodone to transdermal fentanyl patch 2. From Table 2, select the mcg/h dose of transdermal fentanyl based on the 24-h dose of morphine, oxycodone, hydromorphone, A patient is taking 30 mg of sustained-release oral oxycodone every 12 h and must be converted to transdermal fentanyl patch. or codeine as listed. For fentanyl dosage requirements > 100 mcg/h, multiple patches are used. Note:An as-needed (prn) dose of morphine or other short-acting opioid should be prescribed and will be needed particularly during 1. Calculate the total amount of current oral oxycodone in a 24-h period the first 8 to 24 h. Once the levels have reached steady state after at least 2-3 d, increase the patch dosage based on the (oral oxycodone 30 mg x 2 = 60 mg/d oral oxycodone) average amount of stable daily prn opioid required. Continue breakthrough medication once the patch dose is stabilized. 2. Using Table 2, select the the mcg/h dose of transdermal fentanyl (60 mg/d oral oxycodone is approximately 50 mcg/h transdermal fentanyl patch) Example of opioid not listed on Table 2: Table 2: Recommended Dose Conversion From Other Opioids to Transdermal Fentanyl1 See facing page for case examples Case example of converting oral oxymorphone to transdermal fentanyl patch A patient is taking 10 mg of sustained-release oral oxymorphone every 12 h and needs to be converted to transdermal fentanyl patch. Transdermal Morphine2 Oxycodone Hydromorphone Codeine 1. Calculate the total amount of current oral oxymorphone in a 24-h period Fentanyl (oral oxymorphone 10 mg x 2 = 20 mg/d oral oxymorphone) IV/SubQ* Oral Oral IV/SubQ* Oral IV/SubQ* Oral 2. From Table 1 on page 1062,econvert the quianalgesic dose of oral morphine (Based on Table 1, 10 mg oral oxymorphone = 30 mg oral morphine, therefore 25 mcg/h 20 mg/d 60 mg/d 30 mg/d 1.5 mg/d 7.5 mg/d 130 mg/d 200 mg/d 20 mg/d oral oxymorphone x 3 = total daily dose oral morphine of 60 mg/d)

50 mcg/h 40 mg/d 120 mg/d 60 mg/d 3.0 mg/d 15.0 mg/d 260 mg/d 400 mg/d 3. Using Table 2 on page 1064, select the mcg/h dose of transdermal fentanyl (60 mg/d oral morphine is approximately 25 mcg/h transdermal fentanyl patch)

75 mcg/h 60 mg/d 180 mg/d 90 mg/d 4.5 mg/d 22.5 mg/d 390 mg/d 600 mg/d Continued on page 1066 100 mcg/h 80 mg/d 240 mg/d 120 mg/d 6.0 mg/d 30.0 mg/d 520 mg/d 800 mg/d

NOTE: Because of patient variability, the doses suggested in *Parenteral dosing such as IV (intravenous) or this guide are approximate and clinical judgement must be SubQ (subcutaneous) used to titrate to the desired response.

Special Notes Regarding Transdermal Fentanyl: • Pain should be relatively well controlled on a short-acting opioid before initiating the fentanyl patch. Patches are NOT recommended for unstable pain requiring frequent dose changes. Use fentanyl patch only in patients tolerant to opioid therapy. • Fever or topical application of heat (e.g., heat from heat lamps, electric blankets) may accelerate transdermal fentanyl absorption and are contraindications to transdermal fentanyl. • When converting from continuous parenteral infusion fentanyl to transdermal fentanyl, a straight 1:1 ratioi3 s appropriate (i.e., the mcg/h of parenteral fentanyl should be approximately equal to the mcg/h of transdermal fentanyl). In some patients, additional dose titration of the fentanyl patch may be necessary. • The fentanyl patch analgesic duration is usually 72 h, but some patients require fentanyl patch replacement every 48 h.

1BreitbartW,Chandler S, Eagel B, et al.Analternativealgorithm for dosingtransdermalfentanylfor cancer-related pain. Oncology 2000;14:695-702. 2Equianalgesic doses to morphine adapted from FoleyK.The treatment of cancer pain. NEngl JMed 1985;313:84-95. 3KornickCA, Santiago-PalmaJ,KhojainovaN,etal. Asafe and effectivemethod forconverting patientsfromintravenous to transdermalfentanyl. Cancer 2001;92:3056-3061.

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75 mcg/h 60 mg/d 180 mg/d 90 mg/d 4.5 mg/d 22.5 mg/d 390 mg/d 600 mg/d Continued on page 1066 100 mcg/h 80 mg/d 240 mg/d 120 mg/d 6.0 mg/d 30.0 mg/d 520 mg/d 800 mg/d

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1 CONVERT FROM ORAL MORPHINE TO ORAL METHADONE CONVERTFROM ORAL MORPHINE TO ORAL METHADONE (continued) • To convert from oral morphine to oral methadone: Case example of converting oral morphine to oral methadone 1. Calculate the total daily oral morphine dose (or morphine-equivalent dose) the patient is using A patient is taking oral morphine at 30 mg every 4 hours and must be converted to oral methadone 2. Based on the oral morphine dose, useTable 3 (below) to determine the appropriate dose conversion ratio and calculate the oral methadone dose 1. Calculate the total amount of current oral morphine in a 24-h period for this patient 3. Reduce the calculated equianalgesic dose of oral methadone by 25%-50% to account for incomplete cross-tolerance, dosing (30 mg x 6 = 180 mg/d) ratio variability, and patient variability (Total amount of oral morphine this patient is taking is 180 mg/d) 4. Divide the total daily oral methadone dose into 3 or 4 daily doses 2. From Table 3 (Dose Conversion Ratios for Oral Morphine to Oral Methadone, previous page), calculate equianalgesic dose of oral methadone Table 3: Dose Conversion Ratios for Oral Morphine to Oral Methadone (for 180 mg/d of oral morphine:oral methadone, the dose conversion ratio is 8:1, therefore 180 mg/d morphine = 22.5 mg/d methadone) ORAL MORPHINE DOSE CONVERSION RATIO (oral morphine:oral methadone) 30-90 mg 4:1 3. Reduce the calculated equianalgesic dose of oral methadone by 25%-50% to account for incomplete cross-tolerance, dosing 91-300 mg 8:1 ratio variability, and patient variability > 300 mg 12:1 (e.g., 22.5 mg/d oral methadone reduced by 25% = 16.875 mg/d oral methadone equal to approximately 15 mg/d oral methadone) Note: If the total daily dose equivalent of morphine is > 800 mg, a higher dose ratio is necessary and cross- titration is recommended. A pain or palliative care specialist should be consulted. 4. Divide the total daily oral methadone dose into 3 daily doses (e.g., reduced dose of 15 mg/d oral methadone divided by 3 daily doses = 5 mg oral methadone every 8 h)

Special Notes Regarding Oral Methadone: • The conversion ratio varies with the amount of morphine (or other opioid) a patient is using chronically.The higher the dose of morphine, the more potent the methadone. • To a significantly greater extent than with other opioids, methadone has been associated with several drug-drug interactions. The potential for such interactions must be investigated in each patient before initiating methadone. • Methadone is widely available in 5- and 10-mg tablets. • Methadone may be titrated up every 5-7 d, usually by 5 mg per dose. • Because methadone is associated with QTc prolongation, a baseline and follow-up ECG is recommended for methadone doses > 100 mg/d and for patients with cardiac disease, or when methadone is used in patients taking other medications also known to prolong QTc (including tricyclic antidepressants), if consistent with patient’s goals of care. • These conversion ratios should NOT be used in converting methadone to other opioids. After methadone is discontinued, it will take several days for it to be cleared, because of a long elimination half-life; therefore, the amount of other opioids needed for an equivalent effect will seem to change as the residual methadone is cleared. On the first day of conversion (while there is still significant methadone present), a conservative conversion ratio for oral methadone to oral morphine of 1:1 may be used, and supplemented with additional short-acting opioid, as needed. As methadone is cleared, morphine (or other opioid) doses will likely require frequent adjustment (every day or two) toward the higher conversion ratios listed for morphine-to-methadone conversion.

1Manfredi PL, Houde RW. Prescribing methadone, a unique analgesic. J Support Oncol 2003;1:216-220.

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1Manfredi PL, Houde RW. Prescribing methadone, a unique analgesic. J Support Oncol 2003;1:216-220.

