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ONCOLOGY BOARD REVIEW MANUAL PUBLISHING STAFF

Cancer Pain Management: II

PRESIDENT, PUBLISHER

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Bruce M.White EXECUTIVE EDITOR

Debra Dreger SENIOR EDITOR

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Tish Berchtold Klus Christie Grams Mary Beth Cunney

Attending Physician, Department of Adult Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Associate Professor of Medicine, Harvard Medical School, Boston, MA

Contributing Authors: Maureen Lynch, MS, RN, CS, AOCN, CHPN Oncology Nurse Practitioner, Pain and Symptom Management Service, Dana-Farber Cancer Institute, Boston, MA

Nathaniel P. Katz, MD Medical Co-Director, Pain and Symptom Management Service, Dana-Farber Cancer Institute, Director, Pain Clinical Trials Center, Neurologist, Pain Management Center, Brigham and Women’s Hospital, Assistant Professor of Anesthesia, Harvard Medical School, Boston, MA

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Table of Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 2

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Pharmacologic Management. . . . . . . . . . . . . 2 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Board Review Questions. . . . . . . . . . . . . . . 11 Detailed Answers . . . . . . . . . . . . . . . . . . . . 12 References . . . . . . . . . . . . . . . . . . . . . . . . . 12 Cover Illustration by Christie Grams

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Oncology Volume 5, Part 2 1

ONCOLOGY BOARD REVIEW MANUAL

Cancer Pain Management: II Maureen Lynch, MS, RN, CS, AOCN, CHPN Nathaniel P. Katz, MD a. b. c. d.

I. INTRODUCTION A. This manual is the second of 2 parts on cancer pain management. Part 1 focused on the etiology of cancer pain, assessment of pain, common cancer pain syndromes, nonpharmacologic pain management, invasive techniques for pain management, and pain management in patients with substance abuse problems or in those who are elderly. Part 2 focuses on pharmacologic therapy and also provides review questions for self assessment. B. Comprehensive cancer pain management recognizes and treats the physical, psychological, social, and spiritual distress evoked by pain. C. The patient’s self report of pain provides best indicator of pain’s existence and extent. D. Successful pain management begins with assessment and formulation of the pain diagnosis. 1. Assessment includes location, intensity, and quality of the pain as well as information about factors that intensify or alleviate the pain, including medications and other therapies. 2. Pain diagnosis includes the etiology of pain and type of pain (eg, somatic, visceral, and/or neuropathic). E. Rational pain management includes treating causes of pain when possible, optimizing analgesic medications, using nonpharmacological interventions for function and comfort, and using invasive procedures when appropriate. Cancer pain can be successfully managed in 75% to 90% of patients using relatively simple interventions.

II. PHARMACOLOGIC MANAGEMENT A. World Health Organization (WHO) analgesic ladder (Figure 1) 1. The WHO 3-step analgesic ladder is a guide to rational use of analgesic medications. 2. The WHO approach emphasizes:

2 Hospital Physician Board Review Manual

3. 4.

Use of oral medication Use of scheduled analgesic administration Consideration of individual needs Attention to timing, dosing, effectiveness, and side-effect management This approach is effective in relieving 75% to 90% of cancer-related pain.1 Breakdown of the 3-step analgesic ladder a. Step 1: Patients with mild-to-moderate pain who have not taken any analgesic therapy are treated with nonopioid medications (nonsteroidal anti-inflammatory drugs [NSAIDs] or acetaminophen); use of appropriate adjuvants is optional. b. Step 2: If pain persists or worsens despite maximum doses of nonopioids, add an opioid for mild-to-moderate pain. 1) Clinically, the use of a nonopioid on a scheduled basis and short-acting opioids on an as-needed basis is effective. 2) Products containing a combination of acetaminophen with codeine, hydrocodone, or oxycodone are often used at this step. 3) The daily doses of combination products are limited by acetaminophen because doses of acetaminophen greater than 4 g per day are not recommended. 4) Tramadol, a weak mu agonist that inhibits reuptake of serotonin and norepinephrine, acts an opioid and nonopioid.2 – 4 a) Tramadol, 50 mg orally, provides analgesia equal to oral codeine, 60 mg. b) Tramadol may be useful in patients who cannot tolerate NSAIDs or who wish to defer use of traditional opioids.4 c) Tramadol reaches ceiling effect (ie, increased doses will not

