Bethesda Handbook of Clinical Oncology, 2nd Edition

Supportive Care

37

General Principles of Cancer Pain Management

Jason R. Beckrow*

Richard A. Messmann^†

*Department of Internal Medicine, Michigan State University, East Lansing, Michigan

^†Department of Hematology/Oncology, Michigan State University, East Lansing, Michigan

Inappropriate or inadequate pain management is a considerable problem that results in suffering and decreased quality of life for patients with cancer. Most patients with advanced cancer, and up to 60% of patients with any stage of cancer diagnosis, experience considerable pain. The problem is not trivial, and unrelieved pain is a risk factor for suicide in patients with cancer. This chapter is designed to help clinicians focus on the three major components of any comprehensive pain-management plan: (a) initial patient assessment followed by (b) analgesic therapy, and (c) reassessment. The chapter is not intended to be an exhaustive review of pain management, but it may act as a helpful guide to facilitate an understanding of pain assessment and control.

INITIAL PATIENT ASSESSMENT

The initial assessment of any patient with cancer who is in pain should include a comprehensive history, with documentation of the following:

• The primary cancer diagnosis and current extent of disease: This may help define the etiology of the painful stimuli (e.g., prostate cancer and bone pain).
• Any current or earlier treatment of pain: Is the patient opiate naïve? Earlier analgesic interventions and documentation of outcomes may affect dosing considerations. The type(s) of analgesics being used by the patient as well as the administration route (Is the delivery of the medication optimized?), dose (Is the dose sufficient for analgesia?), schedule (Is there appropriate regularly scheduled “around-the-clock” coverage? Is the dosing interval consistent with the duration of action of the prescribed drug?), and change in effectiveness of current regimen (Is there a tolerance developing to the current regimen?) should be identified.
• Location of pain: Identify the specific area, depth or site from which the pain originates.
• Date of onset: Is this an acute or a chronic problem?
• Quality of pain: Characterization may help elucidate the etiology of pain. Is the pain cramping, burning, aching, dull, or sharp?
• Character of pain: Is the pain waxing or waning? What are the aggravating and alleviating factors? Is it constant or intermittent?
• Intensity and severity of pain: A visual analog scale (VAS) and a numeric scale (see Fig. 37.1) should be used to quantify and document the intensity of pain. The patient's subjective interpretation of the level of pain should be believed. Chronic cancer pain may not be accompanied

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by sympathetic stimulation, which is normally manifested as tachypnea or tachycardia, despite severe pain.

FIG. 37.1. Pain intensity scales: (Top) Visual analog scale (VAS). (Bottom) Simple descriptive pain intensity scale.

• Psychosocial evaluation (any concomitant major stresses?): Psychological dependency on prescription or illicit drugs, and on alcohol, should be identified.
• Pertinent medical history should be documented. Physical examination: The physical examination should characterize the manifestations of pain, such as atrophy, muscle weakness, and trigger points. A thorough neurologic examination is essential, especially if neuropathic pain is suspected. Appropriate laboratory and imaging studies should be obtained.
• These baseline findings should be documented in the patient's chart to facilitate future management.

PHARMACOLOGIC THERAPY

The six principles of pharmacologic pain management modified from the World Health Organization (WHO) report are as follows:

1. By the mouth:The oral route is the preferred route whenever possible (for the sake of the patient's convenience and to avoid painful i.m. injections).
2. By the clock:Basal analgesic administration should be based on a fixed schedule— “around the clock” (ATC) and not on an “as needed” (p.r.n.) basis. A rationally designed, regularly scheduled ATC dosing avoids the peak-and-trough effect of prn dosing, in which high serum levels of the analgesic correlate with adverse effects such as nausea, pruritus, or somnolence, and low levels correspond to periods of suboptimal analgesia. Patients should not rely on prn analgesics to cover basal pain-control requirements. However, prn analgesics should always be ordered for breakthrough pain control.
3. WHO three-step ladder(see Fig. 37.2):

FIG. 37.2. Three-step World Health Organization (WHO) analgesic ladder. (From Cancer pain relief, 2nd ed. Geneva: World Health Organization, 1996, with permission.)

4. Step 1: For mild pain, use nonopioid analgesics (see Table 37.1) with or without adjuvant therapy (see Table 37.2), at recommended dose and frequency.