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MANAGEMENT OF OPIOID SIDE EFFECTS MANAGEMENT OF OPIOID SIDE EFFECTS

Principles of Management of Opioid Side Effects Pruritus • Opioid side effects generally improve over time, except with constipation. Maximize nonopioid and nonpharmacologic • If pruritus develops interventions to limit opioid dose and treat side effects. If side effects persist, consider opioid rotation. Assess for other causes (other medications, etc.) • Multisystem assessment is necessary. Consider antihistamines such as diphenhydramine, 25-50 mg IV or PO every 6 h; or promethazine, 12.5-25 mg PO every 6 h • Recognize that pain is rarely treated in isolation in cancer and side effects may be from other treatments or cancer itself. • If pruritus persists Consider changing to another opioid if symptomatic management has failed. Constipation Consider adding to analgesic regimen: small doses of mixed agonist-antagonist, nalbuphine, 0.5-1 mg IV every 6 h as needed • Preventive measures • Consider continuous infusion of naloxone, 0.25 mcg/kg/h and titrate up to 1 mcg/kg/h for relief of pruritus without decreasing Prophylactic medications Stimulant laxative ± stool softener (e.g., senna ± docusate, 2 tablets every morning; maximum 8-12 tablets per day). effectiveness of the analgesic. Increase dose of laxative when increasing dose of opioids Delirium Maintain adequate fluid intake • Assess for other causes of delirium (e.g., hypercalcemia, CNS, metastases, other psychoactive medications) Maintain adequate dietary fiber intake; compounds such as Metamucil are unlikely to control opioid induced constipation and • If one cannot determine other possible causes of delirium, consider changing the opioid are not recommended • Consider nonopioid analgesic to allow reduction of the opioid dose Exercise, if feasible • Consider haloperidol, 0.5-2 mg PO or IV every 4-6 h; or olanzapine, 2.5-5 mg PO or sublingual every 6-8 h; • If constipation develops or risperidone, 0.25-0.5 mg 1-2 times day Assess for cause and severity of constipation • For further information about delirium, see NCCN Guidelines on Palliative Care* Rule out obstruction Treat other causes Motor and Cognitive Impairment Titrate stool softner/laxatives as needed with goal of one nonforced bowel movement every 1-2 d • Studies have shown that stable doses of opioids (> 2 wk) are not likely to interfere with psychomotor and cognitive function, but Consider coanalgesic to allow reduction of the opioid dose these functions should be monitored during analgesic administration and titration. • If constipation persists Reassess for the cause and severity of constipation, rule out bowel obstruction Check for impaction Respiratory depression Consider adding another agent, such as magnesium hydroxide, 30-60 mL daily; bisacodyl, 2-3 tablets PO daily, or 1 rectal • Use reversing agents cautiously. If reversing an opioid with a long half-life, such as methadone, consider naloxone infusion. suppository daily; lactulose, 30-60 mL daily; sorbitol, 30 mL every 2 h x 3, then as needed, or magnesium citrate, 8 oz PO daily, • If respiratory problems or acute changes in mental status occur, consider naloxone administration. Dilute one ampule of naloxone polyethelene glycol (1 capful/8 oz water PO 2 times a day) (0.4 mg/1 mL) into 9 mL of normal saline for a total volume of 10 mL. Give 1-2 mL (0.04-0.08 mg) every 30-60 seconds until Fleet, saline, or tap water enema improvement in symptoms is noted. Be prepared to repeat this process (the half-life of opioids is generally longer than that of the Consider use of a prokinetic agent (e.g., metoclopramide, 10-20 mg PO 4 times a day) naloxone). If the patient is not responsive within 10 min and total naloxone dose of 1 mg, consider another reason for the change When response to laxative therapy has not been sufficient for opioid-induced constipation in patients with advanced illness, in neurological status. consider methylnaltrexone, 0.15 mg/kg subcutaneously, maximum 1 dose per day Consider neuraxial analgesics or neuroablative techniques to potentially reduce opioid dose Sedation • If sedation develops and persists for more than 1 wk after initiating opioids Nausea Assess for other causes of sedation (e.g., CNS pathology, other sedating medications, hypercalcemia, dehydration, sepsis, • Preventive measures hypoxia) For patients with a prior history of opioid induced nausea, prophylactic treatment with antiemetic agents (see below) are highly Decrease the dose of opioid if pain control can be maintained at a lower dose recommended. Consider changing the opioid • If nausea develops Consider nonopioid analgesic to allow reduction of the opioid dose Assess for other causes of nausea (e.g., constipation, central nervous system pathology, chemotherapy, radiation therapy, Consider a lower dose of opioid given more frequently to decrease peak concentrations hypercalcemia) Consider the addition of caffeine, 100-200 mg PO every 6 h; or methylphenidate, 5-10 mg 1-3 times per day; or Consider prochlorperazine, 10 mg PO every 6 h as needed; or thiethylperazine, 10 mg PO every 6 h as needed; dextroamphetamine, 5-10 mg PO 1-3 times per day; or modafinil, 100-200 mg per day. When using CNS stimulants for sedation, or haloperidol, 0.5-1 mg PO every 6-8 h; or metoclopramide, 10-20 mg PO every 6 h as needed limit dosing to morning and early afternoon to avoid insomnia at night If nausea persists despite as needed regimen, administer antiemetics around the clock for 1 wk, then change to as needed • If sedation persists despite several changes of opioids and the above measures Consider adding a serotonin antagonist (e.g., granisetron, 2 mg PO daily; or ondansetron, 8 mg PO 3 times a day; Reassess cause and severity of sedation or dolasetron, 100-200 mg PO; or palonosetron, 300 mcg/kg IV); use with caution as constipation is a side effect Consider neuraxial analgesics or neuroablative techniques to potentially reduce opioid dose Dexamethasone can be considered • If nausea persists for more than 1 wk Reassess cause and severity of nausea Consider opioid rotation • If nausea persists after a trial of several opioids and above measures *To view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org. Reassess cause and severity of nausea Consider neuraxial analgesics or neuroablative techniques to potentially reduce opioid dose

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COANALGESICS FOR NEUROPATHIC PAIN PSYCHOSOCIAL SUPPORT ()ANTIDEPRESSANTS, ANTICONVULSANTS, ANDTOPICAL AGENTS

PRINCIPLES OF COANALGESIC USE Support • Inform patient and family that emotional reactions to pain are normal and are evaluated and treated as part of pain treatment. • Antidepressant and anticonvulsants are first-line coanalgesics for the treatment of cancer-related neuropathic pain. • Provide emotional support to patients and families that acknowledges the pain is a problem to be addressed. • These drugs can be helpful for patients whose pain is only partially responsive to opioids. • Assist in accessing treatment as needed. • The use of coanalgesics in the cancer population is still often guided solely by anecdotal experience or guidelines derived • State that you will work together with the patient and family as part of the team to address the pain problem. from data in nonmalignant pain populations. • Describe the plan of action to be taken and when results can be expected. • Effective use is predicated on an assessment that clarifies the nature of the pain. • Express your commitment to staying available until the pain is better managed. • As with opioids, it is likely that response to different coanalgesics may vary among types of neuropathic pain and individual • Verbally repeat your concern and the plan of action to be taken. patients. • Inform patient and family that there is ALWAYS something else that can be done to try to adequately manage pain and other • Drug selection may be influenced by the presence of certain nonpain symptoms and comorbidities. For example, a sedating noxious symptoms. drug may be useful in a patient in whom insomnia is a problem. • Assess impact upon family and significant others and provide education and support as indicated. • Patient education should emphasize the trial and error nature of the treatment so that patients do not get discouraged. • Doses should be increased until the analgesic effect is achieved, side effects become unmanageable, or the conventional Skills Training maximal dose is reached. • Teach coping skills to provide pain relief, enhance a sense of personal control, and refocus energy on optimizing quality of life. • Coping skills for acute pain include Lamaze-type breathing exercises, distraction techniques, and cognitive coping statements to encourage assertiveness and to maximize comfort. • Coping skills for chronic pain (not pain emergency) include all of the above plus relaxation techniques, guided imagery, graded task EXAMPLES OF COANALGESIC USE assignments, and hypnosis to maximize function. (Extrapolated from noncancer neuropathic pain management ) • Educate patient and family that pain management is a team effort. Members of the team may include: oncologist, nurse, pain specialist, palliative care clinician, physiatry, neurologist, psychologist, social worker, psychiatrist, physical therapist, and spiritual • Trial of antidepressant:Analgesic effectiveness is not dependent on its antidepressant activity. Effective analgesic dose is often counselor. See Patient and Family Education (page 1072). lower than that required to treat depression. The onset of analgesic action is usually earlier. Frequently used as a coanalgesic in combination with an opioid for the neuropathic component of the pain. Tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline ,) desipramine Start with low dose and increase every 3-5 days if tolerated. (e.g., nortriptyline and desipramine starting dose 10-25 mg nightly increase to 50-150 mg nightly.The tertiary amines [amitriptyline, imipramine] may be more efficacious but secondary amines [nortriptyline, desipramine] are better tolerated. Anticholinergic adverse effects such as sedation, dryness of mouth, urinary hesitancy are more likely to occur with amitriptyline and imipramine.) Other examples: Duloxetine: Starting dose 30-60 mg daily, increase to 60-120 mg daily Venlafaxine: Starting dose 50-75 mg daily, increase to 75-225 mg daily Bupropion: Starting dose 100-150 mg daily, increase to 150-450 mg daily

• Trial of anticonvulsants: Frequently used as a coanalgesic in combination with an opioid for the neuropathic component of the pain. Anticonvulsant examples: Gabapentin: Starting dose 100-300 mg nightly, increase to 900-3600 mg daily in divided doses 2 to 3 times a day. Dose increments of 50%-100% every 3 days. Slower titration for the elderly or medically frail. Dose adjustment required for those with renal insufficiency. Pregabalin: Starting dose 50 mg 3 times a day, increase to 100 mg 3 times a day. Slower titration for the elderly or medically frail. Dose adjustment required for those with renal insufficiency. Pregabalin more efficiently absorbed through the GI tract than gabapentin. May increase further to a maximum dose of 600 mg in divided doses 2 to 3 times a day. Consider other anticonvulsant agents, many of which have been shown to have efficacy in non cancer neuropathic pain.