Cancer Pain Management: II increase analgesia and may precipitate side effects or toxicity) at 400 mg in 24 hours. d) Tramadol should not be mixed with other opioids. 5) Propoxyphene is not recommended for routine use because of its long half-life and the risk of accumulation of its toxic metabolite, norpropoxyphene, which is associated with pulmonary edema and cardiotoxicity.4,5 c. Step 3: If pain persists or worsens, an opioid for moderate-to-severe pain is added. 1) Typical opioids include morphine, hydromorphone, fentanyl, oxycodone, and methadone. 2) Methadone or long-acting formulations of morphine, oxycodone, hydromorphone, and fentanyl are used on a fixed schedule to provide background analgesia. In addition, shortacting formulations are used as rescue doses for breakthrough pain on an as-needed basis. B. Nonopioid analgesics (Table 1) 1. Acetaminophen is an analgesic for mild-tomoderate pain and is also an antipyretic. a. Single doses higher than 1000 mg do not improve analgesia. b. Total daily doses higher than 4000 mg are not recommended because of potential hepatotoxicity. c. Hepatotoxicity is possible if acetaminophen is used in excessive doses or in the presence of hepatic disease or alcoholism. 2. NSAIDs a. Heterogeneous class of drugs that have analgesic, antipyretic, and anti-inflammatory activities b. Recommended for all cancer pain unless specific contraindications (such as gastrointestinal [GI] ulceration or bleeding, impaired coagulation, or decreased hepatic and/or renal function) are present. Primary uses are: 1) As sole analgesics for mild-to-moderate pain 2) In the treatment of bone pain1,2,4,5 c. The mechanism of action involves producing an analgesic effect via inhibition of cyclooxygenase, an enzyme needed for prostaglandin production. Two forms of

No cancer pain

Add “strong” opioid for moderate-to-severe pain ± adjuvant ± nonopioid

Pain increases or persists

Add “weak” opioid for mild-to-moderate pain ± adjuvant ± nonopioid

Pain increases or persists Nonopioid ± adjuvant

Pain Figure 1. World Health Organization (WHO) analgesic ladder. Adapted from World Health Organization: Cancer Pain Relief and Palliative Care. WHO, 1990.

cyclooxygenase (COX) are known, referred to as COX-1 and COX-2. 1) COX-1 is present in normal tissues of the GI tract, kidney, and platelets; COX-1 provides functional and protective effects. 2) COX-2 is present primarily in inflamed tissue.6 3) Traditional NSAIDs (eg, ibuprofen, naproxen) inhibit COX-1 and COX-2, producing analgesia and common NSAID-associated side effects.6,7 4) New agents, such as celecoxib and rofecoxib, primarily inhibit COX-2, producing analgesia with decreased incidence of GI ulceration and with no effect on platelet function. COX-2 inhibitors have not demonstrated renal- or hepatic-sparing effects. Currently, these agents are approved by the Food and Drug Administration (FDA) for arthritis pain management. Rofecoxib is also approved for management of acute pain.


Cancer Pain Management: II Table 1. Commonly Used Nonopioid Analgesic Agents Usual Dose, mg

Drug

Maximum Dose, mg/day

Comments Hepatic toxicity

Acetaminophen

650–1000 every 4–6 h

4000

Ibuprofen

400–800 every 4–8 h

3200

Naproxen

250–500 bid or tid

1500

Nabumetone

500–1000 bid

2000

Sulindac

150–200 bid or tid

0400

Ketoralac

15–30 IV every 6 h

0120

Limit use to 5 days to avoid increased GI complications

Choline magnesium trisalicylate

500–1500 bid

3000

May be platelet sparing

Celecoxib

100–200 bid

Cross-sensitivity to sulfa allergy, platelet sparing

Rofecoxib

25 every day

Available as suspension; platelet sparing

bid = twice daily; GI = gastrointestinal; IV = intravenous; tid = three times daily. Data from U.S. Management of Cancer Pain Guideline Panel: Management of Cancer Pain, Clinical Practice Guideline No. 9. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1994. AHCPR Publication No. 94-0592; and from McCaffery M, Portenoy RK: Nonopioids. In Pain Clinical Manual, 2nd ed. McCaffery M, Pasero CL, eds. St. Louis, MO: Mosby, 1999:129–160.

d. NSAID doses should be gradually increased until analgesia, side effects, or ceiling dose is reached. All NSAIDs have ceiling doses (Table 1). e. Agent selection is based on dose schedule, toxicity profile, cost, and effectiveness for the individual patient. f. No particular oral NSAID has demonstrated analgesic superiority; toxicity profiles vary. g. Use of more than 1 NSAID at a time is not recommended.5 If 1 NSAID is ineffective, the trial of another is recommended, especially for bone-related pain. h. The most common route of administration is oral. Liquid and rectal suppository forms are available for some agents. i. Ketorolac is a highly effective analgesic and the only available intravenous (IV) NSAID. It is equianalgesic to 10 mg intramuscular (IM) morphine, but its use is limited to 30 mg every 6 hours for a maximum of 5 days because of substantial GI toxicity. Oral ketorolac is no more efficacious than other NSAIDs. j. GI toxicity of NSAIDs includes dyspepsia, nausea/vomiting, hemorrhagic gastritis, and ulceration.


k.