TABLE 37.1. Select Nonopioid Analgesics

Generic drug name Usual dose and administration schedule Maximum daily dosea Comments GI, gastrointestinal; APAP, acetaminophen; NSAIDs, nonsteroidal antiinflammatory drugs; PO, orally; i.m., intramuscularly; i.v., intravenously; GFR, glomerular filtration rate. a In the absence of concomitant diseases and other contraindications. b NSAIDs' analgesic, antiinflammatory, and antipyretic effects vary among compounds. Consider alternative NSAID if one agent is ineffective. Potency and duration of inhibitory effect on platelet aggregation varies among compounds but is reversible. NSAIDs are irritating to GI mucosa; these may cause GI erosion and bleeding. NSAIDs may trigger allergic reactions in atopic patients. NSAIDs may produce dermatitis. NSAIDs decrease renal blood flow and may exacerbate renal insufficiency. Aspirin 325–650 mg PO every 4–6 h Usually ≤4,000 mg daily Analgesic, antiinflammatory, and antipyretic Therapeutic salicylate concentration range, 150–300 µg/mL Irreversibly inhibits platelet aggregation; irritating to GI mucosa; may cause GI bleeding; may trigger allergic reactions inatopic patients APAP 325–650 mg PO every 4–6 h, or 975–1,000 mg PO every 4–6 h Limit total daily APAP dose to ≤4,000 mg Analgesic and antipyretic; may be hepatotoxic high doses and in chronic alcohol users Ibuprofen 200–400 mg PO every 4–6 h Limit total daily Ibuprofen dose to ≤3,200 mg   Naproxen Naproxen immediate release: 250–500 mg PO every 12 h Limit total daily dose to ≤4,000 mg naproxen See NSAIDs general statementb Limit total daily dose to ≤1,375 mg naproxen sodium See NSAIDs general statementb Naproxen delayed release: 375–500 mg PO every 12 h     Naproxen controlled release: 750–1,000 mg PO once daily Naproxen sodium: 275–550 mg PO every 12 h Limit total daily ketorolac dose to ≤40 mg PO, ≤120 mg i.v./i.m. See NSAIDs general statementb Ketorolac Parenterally     Age <65 yr: 30 mg i.m./i.v. every 6 h Duration of use by all routes of administration should not exceed 5 consecutive days For patients aged ≥65 yr, renal impairment, or with body weight <55 kg, the total daily dose should not exceed 60 mg. Age ≥65 yr, renal impairment, or with body weight <55 kg: 15 mg i.m./i.v. every 6 h Doses and treatment duration greater than recommended and shorter dosing intervals increase the potential for adverse effects Tramadol 50–100 mg PO every 4–6 h Limit total daily tramadol dose to ≤400 mg Potential adverse effects in drug accumulation and overdose include respiratory depression and seizure In renal impairment (GFR <30 mL/min), the recommended tramadol dosage is 50–100 mg PO every 12 h For patients aged ≥75 yr, maximal daily tramadol dose should not exceed 300 mg In patients with cirrhosis, the recommended dosage is tramadol, 50 mg PO every 12 h In renal impairment (GFR, <30 mL/min) maximal daily tramadol dose should not exceed 200 mg

TABLE 37.2. Select Adjuvant Therapy

Modality Comments Considerations TCAs, tricyclic antidepressants; REM, rapid eye movement; GI, gastrointestinal; NSAIDs, nonsteroidal antiinflammatory drugs. TCAs Relieves neuropathic pain and posttherapeutic neuralgia Use is associated with anticholinergic effects such as dry mouth, urinary retention, orthostatic hypotension, and conduction abnormalities Analgesic effects start at doses lower than those required for antidepressant effect Benzodiazepines/anxiolytics Decrease anxiety, as a sedative or muscle relaxant Prolonged use may affect REM sleep Steroids Decrease inflammatory component (i.e., nerve-root compression); may potentiate analgesia, provide euphoria, and increase appetite; particularly useful in managing neuropathic pain Prolonged use associated with a variety of side effects including weight gain and adrenal insufficiency; increase risk of GI bleeding, especially when used with NSAIDs

5. Step 2: For moderate pain, add a weak opioid analgesic (see Table 37.3) to the nonopioid analgesic, or, alternatively, use a narcotic analgesic combination (see Table 37.4) with or without adjuvant therapy.