• Trial of topical agents: Act locally and may be used as a coanalgesic in combination with an opioid, antidepressant, and/or an anticonvulsant. Topical agent examples: Lidocaine patch, 5%:Apply daily to the painful site. Minimal systemic absorption. Consider NSAID: diclofenac gel, 1%, 4 times daily; or diclofenac patch, 180 mg, one patch daily or one patch twice daily

• Trial of corticosteroids: Long half-life of these drugs allows for once daily dosing. Useful in the acute management of a pain crisis when neural structures or bones are involved. Long-term adverse effects significant.

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PATIENT AND FAMILY EDUCATION NONPHARMACOLOGIC INTERVENTIONS

• Assess patient and family for literacy to ensure understanding of education. Consider nonpharmacologic interventions for: • Messages to be conveyed to patient and family: Relief of pain is medically important and there is no medical benefit to suffering with pain. Pain likely to be relieved or function improved with physical, cognitive, or interventional modalities Pain can usually be well controlled with pain medications. For persistent pain, taking analgesic on a regular schedule will • Physical modalities improve pain control. Bed, bath, and walking supports If these medications do not work, many other options are available. Positioning instruction Potent analgesics should be taken only as prescribed and by the person for whom the medication is prescribed; do not Physical therapy self adjust dosage or frequency unless discussed with your health care provider. Energy conservation, pacing of activities Morphine and morphine-like medications are often used to relieve pain. For patients with a history of substance abuse, Massage see page 1075. Heat and/or ice When these drugs are used to treat cancer pain, addiction is rarely a problem. Transcutaneous electrical nerve stimulation (TENS) If you take these medications now, they will still work later. Acupuncture or acupressure Ultrasonic stimulation These are controlled substances that need to be properly safeguarded in the home. • Cognitive modalities These medications must be used with caution, and should not be mixed with alcohol or illicit substances. Imagery/hypnosis Communication with the health care provider is critical. Distraction training Health care providers cannot tell how much pain you have unless you tell them. Relaxation training Health care providers want to know about any problems that you think the pain medications may be causing, as Active coping training there are probably ways to make these better. Graded task assignments, setting goals, pacing and prioritizing Tell your health care providers if you are having any difficulty getting your medication or concerns about taking them. Cognitive behavioral training They have dealt with such issues before and will help you. Depression/distress consultation (see NCCN Guidelines on Distress Management*) Expect optimal management for pain and side effects. Inform patient of right to expect pain management as part of Consider pain and palliative care specialty consultation (see NCCN Guidelines on Palliative overall care. Care*) • The following must be reviewed with each patient and family and provided in written form, which is dated: Complex management A list of each medication prescribed, a description of what each medication is for, and instructions as to how and when to Diagnosis and treatment of underlying condition take each one Spiritual care A list of potential side effects of these medications and what to do if they occur A list of all medications to be discontinued A list of telephone numbers to reach an appropriate healthcare provider and specific instructions to call regarding: See Interventional Strategies (page 1076) Any problems in getting the prescriptions or taking the medication New pain, change in pain, or pain not relieved with medication Nausea and vomiting that prevents eating for 1 day No bowel movements for 3 days Difficulty arousing the patient from sleep easily during the daytime Confusion Aplan for follow-up visits and/or phone calls • The health care team should be familiar with local regulations pertaining to the operation of machinery or motor vehicles while taking potentially sedating medication and advise patient and family accordingly.

*To view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org.

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*To view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org.

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NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) AND ACETAMINOPHEN PRESCRIBING SPECIALITY CONSULTATIONS FOR IMPROVED PAIN MANAGEMENT

NSAID Major indication for referral is: Use NSAIDs with caution in patients at high risk for renal, GI, cardiac toxicities, thrombocytopenia, or bleeding disorder. Note Pain likely to be relieved or function improved with physical, cognitive, or interventional modalities that the potential side effects of chemotherapy, such as hematologic, renal, hepatic, and cardiovascular toxicities, can be delivered by a specialty service provider. Note the specific provider of these services may vary in increased by the concomitant prescription of NSAIDS. Opioid analgesics are a safe and effective alternative analgesic to different treatment settings. NSAIDs. Use any NSAID that the patient has found effective and tolerated well in the past, otherwise consider ibuprofen to the maximal Pain and palliative care specialty consultation dose. See NCCN Guidelines on Palliative Care* Ibuprofen, 400 mg, 4 times a day (daily maximum = 3200 mg) Consider interventional strategies (see page 1076) If needed, consider short-term use of ketorolac, 15-30 mg IV, every 6 h for maximum of 5 days Management of symptoms refractory to initial treatment Compounds that do not inhibit platelet aggregation: Diagnosis and treatment of underlying condition Nonacetylated salicylate Consider palliative sedation for intractable pain Choline + magnesium salicylate combinations, 1.5-4.5 g/d, in 3 divided doses Salsalate, 2-3 g/d, in 2 or 3 divided doses Substance abuse and diversion consultation if questions/concerns about medication misuse or diversion Selective COX-2 inhibitor Evaluation for substance use disorder NSAIDs and toxicities Assist with establishing treatment agreements, limit setting, single provider/ pharmacy as needed Patients at high risk for renal toxicities: age > 60 y, compromised fluid status, interstitial nephritis, papillary necrosis, and Communicate regarding need to accomplish pain relief, but avoid misuse/diversion concomitant administration of other nephrotoxic drugs (including cyclosporin, cisplatin) and renally excreted chemotherapy Treatment of renal toxicities: discontinue NSAIDs if BUN or creatinine doubles or if hypertension develops or worsens Depression/Distress consultation (see NCCN Guidelines on Distress Management*) Patients at high risk for GI toxicities: age > 60 y, history of peptic ulcer disease or significant alcohol use (3 alcoholic beverages per day), major organ dysfunction including hepatic dysfunction, high-dose NSAIDs given for long periods Spiritual care Treatment of GI toxicities: if patient develops gastric upset or nausea, consider discontinuing NSAIDs or changing to Determine importance to patient/family and current availability of support selective COX-2 inhibitor. COX-2 inhibitors are associated with lower incidence of GI side effects and do not inhibit platelet aggregation; however, they have not been shown to have reduced renal side effects. Psychological supportive services Consider adding antacids, H2 receptor antagonists, misoprostol, omeprazole. If patient develops gastrointestinal Cognitive modalities peptic ulcer or gastrointestinal hemorrhage, discontinue NSAIDs. Imagery/hypnosis Discontinue NSAIDs if liver function studies increase 1.5 times the upper limit of normal. Distraction training Patients at high risk for cardiac toxicities: history of cardiovascular disease, or at risk for cardiovascular disease or Relaxation training complications. NSAIDs taken with prescribed anticoagulants, such as warfarin or heparin, may significantly increase the risk Active coping training of bleeding complications. Graded task assignments, setting goals, pacing, and prioritizing Treatment of cardiac toxicities: discontinue NSAIDs if hypertension develops or worsens Cognitive behavioral training Monitoring for NSAID toxicities: Baseline blood pressure, BUN, creatinine, liver function studies (alkaline phosphatase, LDH, SGOT, SGPT), CBC, and Physical/occupational therapy, rehabilitation/mobility specialists fecal occult blood Physical modalities Repeat every 3 mo to ensure lack of toxicity Bed, bath, and walking supports Further NSAID considerations: Positioning instruction If 2 NSAIDs are tried in succession without efficacy, use another approach to analgesia Physical therapy If NSAIDs are effective but treatment is limited by toxicities that are not deemed serious, consider trial of another NSAID Massage When systemic administration is not feasible, consider topical NSAID preparations Heat and/or ice Toxicity of anticancer treatment may increase the risk profile of anti-inflammatory treatment TENS Acupuncture or acupressure Acetaminophen Ultrasonic stimulation Acetaminophen, 650 mg every 4 h, or 1 g every 6 h (daily maximum 4 g/d).The FDAis currently evaluating daily maximum dosing. Becuase of concerns with liver toxicity, acetaminophen should be used with caution or not used at all with combination opioid-acetaminophen products to prevent excess acetaminophen dosing. See FDAWeb site for latest information on acetaminophen side effects and dosing. For further prescribing and safety information, see FDAWeb site (www.fda.gov).