1) Severe GI toxicity can occur without prodrome. 2) Patients are at increased risk for serious GI toxicity if they have any of the following risk factors: increased age (ie, > 65 years), history of peptic ulcerations, concomitant use of anticoagulants and/or corticosteroids, and excessive alcohol use. 3) Of traditional NSAIDs, ibuprofen may be least toxic to the GI system.4,5 4) Use of misoprostol, 100 to 200 µg 4 times daily, reduces incidence of NSAID-related ulcerations but not dyspepsia. Side effects and expense may limit usefulness. 5) The use of a combination of H2-receptor blockers, sucralfate, and antacids may be an alternative. Ranitidine and famotidine were associated with decreased GI ulceration.7 6) As with traditional NSAIDs, COX-2 inhibitors are sometimes associated with serious GI toxicity. Bleeding caused by inhibition of platelet function associated with NSAID use is a common concern. 1) Thrombocytopenia or use of

Cancer Pain Management: II anticoagulants are relative contraindications to use of NSAIDs because of inhibition of platelet aggregation. 2) Nonacetylated salicylates (eg, salsalate, sodium salicylate, choline magnesium trisalicylate) appear not to alter platelet function but may not provide analgesia equal to that of other traditional NSAIDs.1 3) COX-2 inhibitors have minimal effect on platelet aggregation. l. Renal failure or impaired renal function induced by NSAIDs is usually reversible with cessation of the agent. Patients with congestive heart failure, cirrhosis, or impaired renal blood flow are at increased risk.5 m. Hepatic dysfunction may occur even if ceiling doses are not exceeded. n. Bronchospasm may be precipitated in patients with a history of asthma. o. Allergies to NSAIDs are uncommon, but bronchospasm, urticarial rash, and laryngeal edema can occur. p. NSAID-associated water retention can cause peripheral edema and decrease effectiveness of diuretics and antihypertensives. C. Opioids 1. Pharmacology and classification a. Produce analgesia by binding to receptors in the brain and spinal cord, inhibiting the release of neurotransmitters and activity of nociceptive pathways 5,8 b. The primary opioid receptors are mu, delta, kappa, and sigma (Table 2).9 c. Classified according to receptor bonding. 1) Full (or pure) agonists have no analgesic ceiling effect, will not reverse analgesia of other opioids in this class, and have similar clinical effectiveness. Morphine, oxycodone, hydromorphone, fentanyl, methadone, and meperidine are full agonists. 2) Agonist-antagonist drugs have an analgesic ceiling effect and reverse analgesia from pure agonist drugs. Agonist-antagonist drugs are NOT recommended for cancer pain management.1,2 Pentazocine, nalbuphine, and butorphanol are in this class. 2. Tolerance, physical dependence, addiction, and pseudo-addiction

a.

3.

Tolerance is the need for increased doses of a drug to maintain effect; it occurs with chronic opioid use. Tolerance to analgesic effect is uncommon in oncology practice.5 Tolerance to opioid side effects is desirable and common, allowing for dose increases over time. b. Physical dependence manifests as withdrawal symptoms if the opioid is abruptly discontinued, dose is significantly (> 50% to 75%) reduced, or an antagonist is given. Physical dependence is an expected effect of chronic opioid use and is not related to addiction. Typical withdrawal symptoms include increased pain, anxiety, irritability, nausea, diarrhea, abdominal pain, diaphoresis, rhinorrhea, and lacrimation. c. Addiction is a behavioral/psychiatric condition characterized by loss of control over opioid use or excessive preoccupation with drug use for psychic effect; the condition is often associated with aberrant, destructive behavior. Addiction in patients with cancer pain is rare. d. Pseudo-addictive behaviors include frequent requests for analgesics, “clockwatching,” and hoarding analgesics during times of acceptable pain control; these behaviors are associated with uncontrolled pain or fear of uncontrolled pain. Pseudo-addictive behaviors are not the same as addiction. Increasing doses or availability of analgesics usually resolves the pseudo-addiction.8 Routes of administration a. Oral route is preferred for managing chronic pain. 1) Convenient, less expensive, acceptable to patients, and effective 2) Opioids given orally undergo first-pass metabolism in the liver, have longer onset and duration of action, and require higher doses for equianalgesia than opioids given parenterally. 3) Formulations include: a) Short-acting tablets and liquids b) Controlled-release, sustainedrelease, or long-acting tablets and capsules c) Sustained-release tablets should not be crushed or chewed. b. Sublingual route can be used for concentrated liquids and soluble tablets. An oral


Cancer Pain Management: II Table 2. Opioid Receptors Receptor Type

Agonist

Major Actions of Receptor Binding

Antagonist*

Mu

Morphine, fentanyl, hydromorphone, methadone, oxycodone, merperidine

Sedation, supraspinal analgesia, bradycardia, respiratory depression, euphoria, physical dependence

