Assessment and Relief of Chronic Cancer Pain and Palliative Care

Part 1: Assessment and Relief of Chronic Cancer Pain

Linda A. King

Mihir M. Kamdar

Eric L. Krakauer

Relief of pain is an essential objective in treating cancer patients at all phases of the illness. Unrelieved pain interferes with a patient’s ability to work, enjoy life, and function maximally in family and society. Effective amelioration of pain can almost always be achieved with the proper use of analgesics. Unfortunately, pain is often undertreated. Barriers to effective pain relief emanate from health care professionals, patients, and the health care system and need to be addressed (Table 90-1).

Fear of unrelieved cancer pain is widespread. Primary care physicians should develop skill at pain assessment and relief, know the limitations of analgesics, and understand how best to provide emotional support. The goal is to minimize the suffering that accompanies the fear and experience of pain.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2 and 3)

Pain in cancer patients may result from direct effects of the tumor (e.g., infiltration into bone, viscera, nerves), from cancer treatments (e.g., chemotherapy, radiation, surgery), or from causes unrelated to the cancer (e.g., arthritis, migraines). There are two broad categories of cancer pain: nociceptive (somatic and visceral) and neuropathic. Multiple pain complaints caused by more than one mechanism are the rule.

Somatic pain results from activation of nociceptors in cutaneous or deep musculoskeletal tissues. This pain is usually well localized and often described as dull or aching. Examples include pain from bone metastases, surgical incision, and radiation burns.

Visceral pain results from infiltration, compression, or distention of thoracic or abdominal viscera. It is usually poorly localized and often described as deep, squeezing, or as if caused by pressure. Referral of the pain to overlying or distant cutaneous sites is common. Causes of visceral pain include hepatic metastases that distend the liver capsule and metastases that obstruct the biliary tree, bowel, or urinary tract.

Neuropathic pain results from direct injury to the peripheral or central nervous system. Pain from nerve injury may be described as constant, aching, or squeezing (and thus may be similar to somatic pain). However, paroxysms of sharp, burning, or electric shock-like pain may be superimposed and are pathognomonic. The pain may follow a nerve distribution and can be associated with sensory or motor (including sphincter) disturbances that indicate a neurologic injury. Causes of neuropathic pain include spinal nerve root compression, radiation-induced plexopathy, and chemotherapy-associated neuropathy.

Common Pain Syndromes

Bone Pain

Metastases to the bony skeleton are the most prevalent cause of chronic pain in cancer patients. The pain associated with bone metastases may be due to direct invasion, secondary pathologic fracture, or damage to adjacent structures. Common sites are vertebrae, long bones, pelvis, and skull. Any tumor type can involve bone; the most common are metastatic lung, breast, and prostate cancers and multiple myeloma. Some tumors produce either lytic or blastic lesions alone, but most produce mixed lesions. Bone pain is typically somatic unless the tumor or a fracture disrupts a nerve.

Back Pain

Back pain in patients with cancer often signifies epidural or vertebral metastases and sometimes malignant vertebral compression fracture. Untreated metastases may destabilize the spine or impinge on the spinal cord or cauda equina. Rapid progression of back pain or acute onset of neurologic deficits in the legs in a patient with cancer is an oncologic emergency and requires prompt evaluation to rule out spinal cord compression and irreversible neurologic compromise (see Chapter 92). Spinal cord compression is most commonly caused by posterior extension of a vertebral body metastasis into the epidural space.

Leptomeningeal carcinomatosis may cause neck and back pain in the absence of vertebral disease. Thoracic pain may be a consequence of local invasion of the intercostal nerves. Pleuritic pain may develop if a malignancy invades the pleura. Invasion of a contiguous bony structure may result in local or referred pain.

Abdominal and Pelvic Pain

Abdominal and pelvic pain from cancer is typically visceral in nature and therefore poorly localized and possibly referred to distant sites. These pain syndromes are particularly common in patients with gastrointestinal and gynecologic malignancies. Anorexia, nausea, and vomiting are common accompaniments. Crampy pain is characteristic of intestinal obstruction (see Chapter 58). Ascites can be uncomfortable because of associated abdominal distention. Hepatic metastases may cause pain by distending the liver capsule or irritating the peritoneum.

TABLE 90-1 Barriers to Cancer Pain Management

Problems Related to Health Care Professionals

Inadequate knowledge of pain relief

Poor assessment of pain

Concern about the regulation of controlled substances

Fear of patient addiction

Concern about side effects of analgesics

Problems Related to Patients

Reluctance to report pain

Concern about distracting the physician from the treatment of underlying disease

Fear that pain means the disease is worse

Concern about not being a “good patient”

Reluctance to take pain medications

Fear of addiction or of being thought of as an addict

Worries about unmanageable side effects

Concern about becoming tolerant to pain medications

Problems Related to the Health Care System

Low priority given to cancer pain treatment

Inadequate reimbursement and prohibitive costs

Restrictive regulation of controlled substances

Problems of availability of treatment or access to it

From Jacox A, Carr DB, Payne R, et al. Management of cancer pain. Clinical practice guideline No. 9 (AHCPR publication No. 94-0592). Rockville, MD: Agency for Health Care Policy and Research, U.S. Department of Health and Human Services, Public Health Service, 1994.