*To view most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org

1Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians. A scientific statement from the American Heart Association. Circulation 2007;115:1634-1642.

Adult Cancer Pain Version 1:2010

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) AND ACETAMINOPHEN PRESCRIBING SPECIALITY CONSULTATIONS FOR IMPROVED PAIN MANAGEMENT

*To view most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org

Adult Cancer Pain Version 1:2010

INTERVENTIONAL STRATEGIES

Interventional Consultation • Major indications for referral: Pain likely to be relieved with nerve block (e.g., pancreas/upper abdomen with celiac plexus block, lower abdomen with superior hypogastric plexus block, intercostal nerve, or peripheral nerve) Failure to achieve adequate analgesia without intolerable side effects (may be handled with intraspinal agents, blocks, spinal cord stimulation, or destructive neurosurgical procedures)

• Commonly used interventional procedures: Regional infusions (requires infusion pump) • If interventional approaches are appropriate, Epidural: easy to place; requires large volumes and an Evaluate which pain site can be relieved externalized catheter; for infusions of opioids, local Verify interventional technique will provide anesthetics, clonidine; useful for acute postoperative pain suffiecient benefit Intrathecal: easy to internalize to implanted pump; for infusions of opioids, local anesthetics, clonidine, and ziconotide Regional plexus: for infusions of local anesthetics; used to anesthetize single extremity Percutaneous vertebroplasty/kyphoplasty Neurodestructive procedures for well-localized pain syndromes (spinal analgesics are used more frequently) Head and neck: peripheral nerve block Upper extremity: brachial plexus neurolysis Thoracic wall: epidural neurolysis, intercostal neurolysis Upper abdominal pain (visceral): celiac plexus block, thoracic splanchnicectomy Midline pelvic pain: superior hypogastric plexus block Rectal pain: intrathecal neurolysis, midline myelotomy or superior hypogastric plexus block • If interventional approaches are not appropriate1 Unilateral pain syndromes: cordotomy Reassess therapeutic plan Consider intrathecal L/S phenol block Neurostimulation procedures for cancer-related symptoms (i.e., peripheral neuropathy) Radiofrequency ablation for bone lesions

1Infection, coagulopathy, very short or lengthy life expectancy, distorted anatomy, patient unwillingness, medications that increase risk for bleeding (e.g., antiangiogenesis agents such as bevacizumab) or technical expertise is not available.

Adult Cancer Pain Text continued from p. 1047 Second, the guidelines acknowledge the range guidelines begin with the premise that all patients of complex decisions faced in caring for these pa- with cancer should be screened for pain (page 1048) tients. As a result, they provide dosing guidelines during the initial evaluation, at regular follow-up in- for NSAIDs, opioids, and coanalgesics. They also tervals, and whenever new therapy is initiated. provide specific suggestions for titrating and rotating If pain is present on a screening evaluation, the opioids, escalation of opioid dosage, management of pain intensity must be quantified by the patient opioid adverse effects, and when and how to proceed whenever possible. Because pain is inherently subjec- to other techniques/interventions for the manage- tive, patient’s self-report of pain is the current stan- ment of cancer pain. dard of care for assessment. Intensity of pain should be quantified using a 0 to 10 numeric rating scale, a categorical scale, or a pictorial scale (e.g., the Faces Pathophysiologic Classification Pain Rating Scale; see page 1055).13–15 The Faces Different types of pain occur in cancer patients. Sev- Pain Rating Scale may be successful for patients who eral attempts have been made to classify pain accord- have difficulty with other scales, such as children, el- ing to different criteria. Pain classification includes derly patients, and patients with language or cultural differentiating between pain associated with tumor, differences or other communication barriers. If the pain associated with treatment, and pain unrelated patient is unable to verbally report pain, an alterna- to either. Acute and chronic pain should also be tive method must be used to assess and rate the pain distinguished when deciding what therapy to use. (see page 1056). Therapeutic strategy depends on the pain patho- In addition to pain intensity, the patient should physiology, which is determined through patient ex- be asked to describe the characteristics of their pain amination and evaluation. Pain has 2 predominant (e.g., aching, burning). If the patient has no pain, mechanisms of pathophysiology: nociceptive and rescreening should be performed at each subsequent neuropathic.10,11 visit or as requested. Identifying the presence of pain Nociceptive pain is the result of injury to somatic through repeated screening is essential to allow im- and visceral structures and the resulting activation of plementation of effective pain management. nociceptors. Nociceptors are present in skin, viscera, If the Pain Rating Scale score is greater than 0, muscles, and connective tissues. Nociceptive pain a comprehensive pain assessment is initiated (see can be further divided into somatic pain and visceral pages 1058 and 1059). The comprehensive pain pain.12 Pain described as sharp, well-localized, throb- assessment should focus on the type and quality of bing, and pressure-like is probably somatic nocicep- pain, pain history (e.g., onset, duration, course), tive pain, and often occurs after surgical procedures pain intensity (e.g., pain experienced at rest or with or from bone metastasis. Visceral nociceptive pain movement, or that interferes with activities), loca- is frequently described as more diffuse, aching, and tion, referral pattern, radiation of pain, associated cramping. It is secondary to compression, infiltra- factors that exacerbate or relieve the pain, current tion, or distension of abdominal thoracic viscera. pain management plan, patient’s response to current Neuropathic pain results from injury to the pe- therapy, prior pain therapies, important psychosocial ripheral or central nervous system. This type of pain factors (e.g., patient distress, family and other sup- might be described as burning, sharp, or shooting. port, psychiatric history, risk factors for aberrant use Examples of neuropathic pain include pain from spi- of pain medication, risk factors for undertreatment of nal stenosis or diabetic neuropathy, or as an adverse pain), and other special issues relating to pain (e.g., effect of chemotherapy (e.g., vincristine) or radia- meaning of pain for patient and family, cultural be- tion therapy. liefs toward pain and pain expression, spiritual or religious considerations and existential suffering).16,17 Finally, the patient’s goals and expectations of pain Comprehensive Pain Assessment management should be discussed, including level of A comprehensive evaluation is essential to ensure comfort and function (see pages 1058 and 1059). proper pain management. Failure to adequately as- In addition, a thorough physical examination sess pain frequently leads to poor pain control. These and review of appropriate laboratory and imaging