Naloxone, pentazocine, nalbuphine, butorphanol

Delta

D-Ala-D-Leu, enkephalins

Weak spinal analgesia, respiratory depression

Kappa

Nalbuphine†, butorphanol†, pentazocine†

Weak spinal analgesia, respiratory depression, sedation, inhibits antidiuretic hormone

Sigma

Pentazocine†

Dysphoria, delirium, hallucinations, tachycardia, hypertension

*Any of these antagonists will block the mu agonists. †These drugs are agonist-antagonist drugs, and they are NOT recommended for cancer pain management. Agonist-antagonist drugs have an analgesic ceiling effect and reverse analgesia from pure agonist drugs. Adapted with permission from Hsieh JC, Carr DB: Choosing a therapeutic approach: opioids. In The Massachusetts General Hospital Handbook of Pain Management. Borsook D, LeBel AA, McPeek B, eds. Boston: Little, Brown, 1996:49.

transmucosal fentanyl lozenge was recently approved for management of breakthrough pain. c. Transdermal fentanyl (patch) is available for stable chronic pain. 1) The pharmacokinetics of this patch may vary substantially among patients. 2) Onset of action is 12 to 24 hours, and drug effect may continue for 12 to 24 hours after patch removal. 3) Patches are changed every 72 hours. Some patients need to change the patch every 48 hours to maintain analgesia. 4) Use of multiple patches is possible, but dosing is limited by body surface area. d. Rectal administration is relatively contraindicated in patients with anorectal disease, diarrhea, impaction, thrombocytopenia and/or neutropenia. It can be used temporarily or chronically when oral route is limited. Suppositories of short-acting morphine (ie, 5 mg, 10 mg, 20 mg, and 30 mg) or hydromorphone, 3 mg, are available. e. Subcutaneous and intramuscular bolus injections are not recommended for rou-


4.

tine use because of discomfort associated with administration. Continuous infusion subcutaneously with or without patientcontrolled analgesia (PCA) can be accomplished with relative comfort. f. The IV route is preferred for rapid titration of opioid dose in a setting of severe pain and may provide long-term analgesia if other routes are not available or suitable. Intermittent boluses, continuous infusion, or PCA may be given via peripheral or central IV access. Selection a. Opioid agonists are equally effective in achieving analgesia, although patients vary in their response to and tolerance of the various opioids. b. Opioids differ in analgesic potency (ie, the dose required to produce equianalgesic effect). c. Initial selection for treatment is based on patient experience with such medications, suitability of available dosing forms, route of administration, specific drug pharmacokinetics (Table 3), and cost. d. Renal impairment delays clearance of opioids and their active metabolites and increases risk for adverse effects.

Cancer Pain Management: II e.

5.

The same drug should be used as longacting opioid and breakthrough medication whenever possible to assist in determining effectiveness and side-effect profile. f. Selecting the most appropriate drug 1) Morphine is the standard opioid (ie, gold standard and standard of comparison). It is metabolized in the liver and excreted in urine and bile. One of its metabolites, morphine6-glucuronide, is more potent than morphine and has a longer half-life. 2) Fentanyl is lipophilic with a short onset and duration of action. With repeat or continuous administration, it may accumulate, leading to delayed sedation and respiratory depression. 3) Methadone is inexpensive, as effective an analgesic as morphine, and highly bioavailable after oral administration. Methadone dosing and titration are highly individual because of its long and variable half-life. 4) Codeine has limited use in managing moderate-to-severe cancer pain. 5) Meperidine is not recommended for use in cancer pain management. It has a short half-life, and accumulation of its active metabolite, normeperidine, may lead to irritability, agitation, tremors, and seizures. Dosing and titration a. The key principle in opioid administration is titration to the point of effective analgesia or unacceptable side effects. 1) Full agonist opioids have no intrinsic ceiling dose. Individual patient tolerance determines maximal dose. 2) Unless unacceptable side effects develop, dose increases should be made until analgesia is achieved. b. Fixed schedules of long-acting opioid formulations with short-acting formulations as needed for breakthrough pain are used to manage moderate-to-severe pain. 1) Initial therapy for patients unaccustomed to taking opioids begins with short-acting as-needed medication available at least every 3 to 4 hours to establish the analgesic requirement. 2) Long-acting medication is added in a daily dose equal to 25% to 100%

6.