TABLE 37.3. Select Opioid Analgesics

Generic (proprietary) drug names Equianalgesic dosesa,b Duration of action Comments Parenteral Oral i.m., intramuscularly. a Equianalgesic doses are approximately equal to 10 mg parenterally administered morphine sulfate. b Generally, elderly patients are much more sensitive to opioid pharmacologic effects. c Duration of action increases with repeated or prolonged use. Alfentanil (Alfenta) 0.4–0.8 mg (i.m.) — — High potency; primarily used for anesthesia induction and maintenance Codeine 120 mg 200 mg 4–6 h Very low potency; high emetic potential; excellent antitussive activity at less-than-analgesic doses (~15 mg) Fentanylc [Sublimaze (injection); Duragesic (transdermal patches); Oralet (lozenges); Actiq (lozenge on a stick)] 0.1 mgc — 1–2 h Available formulations include injectable solution, patches for transdermal drug delivery, and lozenges for transmucosal delivery; Caution: transdermal patches deliver fentanyl continuously Hydromorphone (Dilaudid) 1.5–2 mg 7.5 mg 3–5 h Low emetic potential; solid and liquid oral formulations, rectal suppositories, and injectable formulations available Levorphanol (Levo-Dromoran) 2 mg 4 mg 6–8 h Very low emetic potential Meperidine 100 mg 300 mg 2–4 h Primary metabolite is a neuroexcitatory compound, normeperidine, which is eliminated more slowly than meperidine and may produce muscle tremors, fasciculations, or seizures in patients with renal insufficiency Methadonec (Dolophine) 10 mg 10 mg 4–8 hc Accumulates with repeated use Morphine 10 mg 30–60 mg 4–6 h Immediate-release and sustained-release oral formulations available Oxycodone — 20 mg 4–6 h Immediate-release and sustained-release oral formulations available Oxymorphone (Numorphan) 1–1.5 mg (injection) 5–10 mg (per rectum) — 3–6 h Injectable and rectal suppository formulations available Propoxyphene (Darvon) — 130 mg 3–6 h Low potency; often used in combination with aspirin or acetaminophen Sufentanil (Sufenta) 0.01–0.04 mg — — High potency; primarily used for anesthesia induction and maintenance

TABLE 37.4. Select Opioid Analgesic Combinations

Generic (proprietary) drug names Drug content Usual dose and Administration schedule Notes PO, orally. Acetaminophen (APAP) with codeine (Tylenol with codeine no. 2, no. 3, or no. 4; many others)   APAP Codeine 300–600 mg APAP + 15–60 mg codeine PO every 4–6 h Limit patient's daily APAP use to ≤4,000 mg APAP w/codeine no. 2 300 mg 15 mg APAP w/codeine no. 3 300 mg 30 mg APAP w/codeine no. 4 300 mg 60 mg Acetaminophen + hydrocodone APAP and hydrocodone APAP 500–750 mg Hydrocodone 2.5–5 mg 5–10 mg Hydrocodone PO every 4–6 h Limit patient's daily APAP use to hydrocodone ≤4,000 mg Acetaminophen + propoxyphene (Darvocet-N 50, Darvocet-N 100, Wygesic)   APAP Propoxyphene 50–100 mg Propoxyphene PO every 4–6 h Limit patient's daily APAP use to ≤4,000 mg Darvocet-N 50 325 mg 50 mg Darvocet-N 100 650 mg 100 mg Wygesic 650 mg 65 mg Acetaminophen + oxycodone (Percocet, Roxicet, Tylox, Roxicet 5/500, Roxilox)   APAP Oxycodone 5–10 mg Oxycodone PO every 4–6 h Limit patient's daily APAP use to ≤4,000 mg Percocet, Roxicet:Tylox, Roxicet 5/500, Roxilox: 325 mg 5 mg 500 mg 5 mg Aspirin + oxycodone (Percodan) Percodan Aspirin 325 mg Oxycodone ~5 mg 5–10 mg Oxycodone PO every 4–6 h Gastrointestinal mucosal integrity and platelet aggregation may be adversely affected by aspirin

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8. Step 3: For severe pain, substitute a strong opioid analgesic (Table 37.3) for the weak opioid analgesic, in addition to the nonopioid, with or without adjuvant therapy (Table 37.2).