Adult Cancer Pain

studies are essential for a comprehensive pain assess- Management of Pain Not Related to an ment. This evaluation should enable caregivers to Oncologic Emergency in Opioid-Naïve Patients determine if the pain is related to an underlying cause Opioid-naïve patients (those who are not chroni- that requires specific therapy. For example, provid- cally receiving opioids on a daily basis) experiencing ing only opioids to a patient experiencing pain from severe pain (i.e., pain intensity rating 7–10) should impending spinal cord compression is inappropriate. receive rapid titration of short-acting opioids (see Without glucocorticoids and local radiation therapy, page 1050, and Opioid Principles, Prescribing, Titra- the pain is unlikely to be well controlled and the pa- tion, and Maintenance, facing page). Short-acting tient will remain at high risk for spinal cord injury. formulations have the advantage of rapid onset of The end point of comprehensive pain assess- analgesic effect. The route of opioid administration ment is to diagnose the origin and pathophysiol- (oral vs. intravenous) is decided based on what is ogy (somatic, visceral, or neuropathic) of the pain. best suited to the patient’s ongoing analgesic needs. Treatment must be individualized based on clinical Treatment with opioids must be accompanied by circumstances and patient wishes, with the goal of a bowel regimen, and nonopioid analgesics as indi- maximizing function and quality of life. cated. Details of prophylactic bowel regimens and antiemetics are provided on pages 1068 and 1069; management of these common opioid adverse effects Management of Pain should be started simultaneously with initiation of opioid therapy. Opioid-induced bowel dysfunction For management of cancer-related pain in adults, should be anticipated and treated prophylactically the algorithm distinguishes 3 levels of pain intensity, with a stimulating laxative to increase bowel motil- based on a 0 to 10 numeric rating scale (with 10 be- ity, with or without stool softeners as indicated.18 ing the worst pain): severe pain (7–10); moderate The pathways are similar for opioid-naïve pa- pain (4–6); and mild pain (1–3).12,14 tients who have a pain intensity rating between 4 Pain related to an oncologic emergency is im- and 6 at presentation and those who have a pain portant to separate from pain not related to an onco- intensity rating of 7 to 10. The main differences in- logic emergency (e.g., from bone fracture or impend- clude treatment beginning with slower titration of ing fracture of weight-bearing bone; brain, epidural, short-acting opioids. or leptomeningeal metastases; infection; obstructed Opioid-naïve patients experiencing mild pain or perforated viscus). Pain associated with oncologic intensity (1–3) should undergo treatment with emergency should be directly treated while proceed- NSAIDs or acetaminophen, or treatment with con- ing with treatment of the underlying condition. sideration of slower titration of short-acting opioids. The algorithm also distinguishes pain that is Addition of coanalgesics for specific pain syn- unrelated to oncologic emergencies in patients not dromes should be considered for all groups of pa- chronically taking opioids (opioid-naïve) from the tients (see Additional Therapies, page 1082, and pain experienced by those who have previously or page 1070). Coanalgesics are drugs used to enhance are chronically taking opioids for cancer pain (opi- the effects of opioids or NSAIDs.19 oid-tolerant), and also from anticipated procedure- For all patients experiencing pain, health care related pain and anxiety. providers should also provide psychosocial support According to the FDA, “patients considered and begin educational activities. Psychosocial sup- opioid tolerant are those who are taking at least: 60 port is needed to ensure that appropriate aid is pro- mg oral morphine/day, 25 mcg transdermal fentanyl/ vided to patients encountering common barriers to hour, 30 mg oral oxycodone/day, 8 mg oral hydro- appropriate pain control (e.g., fear of addiction or morphone/day, 25 mg oral oxymorphone/day, or an side effects, inability to purchase opioids) or need- equianalgesic dose of another opioid for one week or ing assistance in managing additional problems (e.g., longer.” Therefore, patients who do not meet these depression, rapidly declining functional status; page criteria for opioid-tolerant, and who have not had 1071). Patients and families must be educated re- opioid doses at least as much as those stated for a garding pain management and related issues. week or more, are considered to be opioid-naïve. Although pharmacologic analgesics are the cor-

Adult Cancer Pain nerstone of cancer pain management, they are not netics (long half-life ranging from 8 to > 120 hours) always adequate and are associated with many side make its use very difficult in patients with cancer.27 effects, thus often necessitating the implementation Because of its long half-life, high potency, and inter- of additional therapies or treatments. Optimal use of individual variations in pharmacokinetics, metha- nonpharmacologic interventions may serve as valu- done should be started at lower-than-anticipated able additions to pharmacologic interventions. A doses and slowly titrated upwards with provision of list of nonpharmacologic interventions that include adequate short-acting breakthrough pain medica- physical and cognitive modalities are outlined on tions during the titration period. Consultation with page 1073 and interventional strategies are discussed a pain management specialist should be considered in the next section and on page 1076. before its application. Agents such as mixed agonist–antagonists (e.g., Opioid Principles, Prescribing, Titration, and Maintenance butorphanol, pentazocine), propoxyphene and me- Selecting an Appropriate Opioid: While starting peridine, and placebos are not recommended for therapy, attempts should be made to determine the cancer patients. For treatment of severe pain, mixed underlying pain mechanism and diagnose the pain agonist–antagonist drugs have limited efficacy and syndrome. Optimal analgesic selection will depend may precipitate opioid withdrawal if used in patients on the patient’s pain intensity, any current analgesic receiving pure opioid agonist analgesics. Meperidine therapy, and concomitant medical illnesses. Mor- and propoxyphene are contraindicated for chronic phine, hydromorphone, fentanyl, and oxycodone pain, especially in patients with impaired renal func- are the opioids commonly used in the United States. tion or dehydration, because accumulation of renally An individual approach should be used to deter- cleared metabolites may result in neurotoxicity or 28 mine opioid starting dose, frequency, and titration to cardiac arrhythmias. Use of placebo in the treat- achieve a balance between pain relief and medica- ment of pain is unethical. tion adverse effects. Propoxyphene is an inhibitor of the hepatic In patients not previously exposed to opioids, enzyme, CYP2D6.29,30 Because data suggest that morphine is generally considered the standard pre- CYP2D6-inhibiting antidepressants increase risk 20,21 ferred starting drug. An initial oral dose of 5 to 15 of recurrence in patients with breast cancer treated mg of morphine sulfate or equivalent or 2 to 5 mg of with tamoxifen31,32 (see Additional Therapies, page intravenous morphine sulfate or equivalent is recom- 1082), it is reasonable to assume that propoxyphene mended for opioid-naïve patients. may have the same effect. Therefore, propoxyphene Pure agonists (e.g., codeine, oxycodone, oxy- should be avoided in patients treated with tamoxi- morphone, fentanyl) are the most commonly used fen. In general, propoxyphene should be avoided in medications in the management of cancer pain. The cancer pain management because its risks far out- opioid agonists with a short half-life (morphine, weigh any benefits. hydromorphone, fentanyl, and oxycodone) are pre- Selecting a Route of Administration: The least in- ferred because they can be more easily titrated than vasive, easiest, and safest route of opioid administra- the analgesics with a long half-life (methadone and tion should be provided to ensure adequate analgesia. levorphanol).22 Transdermal fentanyl is not indicated Oral is the preferred route of administration for for rapid opioid titration and only should be recom- chronic opioid therapy.28,33,34 The oral route should mended after pain is controlled by other opioids.23 be considered first in patients who can take oral Conversion from intravenous fentanyl to transder- medications unless a rapid onset of analgesia is re- mal fentanyl can be accomplished effectively using a quired or the patient experiences side-effects as- 1:1 conversion ratio24 (see pages 1061–1067). sociated with the oral administration. Continuous Morphine should be avoided in patients with parenteral infusion, intravenous or subcutaneous, is renal disease and hepatic insufficiency. Morphine-6- recommended for patients who cannot swallow or glucoronide, an active metabolite of morphine, con- absorb opioids enterally. Opioids, given parenter- tributes to analgesia and may worsen adverse effects as ally, may produce fast and effective plasma concen- 25,26 it accumulates in patients with renal insufficiency. trations compared with oral or transdermal opioids. Individual variations in methadone pharmacoki- Intravenous route is considered for faster analgesia

Adult Cancer Pain

because of the short lag-time between injection and tenance, and clinical examples of converting from effect (peak, 15 minutes) compared with oral dosing one opioid to another are listed on pages 1061–1067. 35 (peak, 60 minutes). Initiating Short-Acting Opioids in Opioid-Naïve The following methods of ongoing analgesic Patients administration are widely used in clinical practice: The route of administration of opioid (oral or intra- around-the-clock, as-needed, and patient-controlled. venous) must be selected based on the needs of the Around-the-clock dosing is provided for continuous patient. pain relief in patients with chronic pain, and a res- For opioid-naïve patients experiencing a pain cue dose of short-acting opioids should be provided intensity of 4 or higher, or a pain intensity less than as a subsequent treatment for pain that is not relieved 4 whose goals of pain control and function are not (see pages 1061–1067). Opioids administered on an met, an initial dose of 5 to 15 mg of oral morphine as-needed basis are for patients who have intermit- sulfate or 1 to 5 mg of intravenous morphine sulfate tent pain with pain-free intervals. The as-needed or equivalent is recommended (see page 1051). As- method is also used when rapid dose titration is re- sessment of efficacy and side effects should be per- quired. The patient-controlled analgesia technique formed every 60 minutes for orally administered opi- allows patients to control a device that delivers a bo- oids, and every 15 minutes for intravenous opioids, lus of analgesic on demand (according to, and limited to determine a subsequent dose (see page 1051). If by, parameters set by a physician). assessment shows that the pain score is unchanged Opioid Adverse Effects or is increased, the panel recommends increasing the Constipation, nausea and vomiting, pruritus, deliri- dose by 50% to 100% to achieve adequate analgesia. um, respiratory depression, motor and cognitive im- If the pain score decreases to 4 to 6, the same dose of pairment, and sedation are fairly common, especially opioid is repeated and reassessment is performed at when multiple agents are used.36–41 Each adverse 60 minutes for orally administered opioids and every effect requires a careful assessment and treatment 15 minutes for intravenously administered opioids. If strategy. Proper management is necessary to prevent inadequate response is seen in patients with moder- and reduce analgesic adverse effects (see pages 1068 ate to severe pain on reassessment after 2 to 3 cycles and 1069).36,42–50 Constipation can almost always be of the opioid, changing the route of administration anticipated with opioid treatment; administration of from oral to intravenous or subsequent management prophylactic bowel regimen is recommended. How- strategies (outlined on page 1053) can be considered. ever, evidence is limited on which to base the se- If the pain score decreases to 0 to 3, the current ef- lection of the most appropriate bowel regimen. One fective dose of opioid is administered as needed over study shows that adding a stool softener, docusate, to an initial 24 hours before proceeding to subsequent the laxative, sennosides, was less effective than the management strategies (see page 1051). laxative alone.51 Therefore, the panel recommends a Management of Pain Not Related to an stimulant laxative with or without a stool softener. Oncologic Emergency in Opioid-Tolerant Patients Details of prophylactic bowel regimens and other Opioid-tolerant patients take opioids chronically for measures to prevent constipation, and antiemetics pain relief. According to the FDA, opioid tolerant are provided on page 1068. patients “are those who are taking at least: 60 mg Opioid Rotation oral morphine/day, 25 mcg transdermal fentanyl/ No single opioid is optimal for all patients.52 If opi- hour, 30 mg oral oxycodone/day, 8 mg oral hydro- oid adverse effects are significant, an improved bal- morphone/day, 25 mg oral oxymorphone/day, or an ance between analgesia and adverse effects might be equianalgesic dose of another opioid for one week achieved by changing to an equivalent dose of an or longer.” alternative opioid. This approach is known as opi- In opioid-tolerant patients experiencing break- oid rotation.36 Relative effectiveness is important to through pain intensity of 4 or greater, or less than consider when switching between oral and parenter- 4 whose goals of pain control and function are not al routes to avoid subsequent over- or underdosing. met, the previous 24-hour total oral or intravenous Equianalgesic dose ratios, opioid titration and main- opioid requirement must be calculated and the new