(depending on pain severity) of the daily dose of short-acting medication consumed; as-needed medication for breakthrough pain is continued.4 3) Each dose for breakthrough pain should equal 10% to 15% of the 24-hour dose of the background analgesia.2,8 4) Use of more than 3 to 4 doses per day for breakthrough pain indicates the need to increase background analgesia. 5) Doses continue to be titrated up using this method until optimum analgesia or unacceptable side effects occur. 6) The patient’s analgesic plan should include only 1 long-acting opioid and 1 short-acting opioid at a time. Equianalgesia a. Equianalgesia refers to the determination of doses of various opioids needed to achieve the same analgesic effect via oral or parenteral routes. b. Conversion charts, established via research and clinical experience, are used to determine the dose of a specific opioid that will maintain analgesia when switching opioids or routes of administration. However, dose calculations using these conversion charts are estimates. Clinical judgment and patient response should guide dose titration (Table 4). c. Changing opioid medication (opioid rotation) may be necessary under certain circumstances. 1) When unacceptable side effects occur, such as sedation, persistent nausea/vomiting, pruritus, urinary retention, or myoclonus 2) When the route of administration must be changed 3) When metabolite accumulation of a specific opioid becomes problematic 4) When a less expensive opioid is needed d. Poor analgesic effect is usually a function of dose, not the specific opioid used. e. Cross-tolerance is the development of tolerance to effects and side effects of pharmacologically related drugs. 1) Cross-tolerance among opioids is incomplete.


Cancer Pain Management: II Table 3. Pharmacokinetics of Commonly Used Opioid Analgesic Agents Drug

Onset

Peak

Duration of Action

Fentanyl

Half-Life 2–4 hr

IV

Rapid

Transdermal

12–18 hr

Transmucosal

5–15 min

5–10 min

1–2 hr 48–72 hr

20–30 min

1–2 hr

Hydromorphone

2– 4 hr

IV

Rapid

10–15 min

3– 4 hr

Oral

15–30 min

1–2 hr

3– 4 hr

Rapid

15–20 min

2– 4 hr

Meperidine IV Morphine

2–3 hr 2–4 hr

IV

Rapid

15–20 min

2– 4 hr

Oral IR

15–60 min

30–60 min

2–6 hr

SR

60–90 min

1– 4 hr

6–12 hr

Methadone

18–20 hr

IV

10–15 min

5–20 min

4–6 hr

Oral

30–60 min

90–120 min

4–12 hr

Oral IR

20–60 min

60–90 min

3–6 hr

2–4 hr

SR

60 min

1– 4 hr

6–12 hr

4.5 hr

Oxycodone

IR = immediate release; IV = intravenous; PO = orally; SR = sustained release. Data from U.S. Management of Cancer Pain Guideline Panel: Management of Cancer Pain, Clinical Practice Guideline No. 9. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1994. AHCPR Publication No. 940592; and Portenoy RK: Contemporary Diagnosis and Management of Pain in Oncologic and AIDS Patients. Newtown, PA: Handbooks in Health Care, 1997; and Levy M: Pharmacologic treatment of cancer pain. N Engl J Med 1996;335:1124 –1132; and Hsieh JC, Carr DB: Choosing a therapeutic approach: opioids. In The Massachusetts General Hospital Handbook of Pain Management. Borsook D, LeBel AA, McPeek B, eds. Boston: Little, Brown, 1996:47–75.

7.

2) Conservative calculation of the equianalgesic dose of a new opioid accounts for incomplete cross-tolerance among opioids by starting the new opioid at 50% to 75% of the calculated dose to prevent oversedation and respiratory depression. However, the American Pain Society guidelines no longer make this recommendation.2,4 Side effects a. Opioid side effects of nausea/vomiting, sedation, respiratory depression, constipation, pruritus, and neuropsychologic changes (impaired cognitive function, slowed reactions) are common in patients unaccustomed to taking opioids. Less common opioid side effects are urinary retention, delirium, and myoclonus.


b.

As tolerance to the opioid develops, all of these side effects tend to diminish except constipation. c. Opioid side effects are managed in several ways. 1) Allow tolerance to develop. This approach is often used when sedation occurs with initial opioid use. 2) Adjust dose or schedule of the opioid (eg, decreasing each dose but increasing frequency or adding a long-acting opioid). 3) Initiate opioid rotation in equianalgesic doses. Response to specific opioids is highly individual. 4) Add specific therapies for side effects.4,5,8 d. Respiratory depression is the most feared opioid side effect, but it rarely occurs in