• If a maximum dose of medication fails to adequately relieve pain, move up the ladder, and not laterally to a different drug in the same efficacy group.
• The initial point of entry into the WHO analgesic ladder should correspond to the patient's level of pain. For example, patients with mild pain may start at Step 1, whereas patients experiencing severe pain would start at Step 3 to attain prompt analgesia.

9. Individualized treatment:A comprehensive analgesic regimen requires therapeutic customization to the patient's needs, including careful dose titration and reassessment to eliminate cancer pain and the appropriate management of opioid-related side effects (seeTable 37.5). Once the pain “type” is identified and characterized (e.g., bone, visceral, or neuropathic; see Table 37.6), initiate an appropriate regimen of analgesics by the appropriate route (see Table 37.7).

TABLE 37.5. Management of Opioid-induced Adverse Effects

Reaction Comments Therapeutic alternatives and suggestions PO, orally; h.s., at bedtime; p.r.n., as needed; NS, normal saline. Constipation Very common; requires aggressive vigilance and therapy; always order a bowel regimen for any patient on regularly scheduled opioids Bowel regimen: Senna 2 tabs PO h.s. (up to maximum of 8 tabs/day) + 100 mg docusate sodium PO h.s. (titrate to effect) ± bisacodyl Obstipation: consider lactulose, milk of magnesia, etc., p.r.n. disimpaction                         Nausea Tolerance often develops in 3–5 d Hydrate patient; relieve constipation; decrease opioid dose with increased frequency to avoid high serum peaks; consider antiemetics, anxiolytics, and anticholinergic agents such as prochlorperazine, metoclopramide, lorazepam, meclizine, or Transderm Scop —scopolamine patch                         Pruritus Morphine releases histamine; consider using fentanyl or oxymorphone Consider using diphenhydramine, hydroxyzine, or cyproheptadine                         Sedation Patients may develop a varying degree of tolerance over several days Decrease opioid dose with increased frequency to avoid high serum peaks; consider using stimulants like caffeine, 100–200 mg PO q3–4h, or methylphenidate, 5–10 mg PO at breakfast; repeat at lunch                         Respiratory depression Rarely a significant problem; patients develop rapid tolerance May simply require physical stimulation; if severe/emergency use, 0.4 mg nalox one/10 mL NS as a 0.5 mL i.v. push q2 min, titrating to effect; use with caution; may precipitate acute pain, withdrawal, and/or seizures

TABLE 37.6. Treatment of Cancer Pain by Etiology

Type of pain Characteristics Suggested treatment options NSAIDs, nonsteroidal antiinflammatory drugs; PCA, patient-controlled analgesia. Bone Aching, dull NSAIDs, opioids, strontium, pamidronate, plicamycin, samarium, lexidronam, calcitonin             Soft tissue infiltration/nerve compression/spinal cord compression   Corticosteroids (dexamethasone and prednisone), radiation therapy, neurolytic procedures             Neuropathic Burning, tingling Tricyclic antidepressants, opioids, anticonvulsants             Neuralgic Lancinating (sharp, shooting) Opioids, anticonvulsants (carbamazepine, clonazepam, phenytoin, gabapentin), antidepressants; herpetic neuralgia; sympathetic or epidural blocks             Somatic Deep, dull Chest wall pain: consider intrapleural analgesia, or intercostal nerve block             Visceral Complaint depends on site of disease: If pleural or pericardial, worse with deep breathing, sharp; if organ-based, cramping, gnawing Three-step ladder ± adjuvant therapy; versus mucositis, consider opioids, topical anesthetics, PCA, oral rinses

TABLE 37.7. Selected Routes of Analgesic Administration

Route Advantages Comments Oral Facilitates long-term administration. Tablet/capsule or liquid formulations Preferred route whenever possible Intramuscular None Painful administration, slower onset than i.v. route. Variable time to peak effect Subcutaneous Steady serum levels without peak/trough effect when used to administer continuous infusion of medication As with i.v. and transdermal routes, subcutaneous route is ideal for certain infusional techniques Intravenous Rapid onset-to-peak effect and ease of titration May require repeated i.v. boluses for titration to analgesic effect, followed by maintenance dosing Sublingual Circumvents first-pass hepatic metabolism; fast onset Facilitates ease of use for liquid preparations (e.g., Roxanol) Rectal As an alternative to oral administration of drug Not often considered Transdermal Convenient for nonfluctuating analgesic or basal requirements or for long-term administration Slow onset (~48 h to steady-state levels). Difficult to titrate during changing analgesic requirements Epidural or intrathecal Can utilize opioid or local anesthetics or both in combination Optimally requires “pain service” consult; respiratory depression if dermatome levels are too high Injection techniques Trigger-point injections and nerve blocks Optimally requires “pain service” consult Neurosurgery Neuroablative techniques Requires “pain service” or neurosurgical consult