Adult Cancer Pain rescue dose increased by 10% to 20% to achieve ad- terventions for specific cancer pain syndromes (see equate analgesia33,53 (see page 1052). Efficacy and page 1060), and specialty consultation must be con- side effects should be assessed every 60 minutes for sidered (see page 1075). orally administered opioids and every 15 minutes for For opioid-tolerant patients with mild pain who intravenous opioids to determine a subsequent dose are experiencing adequate analgesia but intolerable or (see page 1052). On assessment, if the pain score is unmanageable side effects, the analgesic dose may be unchanged or increased, administration of 50% to reduced by 25% of the current opioid dose (see page 100% of the previous rescue dose of opioid is recom- 1075). Addition of coanalgesics may be considered. mended. If the pain score decreases to 4 to 6, the Ongoing Care same dose of opioid is repeated and reassessment is Although pain intensity ratings will be obtained fre- performed at 60 minutes for orally administered opi- quently to evaluate opioid dose increases, a formal oids and every 15 minutes for intravenously admin- reevaluation to determine patient goals of comfort istered opioids. If the pain score remains unchanged and function is mandated at each contact. on reassessment after 2 to 3 cycles of the opioid in If an acceptable level of comfort and function has patients with moderate to severe pain, changing the been achieved for the patients and 24-hour opioid re- route of administration from oral to intravenous or quirement is stable, the panel recommends converting alternate management strategies (outlined on page to an extended-release oral medication (if feasible) or 1053) can be considered. If the pain score decreases other extended-release formulation (e.g., transdermal to 0 to 3, the current effective dose of either oral fentanyl) or long-acting agent (e.g., methadone; see or intravenous opioid is administered as needed over page 1054). Subsequent treatment is based on the an initial 24 hours before proceeding to subsequent patient’s continued pain rating score. Rescue doses of management strategies. the short-acting formulation of the same long-acting Subsequent Management of Pain in Opioid- drug may be provided during maintenance therapy for Tolerant Patients the management of pain in cancer patients not expe- Subsequent treatment is based on the patient’s con- riencing relief with extended-release opioids. tinued pain rating score (see page 1053). Approach- Routine follow-up of inpatients should be per- es for all pain intensity levels must be coupled with formed during each outpatient contact, or at least psychosocial support and education for patients and each day, depending on patient conditions and insti- their families. tutional standards. If the pain at this time is severe, unchanged, or Patients should be provided with a written follow- increased, the working diagnosis must be reevaluated up plan and instructed on the importance of adhering to and comprehensive pain assessment performed. For the medication plan, maintaining clinic appointments, patients unable to tolerate dose escalation of their and following up with clinicians (see page 1072). current opioid because of adverse effects, an alternate If an acceptable level of comfort and function opioid must be considered (see pages 1061–1067). has not been achieved, universal screening and as- Addition of coanalgesics (see page 1070) should sessment must be performed and additional strategies be reevaluated to either enhance the analgesic ef- for pain relief considered. fect of the opioids or, in some cases, counter the adverse effects associated with the opioids.18 Given the multifaceted nature of cancer pain, additional inter- Management of Procedure-Related ventions (see page 1060) for specific cancer pain syn- Pain and Anxiety dromes and specialty consultation (see page 1075) Procedure-related pain represents an acute short- must be considered to provide adequate analgesia. lived experience that may be accompanied by a great If the patient is experiencing moderate pain deal of anxiety (see page 1057). Procedures reported intensity of 4 to 6 and adequate analgesic relief on as painful include bone marrow aspirations; wound their current opioid, the current titration of the care; lumbar puncture; skin and bone marrow bi- opioid may be continued or increased. In addition, opsies; intravenous, arterial, and central lines; and similar to patients experiencing severe pain, addi- injections. Many of the data available on procedure- tion of coanalgesics (see page 1070), additional in- related pain are from studies on pediatric patients

Adult Cancer Pain

with cancer, which are then extrapolated to adults. opioids or experience adequate analgesia could be of- Interventions to manage procedure-related pain fered a celiac plexus block. should take into account the type of procedure, the Several interventional strategies (see page 1076) anticipated level of pain, and other individual char- are available for patients who do not experience ade- acteristics of the patients, such as age and physical quate analgesia. Regional infusion of analgesics (epi- condition. The interventions may be multimodal dural, intrathecal, and regional plexus) is one ap- and may include pharmacologic and/or nonpharma- proach. This approach minimizes the distribution of cologic approaches. drugs to receptors in the brain, potentially avoiding Local anesthetics can be used to manage proce- side effects of systemic administration. The intrathe- dure-related pain with sufficient time for effective- cal route of opioid administration should be consid- ness as per package insert. Examples of local anes- ered in patients with intolerable sedation, confusion, thetics include lidocaine, prilocaine, and tetracaine. and/or inadequate pain control with systemic opioid Physical approaches such as cutaneous warming, la- administration. This approach is a valuable tool to ser or jet injection, and ultrasound may accelerate improve analgesia in patients experiencing pain in the onset of cutaneous anesthesia. Sedatives may various anatomic locations (e.g., head and neck, up- also be used. However, deep sedation and general per and lower extremities, trunk).54 Neuroablative anesthesia must be performed only by trained pro- procedures used for well-localized pain syndromes fessionals. In addition, use of nonpharmacologic in- (e.g., back pain from facet or sacroiliac joint ar- terventions listed on page 1073 may be valuable in thropathy; visceral pain from abdominal or pelvic managing procedure-related pain and anxiety. The malignancy), such as percutaneous vertebroplasty/ major goal of nonpharmacologic interventions that kyphoplasty, neurostimulation procedures (i.e., for include physical and cognitive modalities is to pro- peripheral neuropathy), and radiofrequency ablation mote a sense of control, thereby increasing hope and for bone lesions, have proven successful in managing reducing helplessness experienced by many patients pain (see page 1076), especially in patients unable with pain from cancer. to experience adequate analgesia without intolerable Patients usually tolerate procedures better when effects. In some cases, these techniques have been they know what to expect. Therefore, patients and successfully used to eliminate or significantly reduce family members should receive written instructions the level of pain, and/or may allow a significant de- for managing the pain. Preprocedure patient edu- crease in systemic analgesics. cation on procedure details and pain management These interventional strategies are not appropri- strategies is essential. Patients and family members ate in unwilling patients or those with infections, co- should receive written information regarding pain agulopathy, or very short life expectancy. Furthermore, management options. the experts performing the interventions must be made aware of any medications the patients are taking that might increase risk for bleeding (e.g., anticoagulants Interventional Strategies [warfarin, heparin], antiplatelet agents [clopidogrel, di- Some patients experience inadequate pain control pyridamole], antiangiogenesis agents [bevacizumab]). despite pharmacologic therapy, or may not tolerate In these cases, the patient may have to be off the medi- an opioid titration program because of side effects. cation for an appropriate amount of time before the Some patients may prefer procedural options over a pain intervention is initiated and may need to continue chronic medication regimen. The major indications to stay off the medication for a specified amount of time for referral for interventional strategies include pain after the procedure. Interventions are not appropriate if that is likely to be relieved with nerve block (e.g., technical expertise is not available. pancreas/upper abdomen with celiac plexus block, lower abdomen with superior hypogastric plexus block, intercostal nerve, or peripheral nerve) and/or Additional Therapies patients failing to achieve adequate analgesia with- Additional strategies specific to the pain situation out intolerable side effects. For example, a patient can be considered. Specific recommendations for in- with pancreatic cancer who was unable to tolerate flammatory pain, bone pain, nerve compression or