Cancer Pain Management: II opioid-tolerant patients. Sedation usually precedes respiratory depression. 1) In the opioid-tolerant patient, provision of respiratory support may be the most appropriate management. 2) Acute respiratory depression can be reversed with administration of an opioid antagonist, such as naloxone (Table 5). e. Persistent sedation may respond to psychostimulants, such as caffeine, methylphenidate, or dextroamphetamine. These medications also provide additive analgesic effect and antidepressant effects. The usual starting dose of methylphenidate is 5 mg in the morning and at noon.4 f. Neuropsychologic changes (confusion, hallucinations) are usually mild and resolve over days to weeks.8 g. Nausea and vomiting are managed with antiemetics. Monitor for additive sedation effect. h. Constipation is a persistent problem with chronic opioid use. 1) Tolerance does not develop. 2) Untreated opioid-induced constipation may lead to impaction and ileus. 3) Intestinal obstruction may be clinically difficult to differentiate from opioidinduced constipation. 4) Prophylactic use of stool softeners and stimulant laxatives on a fixed (not asneeded) schedule is recommended. a) Docusate sodium, 200 to 400 mg daily, is an effective stool softener. b) Poorly absorbable sugars (eg, lactulose and sorbitol) liquefy stool and increase its bulk. c) Stimulant laxatives (eg, senna, bisacodyl, cascara) increase peristalsis. d) Saline laxatives (eg, magnesium hydroxide and magnesium citrate) are generally administered every 2 to 3 days and can be helpful when the daily regime fails. e) Lubricants such as mineral oil are reserved for treating impaction. Frequent use may cause perirectal irritation and may interfere with absorption of fat-soluble vitamins.

Table 4. Equianalgesic Doses of Commonly Used Opioids* Route of Administration Drug

Oral

Intravenous

Morphine

30 mg

10 mg

Hydromorphone

7.5 mg

1.5 mg

Oxycodone Fentanyl

20 mg †

100 µg

Methadone

20 mg

10 mg

N/A

*These recommendations are for patients who take opioids on a longterm basis. †A 25-µg/hr patch equals about 50 mg oral morphine daily.

Example of equianalgesic conversion: A patient who has breast cancer with painful bone metastasis is admitted because of severe nausea and vomiting after chemotherapy. She is unable to tolerate her usual analgesics, which consist of morphine sulfate controlled release (CR) 60 mg every 12 hours with 4 daily doses for breakthrough pain of immediate release (IR) morphine, 15 mg. Because of elevated blood urea nitrogen/ creatinine levels, her medical team decides to switch her to intravenous (IV) hydromorphone continuous infusion. What is the appropriate dose? 1. Determine total daily dose of oral morphine: Morphine sulfate CR 60 mg every 12 h = 120 mg Morphine sulfate IR 15 mg × 4 doses = 60 mg Total: 180 mg of oral morphine daily 2. Find appropriate conversion from table: 30 mg of oral morphine = 1.5 mg IV hydromorphone 3. Set up equation: 180 mg oral morphine = x mg IV hydromorphone 30 mg oral morphine = 1.5 mg IV hydromorphone 270 = 30x x = 9 mg/24 hr 180 mg oral morphine daily = 9 mg IV hydromorphone daily 4. Divide 9 mg IV hydromorphone/day by 24 hours = 0.375 mg/hr 5. Conservative calculation would reduce the dose to correct for incomplete cross-tolerance:‡ 50% × 9 mg IV hydromorphone = 4.5 mg IV hydromorphone/day = 0.19 mg/hr ‡Note that the American Pain Society guidelines no longer make this recommendation.2,4 Data from U.S. Management of Cancer Pain Guideline Panel: Management of Cancer Pain, Clinical Practice Guideline No. 9. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research,1994:52.AHCPR Publication No.94-0592; and from American Pain Society:Principles of Analgesic Use inTreatment of Acute and Cancer Pain, 4th ed. Glenview, IL:The American Pain Society, 1999:14.


Cancer Pain Management: II Table 5. Naloxone Administration Guide* Step 1. Support respiratory effort. Airway Breathing Oxygen Step 2. If naloxone administration is indicated in the opioidtolerant patient, give incrementally to avoid withdrawal: a. Mix 0.4 mg of naloxone (1 ampule) in 9–10 mL of normal saline. b. Administer 0.5–1 mL of naloxone every 1–2 min as an intravenous push. c. Monitor respiratory rate, depth, and sedation level after each increment. d. Stop administration when respiratory rate and depth increase and/or responsiveness to physical stimuli returns. e. Repeat administration every 30–60 minutes until opioid effect wears off. *Naloxone is an opioid antagonist; it reverses opioid-induced sedation and respiratory depression. However, nalaxone also reverses analgesia and precipitates withdrawal symptoms, cardiac arrhythmias, pulmonary edema, and cardiac arrest if improperly administered to the opioidtolerant patient. Naloxone may not be appropriate for patients who are actively dying in palliative care. Data from U.S. Management of Cancer Pain Guideline Panel: Management of Cancer Pain, Clinical Practice Guideline No. 9. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1994:52. AHCPR Publication No. 94-0592; and from American Pain Society: Principles of Analgesic Use in Treatment of Acute and Cancer Pain, 4th ed. Glenview, IL: The American Pain Society, 1999.

f)

i.