11. Monitoring:Monitoring is required to ensure that the benefits of treatment are maximized and the adverse effects are minimized.
12. Use of adjuvant therapies (Table 37.2):Examples of adjuvant therapies include antidepressants, benzodiazapines, steroids, anticonvulsants, and local anesthetics. Depression often accompanies chronic pain, and tricyclic antidepressants at low doses augment analgesia, whereas full-dose selective serotonin reuptake inhibitors (SSRIs) improve sleep and appetite and elevate mood. Use pain-management consultants (e.g., anesthesia pain-management service). Nonsteroidal antiinflammatory drugs (NSAIDs) are often most efficacious in controlling metastatic bone pain. Gabapentin is effective in controlling neuropathic pain.

GENERAL CONSIDERATIONS ABOUT PHARMACOTHERAPY

Use short-acting opioid analgesics [i.e., shorter acting i.v. or PO morphine sulfate versus long-acting morphine sulfate (MS Contin)] until the patient has attained adequate pain control. Short-acting analgesics may offer advantages over longer-acting formulations in the initial management of acute cancer pain, including (a) ease of dose adjustment and (b) rapid onset of analgesic effect. After attaining effective analgesia, the total daily-dose requirements can be determined, thereby facilitating conversion to long-acting formulations. Be aware that there is wide interpatient variability in the amount of analgesics required for pain control.

Consider using patient-controlled analgesia (PCA), which administers small intravenous or epidural doses of opioids on demand. This modality, often used for treatment of acute varying or postoperative cancer pain, affords a high degree of patient satisfaction and safety. Frequent

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evaluation to determine the analgesic effect and the need for dose modification suggests that PCA may be best used through formal consultation of an in-house anesthetist or multimodality “pain-management teams.” Programmable PCA pumps often allow basal or maintenance rates of opioid infusion in addition to bolus dose amounts and “lockout” intervals. Maintenance PCA orders can be initiated after bolus opioid dosing achieves adequate analgesic effect.

Avoid using agents such as meperidine and pentazocine, as well as i.m. injections. Meperidine (Demerol) is metabolized to normeperidine, a metabolite with neuroexcitatory (seizure-producing) effects. The risk of toxicity is increased after prolonged administration (for more than 48 hours) and in patients with renal insufficiency. Pentazocine (Talwin) is not more potent than codeine, with a high incidence of hallucinations and agitation. Oral and subcutaneous routes of ingestion are as efficacious, without the pain and expense of i.m. injections.

ANESTHETIC AND NEUROABLATIVE MANAGEMENT

Referral to an anesthetist or a pain care team may be necessary to implement specific anesthetic blockade, neurolysis, and intrathecal or epidural analgesia. Local anesthetic neural blockade may achieve both diagnostic and therapeutic ends. Diagnostically, the nerve block may help predict the efficacy of neuroablation. Therapeutically, the intervention will provide pain relief and the pain-relieving effect may also outlast the drug effect. Neuroablation involves intentionally destroying the nervous structures implicated in the transmission of pain. Spinal administration of opioids produces analgesia without changes in motor or sensory function. Local anesthetics and/or steroids may be added in patients with refractory pain to enhance analgesia. Implantable intrathecal delivery systems are also available, with promising improvements in rapid and sustained pain relief.

PATIENT REASSESSMENT

Pain management is a dynamic process that requires frequent reassessment to determine the effectiveness of therapy and to facilitate dose adjustment. Disease progression often requires increasing doses of analgesics, whereas opioid tolerance is often manifested as decreased duration of analgesia.

The appropriate management of opioid-related side effects (Table 37.5), such as constipation or pruritus, is of paramount importance because the mismanagement of these side effects often acts as a barrier that precludes administration of adequate analgesia. Optimization of patient management requires that the clinician be proactive in managing opioid-related side effects and in assessing and reassessing pain related to cancer.

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