Peripheral Nerve Compression

Any malignant process that compresses, invades, or inflames nerve roots may cause a painful neuropathy. Peripheral nerve compression syndromes result in pain in the neck, head or shoulder (cervical plexus), shoulder or arm (brachial plexus), buttocks and perineum (sacral plexus), lumbar area (paraspinal nerves), and mouth or face (glossopharyngeal or trigeminal nerves).

WORKUP (4,5)

Prompt, careful assessment of a cancer patient’s pain is prerequisite to timely design and implementation of a maximally effective treatment plan. Assessment should be carried out at the time of the initial report of pain, at regular intervals thereafter, and with any treatment changes. Cancer patients commonly report multiple types of pain. Each complaint should be individually assessed and prioritized. Because pain is a subjective phenomenon, the patient’s report of pain must be taken seriously. The workup should include a search for underlying mechanism(s) of pain in addition to the impact of pain on the patient’s quality of life and ability to carry out activities of daily living.

History

A careful pain history, with attention to location, intensity, temporal pattern, quality, aggravating and alleviating factors (including medication), and associated symptoms, often enables identification of a specific pain syndrome. Well-localized pain suggests a somatic mechanism, more-diffuse pain is indicative of a visceral source, and pain in a nerve distribution points to a neuropathic cause. Pain that is somatic in quality suggests metastasis to bone or sometimes to muscle or connective tissue. If the pain is more diffuse and visceral in quality, one needs to consider capsular distention or the obstruction of a viscus, whether bowel, biliary tree, or urinary tract. A neuropathic distribution should lead to a check for sensory and motor deficits (including those involving sphincters).

Figure 90-1 Pain assessment intensity scales. (From Jacox A, Carr DB, Payne R, et al. Management of cancer pain. Clinical practice guideline No. 9 [AHCPR publication No. 94-0592]. Rockville, MD: Agency for Health Care Policy and Research, U.S. Department of Health and Human Services, Public Health Service, 1994.)

A numeric rating scale (Fig. 90-1) helps to quantify pain intensity, follow it over time, and standardize assessment among clinicians. Exploring the past use of analgesic therapies, their effectiveness, and their side effects helps in the design of the treatment program.

Another important component of the history is elucidating the effect of the pain on the patient’s psychosocial state (mood, relationships with others) and on activities of daily living (especially sleeping, dressing, eating, and moving around). Identifying how the patient interprets the meaning of the pain provides an opportunity to understand and ease the worry that exacerbates the pain experience.

Physical Examination

A focused physical examination can facilitate identification of the underlying mechanism(s) and site(s) of pain suggested by the history. The painful site should be examined in detail and any physical findings related to the patient’s underlying medical conditions also noted. On neurologic examination, one checks for a neuronal distribution to the pain as well as for motor and sensory deficits and sphincter incompetence. Evidence is sought for allodynia (pain elicited from a nonpainful stimulus) and hyperalgesia (a greater than normal sensitivity to a painful stimulus), signaling a neuropathic process. Similarly, somatic pain may be confirmed by the finding of focal tenderness. If the pain is poorly localized suggesting a visceral etiology, then examination for an obstructed viscus or distended organ capsule is in order.

Laboratory Studies

Imaging studies and other laboratory means of confirming the cause of pain are especially important when a surgical, chemotherapeutic, or radiotherapeutic approach to pain control is being considered. Determining the specific cause of the pain (e.g., bone metastases, bowel obstruction, spinal cord compression) allows appropriate, disease-specific therapy to be instituted. Patients with advanced disease who are not candidates for such aggressive therapeutic measures need not undergo extensive testing unless the results will affect clinical decision making. In such patients, the decision to initiate or escalate an analgesic regimen can be based on a good history and
physical examination alone. While the workup is proceeding, any distressing pain can be treated empirically.

PRINCIPLES OF MANAGEMENT (1, 2, 3, 4, 5, 6, 7, 8, 9 and 10)

A pathophysiologic formulation informs the treatment regimen for pain. Often, a multifaceted approach is necessary. Analgesics, psychological support, cancer-targeted therapies, interventional pain and neurosurgical procedures, and behavioral methods are among the important modalities for the treatment.