Oral naloxone can reverse opioidinduced constipation without reversing analgesia through its local effect on opioid receptors in the bowel. Because oral formulations are not yet available, the injectable form is given orally, making this therapy costly; the bitter taste makes it unpleasant. A starting dose of 1 mg twice daily up to a maximum dose of 16 mg twice daily is suggested. 5) Stool softeners alone and bulk-forming laxatives are not recommended.8 6) Suppositories and enemas can be used for short-term management if no contraindications are present. Accumulation of metabolites of mor-


8.

phine, meperidine, and hydromorphone has been reported. Patients with impaired renal or hepatic function are at risk for irritability, agitation, progressive myoclonus, and seizures. Dose reduction or opioid rotation is recommended. Adjuvant analgesics a. Adjuvants are medications that are not typically analgesic but may provide analgesia alone or in combination with analgesic agents in specific circumstances. b. The most commonly used adjuvants for neuropathic pain are tricyclic antidepressants and anticonvulsants. c. The most commonly used tricyclic antidepressants for neuropathic pain are amitriptyline, doxepin, imipramine, nortriptyline, and desipramine. 1) Analgesic efficacy is similar. 2) Selection is based on side-effect profile. Amitriptyline and doxepin provide night-time sedation; nortriptyline and desipramine have fewer side effects overall. 3) Side effects include dry mouth, constipation, sedation, urinary retention, and orthostatic hypotension. 4) Analgesic effect takes 2 to 4 weeks to develop. 5) Dose is started at 10 to 25 mg at bedtime and increased slowly to the usual analgesic dose of 50 to 75 mg at bedtime. d. Anticonvulsants 1) The most widely used anticonvulsant for neuropathic pain is gabapentin, which has good efficacy and sideeffect profile. a) Severe side effects are uncommon. The most common side effects are nausea, sedation, and dizziness. Leukopenia and peripheral edema are infrequently seen. b) No major drug-drug interactions c) Gabapentin doses of 100 to 1500 mg, 3 times daily, are used. Begin gabapentin at 100 mg, 3 times daily, and titrate every 2 to 3 days to an effective dose. d) Analgesic effect is often evident within 2 to 3 days. 2) Other anticonvulsants (eg, phenytoin,

Cancer Pain Management: II

e.

f.

carbamazepine, valproate) are used in managing certain types of neuropathic pain, but their use is limited because of possible hematologic effects. Corticosteroids are used as adjuvants in managing bone pain, visceral pain, and neuropathic pain associated with tumor infiltration of nerves. 1) Corticosteroids also provide mood elevation, appetite stimulation, and antiemesis. 2) Effectiveness is usually limited to 2 to 3 months before side effects of edema, immune suppression, or myopathy may outweigh benefits. 3) Use of low-dose corticosteroids such as dexamethasone, 2 to 4 mg twice daily, may be beneficial and well tolerated in patients with advanced disease states.4,5 Bisphosphonates inhibit bone resorption and are used in oncology to treat hypercalcemia, prevent pathologic fractures in the presence of osteolytic bone metastases, and decrease pain from bone metastases. Pamidronate, 60 to 90 mg IV monthly, is commonly used in patients with breast cancer and multiple myeloma.10

B. Analgesic side effects require prophylaxis, early recognition, and aggressive intervention. C. Continuous pain requires continuous medication. Use scheduled and as-needed doses. D. Pain that is uncontrolled is undertreated unless opioid side effects prevent adequate analgesia. In that case, other analgesic options should be pursued. E. If systemic analgesics and nonpharmacologic interventions are ineffective or produce intolerable side effects, consider nerve blocks, spinal analgesia, or neurosurgical approaches.

BOARD REVIEW QUESTIONS Choose the single best answer for each question. Questions 1 through 4 refer to the following case study. Patient 1 is a 48-year-old woman who underwent lumpectomy, chemotherapy, and radiation therapy for initial treatment of breast cancer diagnosed 2 years ago. At a routine follow-up, she reports that she has been doing well except for having back pain for the past 2 weeks. She thinks the pain is related to raking leaves and the position of her new computer at work. 1.

Which of the following is the most appropriate intervention for patient 1’s pain at this time? A) Concur with her diagnosis and suggest NSAIDs and heat B) Order dorsal spine radiographs C) Prescribe pamidronate D) Ask for more information about the pain and perform a physical examination

2.

One year later, a follow-up bone scan reveals lesions of the left sacroiliac joint and acetabulum. She reports pain in the left hip and buttock of 9/10 with movement and 6/10 at rest. She has been taking acetaminophen 1000 mg every 6 hours, but this therapy offers minimal pain control. Which of the following is the most appropriate pain management for patient 1 at this time? A) Increase frequency of acetaminophen to every 4 hours B) Add naproxen, 1500 mg twice daily C) Consult radiation oncology D) Switch to an oxycodone/acetaminophen (5 mg/325 mg) combination pill, 2 tablets every 12 hours as needed

III. SUMMARY A. The mainstay of cancer pain management is analgesics used according to the World Health Organization (WHO) ladder (Figure 1). 1. Use oral medications when possible. 2. Do not use meperidine, propoxyphene, or high-dose codeine. 3. Do not use intramuscular or subcutaneous intermittent bolus doses routinely. 4. Remember that the WHO ladder is additive; consider use of NSAIDs or adjuvants at each step. a. For bone pain, consider an NSAID or corticosteroid plus opioid plus bisphosphonate.1,5,10 b. For visceral pain, consider an opioid plus NSAID or corticosteroid.3,5 c. For neuropathic pain, consider an anticonvulsant or tricyclic antidepressant plus opioid.4,5


Cancer Pain Management: II 3.