Adult Cancer Pain inflammation, neuropathic pain, pain cause by bowel perforation. Well-tolerated proton pump inhibitors obstruction, and pain likely to respond to antineoplas- are recommended to reduce gastrointestinal side ef- tic therapies are provided in the algorithm (see page fects induced by NSAIDs. To prevent renal toxici- 1060). Overall, neuropathic pain is less responsive to ties, NSAIDs should be prescribed with caution in opioids than pain caused by other pathophysiologies. patients who are older than 60 years or have compro- Other therapies, including specific nontraditional mised fluid status or renal insufficiency, or when giv- analgesic drugs, are usually indicated for neuropathic en with concomitant administration of other neph- pain syndrome.55 For example, a patient with neuro- rotoxic drugs and renally excreted chemotherapy. pathic pain who failed to gain sufficient relief from Nonpharmacologic specialty consultations for opioids would be given a coanalgesic. physical (e.g., massage, physical therapy) and cogni- Clinically, coanalgesics consist of a diverse range tive modalities (e.g., hypnosis, relaxation) may pro- 56 of drug classes, including anticonvulsants (e.g., ga- vide extremely beneficial adjuncts to pharmacologic bapentin, pregabalin), antidepressants (e.g., tricyclic interventions (see page 1073). antidepressants), corticosteroids, and local anesthet- Attention should also be focused on psychoso- ics (e.g., topical lidocaine patch). cial support (see page 1071), providing education to Several antidepressants are known inhibitors of patients and families (see page 1072), and reducing hepatic drug metabolism through inhibition of cyto- side effects of the opioid analgesics. chrome P450 enzymes, especially CYP2D6. Tamoxi- Continued pain ratings should be obtained and fen is an estrogen receptor blocker commonly used documented in patients’ medical records to ensure in patients with hormone receptor–positive breast that the pain remains under good control and goals of cancer. Tamoxifen undergoes extensive hepatic me- treatment are achieved. Specialty consultations can tabolism, and inhibition of CYP2D6 decreases pro- be helpful in providing interventions to assist with duction of tamoxifen-active metabolites, potentially difficult cancer pain problems (see page 1075). The limiting tamoxifen efficacy. Clinical studies indicate major indication for referral to a specialty service pro- increased risk of breast cancer recurrence in patients vider is whether the pain is likely to be relieved or will with breast cancer treated with tamoxifen and se- help patients become functional in their daily activi- lective serotonin reuptake inhibitor (SSRI) antide- ties. These modalities are delivered by a specialty ser- pressants compared with those receiving tamoxifen vice provider, and pain management is accomplished alone.31,32 If concomitant use of an SSRI is required in patient receiving tamoxifen, use of a mild CY- through establishing individualized goals and provid- P2D6 inhibitor (sertraline, citalopram, venlafaxine, ing specific treatment and education for patients. The escitalopram) may be preferred over a moderate- specialties include physical/occupational therapy and to-potent inhibitor (paroxetine, fluoxetine, fluvox- psychosocial supportive services, and other fields with amine, bupropion, duloxetine).57 expertise in interventional modalities. Coanalgesics are commonly used to help manage bone pain, neuropathic pain, and visceral pain, Summary and to reduce systemic opioid requirement. They are particularly important in treating neuropathic pain In most patients, cancer pain can be successfully that is resistant to opioids.58 controlled with appropriate techniques and safe Acetaminophen59; NSAIDs including selective drugs. The overall approach to pain management en- COX-2 inhibitors; tricyclic antidepressants; anti- compassed in these guidelines is comprehensive. It is convulsant drugs; bisphosphonates; and hormonal based on routine pain assessments, utilizes both phar- therapy are among the most commonly used medi- macologic and nonpharmacologic interventions, and cations. The NSAID and acetaminophen prescrib- requires ongoing reevaluation of the patient. The ing guidelines are presented on page 1074. History NCCN Adult Cancer Pain Guidelines panel advises of peptic ulcer disease, advanced age (> 60 years), that cancer pain can be well controlled in the vast male gender, and concurrent corticosteroid therapy majority of patients if the algorithms presented are should be considered before NSAID administration systematically applied, carefully monitored, and tai- to prevent upper gastrointestinal tract bleeding and lored to the needs of the individual patient.

Adult Cancer Pain

References using a fixed schedule dose escalation. Acta Anaesthesiol Scand 2000;44:656–664. 1. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the 22. Cherny NI. The pharmacologic management of cancer pain. International Association for the Study of Pain, Subcommittee on Oncology (Williston Park) 2004;18:1499–1515. Taxonomy. Pain Suppl 1986;3(Supp 1):226. 23. Hanks GW, Conno F, Cherny N, et al. Morphine and alternative 2. Cohen MZ, Easley MK, Ellis C, et al. Cancer pain management opioids in cancer pain: the EAPC recommendations. Br J Cancer and the JCAHO’s pain standards: an institutional challenge. J Pain 2001;84:587–593. Symptom Manage 2003;25:519–527. 24. Kornick CA, Santiago-Palma J, Khojainova N, et alL. A safe and 3. Goudas LC, Bloch R, Gialeli-Goudas M, et al. The epidemiology of effective method for converting cancer patients from intravenous cancer pain. Cancer Invest 2005;23:182–190. to transdermal fentanyl. Cancer 2001;92:3056–3061. 4. Svendsen KB, Andersen S, Arnason S, et al. Breakthrough pain 25. Tiseo PJ, Thaler HT, Lapin J, et al. Morphine-6-glucuronide in malignant and non-malignant diseases: a review of prevalence, concentrations and opioid-related side effects: a survey in cancer characteristics and mechanisms. Eur J Pain 2005;9:195–206. patients. Pain 1995;61:47–54. 5. Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment 26. Portenoy RK, Foley KM, Stulman J, et al. Plasma morphine and in outpatients with metastatic cancer. N Engl J Med 1994;330:592– morphine-6-glucuronide during chronic morphine therapy for 596. cancer pain: plasma profiles, steady-state concentrations and the consequences of renal failure. Pain 1991;47:13–19. 6. Martin LA, Hagen NA. Neuropathic pain in cancer patients: mechanisms, syndromes, and clinical controversies. J Pain 27. Davis MP, Homsi J. The importance of cytochrome P450 Symptom Manage 1997;14:99–117. monooxygenase CYP2D6 in palliative medicine. Support Care Cancer 2001;9:442–451. 7. Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain 1997;69:1–18. 28. Bruera E, Kim HN. Cancer pain. JAMA 2003;290:2476–2479. 8. Stjernsward J. WHO cancer pain relief programme. Cancer Surv 29. Barkin RL, Barkin SJ, Barkin DS. Propoxyphene (dextro- 1988;7:195–208. propoxyphene): a critical review of a weak opioid analgesic that should remain in antiquity. Am J Ther 2006;13:534–542. 9. Stjernsward J, Colleau SM, Ventafridda V. The World Health Organization Cancer Pain and Palliative Care Program. Past, 30. Goldstein DJ, Turk DC. Dextropropoxyphene: safety and efficacy present, and future. J Pain Symptom Manage 1996;12:65–72. in older patients. Drugs Aging 2005;22:419–432. 10. Caraceni A, Weinstein SM. Classification of cancer pain 31. Aubert R, Stanek, EJ, Yao J, et al. Risk of breast cancer recurrence syndromes. Oncology (Williston Park) 2001;15:1627–1640. in women initiating tamoxifen with CYP2D6 inhibitors [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract CRA508. 11. Hewitt DJ. The management of pain in the oncology patient. Obstet Gynecol Clin North Am 2001;28:819–846. 32. Dezentje V, Van Blijderveen NJ, Gelderblom H, et al. Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage 12. Portenoy RK. Cancer pain. Epidemiology and syndromes. Cancer breast cancer: a pharmacoepidemiologic study [abstract]. J Clin 1989;63:2298–2307. Oncol 2009;27(Suppl 1):Abstract CRA509. 13. Hicks CL, von Baeyer CL, Spafford PA, et al. The Faces Pain Scale- 33. Portenoy RK, Lesage P. Management of cancer pain. Lancet Revised: toward a common metric in pediatric pain measurement. 1999;353:1695–1700. Pain 2001;93:173–183. 34. Stevens RA, Ghazi SM. Routes of opioid analgesic therapy in the 14. Serlin RC, Mendoza TR, Nakamura Y, et al. When is cancer pain management of cancer pain. Cancer Control 2000;7:132–141. mild, moderate or severe? Grading pain severity by its interference with function. Pain 1995;61:277–284. 35. Harris JT, Suresh Kumar K, Rajagopal MR. Intravenous morphine for rapid control of severe cancer pain. Palliat Med 2003;17:248– 15. Soetenga D, Frank J, Pellino TA. Assessment of the validity and 256. reliability of the University of Wisconsin Children’s Hospital Pain scale for Preverbal and Nonverbal Children. Pediatr Nurs 36. McNicol E, Horowicz-Mehler N, Fisk RA, et al. Management of 1999;25:670–676. opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain 2003;4:231–256. 16. Al-Atiyyat HN. Cultural diversity and cancer pain. J Hosp Palliat Nurs 2009;11:154–164. 37. Mercadante S. Comments on Wang et al., PAIN, 67 (1996) 407- 416. Pain 1998;74:106–107. 17. Ezenwa MO, Ameringer S, Ward SE, Serlin RC. Racial and ethnic disparities in pain management in the United States. J Nurs 38. Mercadante S. Pathophysiology and treatment of opioid-related Scholarsh 2006;38:225–233. myoclonus in cancer patients. Pain 1998;74:5–9. 18. American Pain Society. Principles of Analgesic Use in the 39. Wilson RK, Weissman DE. Neuroexcitatory effects of opioids: Treatment of Acute Pain and Cancer Pain, 5th ed. Glenview, IL: patient assessment #57. J Palliat Med 2004;7:579. American Pain Society; 2003. 40. Moryl N, Carver, A, Foley KM. Pain and palliation. In: Holland JF, 19. Mercadante SL, Berchovich M, Casuccio A, et al. A prospective Frei E, eds. Cancer Medicine. Vol. I7. Hamilton, ON: BC Decker randomized study of corticosteroids as adjuvant drugs to opioids in Inc; 2006:1113–1124. advanced cancer patients. Am J Hosp Palliat Care 2007;24:13–19. 41. Moryl N, Obbens EA, Ozigbo OH, Kris MG. Analgesic effect of 20. Klepstad P, Kaasa S, Borchgrevink PC. Start of oral morphine gefitinib in the treatment of non-small cell lung cancer. J Support to cancer patients: effective serum morphine concentrations Oncol 2006;4:111. and contribution from morphine-6-glucuronide to the analgesia 42. Boettger S, Breitbart W. Atypical antipsychotics in the management produced by morphine. Eur J Clin Pharmacol 2000;55:713–719. of delirium: a review of the empirical literature. Palliat Support 21. Klepstad P, Kaasa S, Skauge M, Borchgrevink PC. Pain intensity Care 2005;3:227–237. and side effects during titration of morphine to cancer patients 43. Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of