Pharmacologic Measures

General Principles: The Analgesic Ladder

Analgesic therapy must be individualized for each patient, but the World Health Organization’s analgesic ladder (Fig. 90-2) provides a standard initial approach to drug selection for cancer pain, based on pain severity and previous analgesic use. The ladder begins with acetaminophen, aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDs) for mild to moderate pain. When pain persists or increases, a weak opioid or a strong opioid at a low dose is added. Pain that is moderate to severe at presentation can be treated immediately with a + opioid. The simplest route and dosage schedule and the least invasive analgesic measures should be used. Chronic cancer pain requires around-the-clock (not as-needed) dosing, supplemented by as-needed (PRN) “rescue” doses for breakthrough pain.

Nonopioid Initial Therapy: Acetaminophen, Aspirin, and Nonsteroidal Anti-inflammatory Drugs

These nonopioids serve as initial therapy for mild pain (Table 90-2). Except for acetaminophen (which has little antiinflammatory action), they have analgesic, antipyretic, and anti-inflammatory effects. Unlike opioids, none of these drugs produces tolerance or physical dependence, but they do have a ceiling to their analgesic effects, beyond which there is additional toxicity without additional analgesia.

Acetaminophen Use.

Adding acetaminophen to an opioid regimen can boost analgesic effect, allow use of lower opioid doses, and reduce risk of opioid side effects. Combination products are a convenient option, but the amount of opioid that can be
delivered is limited by the amount of acetaminophen in each unit dose. The risk of acetaminophen-related hepatic toxicity requires that maximal acetaminophen doses not exceed 4 g/d (<2 g/d in patients with liver disease or heavy alcohol consumption). When the maximal dose of acetaminophen is reached and pain persists, an alternative strategy for pain control is necessary.

Figure 90-2 The World Health Organization’s three-step analgesic ladder. (From World Health Organization. Cancer pain relief: with a guide to opioid availability, 2nd ed. Geneva, Switzerland: Author, 1996:15, with permission.)

TABLE 90-2 Commonly Used Analgesics and Adjuvants

Nonopioid Analgesics		Oxycodone
Acetaminophen and salicylates			Roxicodone, 5, 15, 30 mg
	Acetaminophen, up to 650 mg q4h or 975 mg q6h Aspirin, up to 650 mg q4h or 975 mg q6h		OxyContin, 10, 20, 40, 80 mg Liquid, 5 mg/5 mL, 20 mg/mL
Nonsteroidal Antiinflammatory Drugs		Oxycodone with acetaminophen
	Ibuprofen (Motrin, Advil), 600 mg q6h		Percocet, Roxicet, Tylox, Endocet, generic, 2.5, 5, 7.5, 10 mg
	Naproxen (Naprosyn, Aleve), 250-500 mg bid	Oxycodone with aspirin
	Ketorolac (Toradol), 30 mg IM or IV q6h (up to 5 d)		Percodan, 5 mg
	Celecoxib (Celebrex), 100-200 mg bid	Oxymorphone
Opioid Analgesics			Opana IR, 5, 10 mg
Morphine			Opana ER, 5, 10, 20, 40 mg
	MSIR tablets or capsules, 15, 30 mg	Levorphanol
	MSIR “soluble” tablets, 10, 15, 30 mg		Levo-Dromoran, generic, 2 mg
	Roxanol (elixir), 10 mg/5 mL, 20 mg/5 mL, 100 mg/5 mL	Methadone
	MS Contin, 15, 30, 60, 100, 200 mg		Dolophine, generic, 5, 10 mg
	Oramorph SR, 15, 30, 60, 100 mg		Dispertab, 40 mg
	Avinza, 30, 60, 90, 120 mg		Liquid, 1 mg/mL, 10 mg/5 mL, 10 mg/mL
	Kadian, 20, 30, 50, 60, 80, 100, 200 mg	Adjuvants
Fentanyl		Antidepressants
	Duragesic transdermal patches, 12.5, 25, 50, 75, 100 µg		Desipramine 10-150 mg qhs
	Actiq transmucosal lozenges, 200, 400, 600, 800, 1,200, 1,600 µg		Nortriptyline 10-150 mg qhs
	Fentora buccal tablets, 100, 200, 400, 600, 800 µg		Venlafaxine (Effexor, Effexor XR), 75-225 mg/d
Hydromorphone
	Dilaudid, generic, 2, 4, 8 mg; liquid 5 mg/5 mL	Duloxetine (Cymbalta), 30-60 mg daily
	Suppository, 3 mg		Anticonvulsants
	Exalgo extended release, 8, 12, 16 mg		Carbamazepine (Tegretol), 100-800 mg bid
Codeine			Gabapentin (Neurontin), 100-400 mg tid
	Codeine sulfate tablets, 15, 30, 60 mg		Pregabalin (Lyrica), 50-200 mg tid
	Elixir and solution, 15 mg/mL		Phenytoin (Dilantin), 300-500 mg/d
Codeine with acetaminophen		Stimulants
	Tylenol No. 2, No. 3, No. 4 (15, 30, 60 mg, respectively)		Dextroamphetamine (Dexedrine), 5-10 mg/d bid
Codeine with aspirin
	Empirin No. 3, No. 4, 30, 60 mg, respectively		Methylphenidate (Ritalin), 2.5-15.0 mg qd-bid
Hydrocodone with acetaminophen			Modafinil (Provigil), 200-400 mg daily
	Lortab, 2.5, 5, 7.5, 10 mg	Corticosteroids
	Lorcet, 5, 7.5, 10 mg		Dexamethasone (Decadron), 4-96 mg bid-qid
	Vicodin, 5, 7.5 mg		Prednisone, 10-100 mg/d bid
bid, twice daily; q4h, every 4 hours; q6h; every 6 hours; qd, daily; qhs, at bedtime; qid, four times a day; tid, three times a day; PO, orally; IM, intramuscularly. Adapted from Jacox A, Carr DB, Payne R, et al. Management of cancer pain. Clinical practice guideline No. 9 (AHCPR publication No. 94-0592). Rockville, MD: Agency for Health Care Policy and Research, U.S. Department of Health and Human Services, Public Health Service, March 1994; and Fowler B, Lynch M, Abrahm J. Pain management tables and guidelines. Boston, MA: Dana Farber Cancer Institute Pain and Palliative Care Program, 2004.