Six months later, patient 1 is using sustainedrelease morphine, 45 mg every 12 hours, with morphine elixir 10 mg 2 to 3 times daily. She has had good pain control (1/10 to 3/10) for several weeks. However, she calls to report that she is using morphine elixir every 4 hours to control her pain. She requests additional morphine elixir because of the increased use. Which of the following is the most likely cause of the need for increased drug use? A) Increased pain from worsening disease B) Addiction with drug-seeking behavior C) Tolerance D) Anxiety and depression from her lifethreatening illness

4.

Several months later, patient 1 is hospitalized with a pathologic fracture of the left humerus. Because her pain is severe, she is placed on continuous intravenous (IV) infusion of morphine with patient-controlled analgesia. Before admission, she was using sustained-release morphine, 100 mg every 8 hours, and morphine elixir, 45 mg twice daily. Using equianalgesic conversion, the hourly morphine rate should be which of the following? A) 0.5 mg/hr B) 1 mg/hr C) 5 mg/hr D) 10 mg/hr

DETAILED ANSWERS 1. (D) Ask for more information about her pain and examine her. The initial assessment of a new complaint of pain focuses on identifying the etiology of the pain and begins with a detailed history of the pain and its characteristics as well as a physical examination.1 2. (C) Consult radiation oncology. Patient 1 may benefit from radiation therapy. Treating the etiology of the pain is the most effective means of managing it. Simultaneously, comfort is achieved through the use of pharmacologic and nonpharmacologic means. In this case, the analgesics either exceed ceiling doses (A, B) or are inconsistent with pharmacokinetics of the medication (D).1 3. (A) Increased pain from worsening disease. In treating patients with cancer-related pain, increased analgesic requirements usually correlate with worsening disease. Tolerance to oral medication is uncommon in clinical practice.1,5

4. (C) 5 mg/hr. Calculate using the equianalgesic chart (Table 4). The total daily oral opioid dose equals 390 mg (300 mg [100 mg × 3 doses] of long-acting morphine plus 90 mg each day in doses for breakthrough pain [45 mg × 2 doses]). From the equianalgesic chart: 30 mg oral morphine = 10 mg IV morphine 30 mg oral morphine ÷ 10 mg IV morphine = 390 mg oral morphine ÷ x mg IV morphine 30x = 3900 x = 130 mg IV 130 mg IV ÷ 24 hr = 5.4 mg/hr Start the continuous infusion at 5 mg/hr (dose is rounded down to 5 mg/hr for ease of administration)

REFERENCES 1. U.S. Management of Cancer Pain Guideline Panel: Management of Cancer Pain, Clinical Practice Guideline No. 9. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1994. AHCPR Publication No. 94-0592. 2. American Pain Society: Principles of Analgesic Use in Treatment of Acute and Cancer Pain, 4th ed. Glenview, IL: The American Pain Society, 1999. 3. Bamigbade TA, Langford RM: Tramadol hydrochloride: an overview of current use. Hosp Med 1998;59:373–376. 4. Levy M: Pharmacologic treatment of cancer pain. N Engl J Med 1996;335:1124–1132. 5. Portenoy RK: Contemporary Diagnosis and Management of Pain in Oncologic and AIDS Patients. Newtown, PA: Handbooks in Health Care, 1997. 6. Payne R: Pharmacological management of pain. In Principles and Practice of Supportive Oncology. Berger A, Portenoy RK, Weissman DE, eds. Philadelphia: LippincottRaven, 1998:61–75. 7. McCaffery M, Portenoy RK: Nonopioids. In Pain Clinical Manual, 2nd ed. McCaffery M, Pasero CL. St. Louis, MO: Mosby, 1999:129–160. 8. Pasero CL, Portenoy RK, McCaffery M: Opioid analgesics. In Pain Clinical Manual, 2nd ed. McCaffery M, Pasero CL. St. Louis, MO: Mosby, 1999:161–290. 9. Hsieh JC, Carr DB: Choosing a therapeutic approach: opioids. In The Massachusetts General Hospital Handbook of Pain Management. Borsook D, LeBel AA, McPeek B, eds. Boston: Little, Brown, 1996:47–75. 10. Mercadante S: Malignant bone pain: pathophysiology and treatment. Pain 1997;69(1–2):1–18.

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