Adult Cancer Pain

haloperidol, chlorpromazine, and lorazepam in the treatment pain. J Pain Symptom Manage 2005;30:485–491. of delirium in hospitalized AIDS patients. Am J Psychiatry 54. Greenberg HS, Taren J, Ensminger WD, Doan K. Benefit from 1996;153:231–237. and tolerance to continuous intrathecal infusion of morphine for 44. Bruera E, Belzile M, Neumann C, et al. A double-blind, crossover intractable cancer pain. J Neurosurg 1982;57:360–364. study of controlled-release metoclopramide and placebo for the 55. Chen H, Lamer TJ, Rho RH, et al. Contemporary management of chronic nausea and dyspepsia of advanced cancer. J Pain Symptom neuropathic pain for the primary care physician. Mayo Clin Proc Manage 2000;19:427–435. 2004;79:1533–1545. 45. Challoner KR, McCarron MM, Newton EJ. Pentazocine (Talwin) 56. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in intoxication: report of 57 cases. J Emerg Med 1990;8:67–74. cancer pain management. Oncologist 2004;9:571–591. 46. Katcher J, Walsh D. Opioid-induced itching: morphine sulfate and hydromorphone hydrochloride. J Pain Symptom Manage 57. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant 1999;17:70–72. use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 2005;97:30–39. 47. Marinella MA. Acute colonic pseudo-obstruction complicated by cecal perforation in a patient with Parkinson’s disease. South Med 58. Manfredi PL, Gonzales GR, Sady R, et al. Neuropathic pain in J 1997;90:1023–1026. patients with cancer. J Palliat Care 2003;19:115–118. 48. Reissig JE, Rybarczyk AM. Pharmacologic treatment of opioid- 59. Stockler M, Vardy J, Pillai A, Warr D. Acetaminophen induced sedation in chronic pain. Ann Pharmacother 2005;39:727– (paracetamol) improves pain and well-being in people with 731. advanced cancer already receiving a strong opioid regimen: a 49. Tarcatu D, Tamasdan C, Moryl N, Obbens E. Are we still scratching randomized, double-blind, placebo-controlled cross-over trial. J the surface? A case of intractable pruritus following systemic opioid Clin Oncol 2004;22:3389–3394. analgesia. J Opioid Manag 2007;3:167–170. 50. Prommer E. Modafinil: is it ready for prime time? J Opioid Manag Recommended Readings 2006;2:130–136. Levy MH, Chwistek M, Mehta RS. Management of chronic pain in cancer survivors. Cancer J 2008;14:401–409. 51. Hawley PH, Byeon JJ. A comparison of sennosides-based bowel protocols with and without docusate in hospitalized patients with Levy MH, Samuel TA. Management of cancer pain. Semin Oncol cancer. J Palliat Med 2008;11:575–581. 2005;32:179–193. 52. Slatkin NE. Opioid switching and rotation in primary care: Kochhar R, Legrand SB, Walsh D, et al. Opioids in cancer pain: implementation and clinical utility. Curr Med Res Opin common dosing errors. Oncology (Williston Park) 2003;17:571– 2009;25:2133–2150. 575; discussion 575–576, 579. 53. Mercadante S, Arcuri E, Ferrera P, et al. Alternative treatments of Ripamonti C, Zecca E, Bruera E. An update on the clinical use of breakthrough pain in patients receiving spinal analgesics for cancer methadone for cancer pain. Pain 1997;70:109–115.

Adult Cancer Pain Date Completed 10/28/09 10/28/09 1/6/10 7/6/09 10/28/09 8/16/10 10/28/09 4/6/10 12/21/09 1/18/10 12/21/09 10/28/09 10/28/09 10/28/09 Pending* 10/28/09 10/28/09 12/21/09 7/9/09 10/28/09 9/30/09 10/28/09 10/28/09 10/28/09 10/28/09 Other None None None None None None None None None None Accuray Incorporated; and ICON Contract Research Organization None None None None None None None None None None None None None Patent, or Equity, Royalty None None None None None None None None None None None None None None None None None None None None None None None None Advisory Boards, Speakers Bureau, Speakers Bureau, Advisory Boards, Expert Witness, or Consultant Pfizer Inc. None None Cephalon, Inc. Bayer HealthCare; Onyx Pharmaceuticals, Inc.; Pfizer and sanofi-aventis U.S. None None Forrester Pharma; King Pfizer Inc.; Pharmaceuticals Incorporated; and Vertex Wyeth Pharmaceuticals Novartis Pharmaceuticals Corporation; and EUSA Pharmaceuticals None Accuray Incorporated; and ICON Contract Research Organization Eli Lilly and Company; Wyeth Pharmaceuticals None None None None None None None None None None Merck & Co., Inc.; and Wyeth Pharmaceuticals None for updates. www.NCCN.org Clinical Research Support Clinical Research DARA Pharmaceuticals; and Wyeth Pharmaceuticals None None None BEST None None None None None Accuray Incorporated; and ICON Contract Research Organization None Cephalon, Inc.; Johnson & Johnson; and Wyeth Pharmaceuticals None None Medtronic, Inc. None None None None None None Eisai Inc. None Panel Member MD Amy Pickar Abernethy, Doralina L. Anghelescu, MD Costantino Benedetti, MD Craig D. Blinderman, MD, MA Barry Boston, MD Charles Cleeland, PhD Nessa Coyle, PhD, NP Oscar A. deLeon-Casasola, MD June G. Eilers, PhD, APRN Betty Ferrell, RN, PhD Nora A Janjan, MD, MPSA, MBA MD Sloan Beth Karver, MD, PhD Michael H. Levy, MS, APRN Maureen Lynch, Natalie Moryl, MD MD Barbara A. Murphy, Suzanne A. Nesbit, PharmD, BCPS Linda Oakes, RN, MSN Eugenie A. Obbens, MD, PhD Judith A. Paice, PhD, RN MD Rabow, Michael W. Robert Swarm, MD Karen L. Syrjala, PhD Susan Urba, MD MD Sharon M. Weinstein, Individual Disclosures of the NCCN Adult Cancer Pain Panel Individual Disclosures The NCCN Guidelines staff have no conflicts to disclose. The NCCN Guidelines staff *Information not available at press. Please go to