Nonsteroidal Anti-inflammatory Drugs Use.

The long-term use of oral NSAIDs for pain control in cancer has not been well studied, but available evidence suggests reasonable efficacy, especially for bone pain or pain with an inflammatory component. NSAIDs are available in various oral formulations, including tablets, capsules, and liquids; ketorolac, the only parenteral NSAID preparation, is recommended for short-term (<5 days) use only. Because responses to individual NSAIDs vary, titration of the dose and trials of different preparations are occasionally necessary to achieve the best response (see also Chapters 68 and 156).

Selective cyclooxygenase-2 (COX-2) inhibitors offer potential benefit in being less likely than nonselective NSAIDs to cause gastrointestinal side effects and platelet inhibition, but they are significantly more expensive and, with chronic use, associated with an increased risk of adverse cardiovascular events (see Chapter 156). Other nonselective NSAIDs with a preponderance of COX-2 inhibitory activity also carry some increase in cardiovascular risk.

Opioids

Opioids are the preferred analgesics for relief of moderate to severe cancer pain. They are effective for both nociceptive and neuropathic pain, easily titrated, generally safe and well tolerated when dosed correctly, and available in a variety of formulations. Opioids act by binding to specific receptors throughout the body, particularly in the peripheral and central nervous systems.

Titration and Dosing.

Opioid dosing should be titrated rapidly to achieve prompt, maximum relief of pain while minimizing adverse effects.

Titration.

Dose titration is best accomplished by using a short-acting preparation and increasing the dose until pain resolves. Each dose can be increased by about 25% if pain persists; 50% increases are appropriate if the pain remains severe. The goal is rapid implementation of effective pain control. Dose requirements vary greatly among patients and change over time; careful, ongoing titration is necessary to achieve and maintain adequate analgesia.

Dosing.

Once the necessary daily opioid dose is established, a long-acting oral preparation that is taken two or three times daily or transdermal fentanyl can be substituted at an equianalgesic total daily dose. To provide optimal chronic pain control, opioids should be given around the clock (regularly scheduled) rather than PRN (as needed). This regimen reduces the total daily amount of
opioid required to control pain as compared to a purely PRN regimen.

For breakthrough pain, concomitant shorter-acting oral opioids, the so-called rescue doses, should always be prescribed. Rescue doses should be approximately equivalent to 5% to 15% of the total 24-hour dose and generally should be used every 2 to 4 hours as needed. In patients with acute worsening of pain who require frequent rescue doses or when pain is difficult to control or sedation is problematic, intravenous patient-controlled analgesia (PCA) can be useful. The patient’s use of bolus doses becomes a guide to establishing an appropriate continuous infusion.

Routes of Administration.

The oral route of opioid administration (Table 90-2) is preferred if possible; for those who cannot take medication by mouth, the intravenous (IV) and transdermal routes are available. Intramuscular (IM) dosing should be avoided because of the discomfort associated with injection and the availability of other, equally effective routes of delivery. The IV route is more costly than the oral route, but allows for continuous infusion as well as intermittent boluses. In switching routes, care must be taken to ensure equianalgesic dosing; the total daily parenteral dose should equal one third of the total daily oral dose and account for the differences in duration of action when switching between opioids or their routes of administration (see Table 90-3). In general, an opioid can be given at the same dose orally, sublingually, buccally, and rectally. Similarly, the same doses of an opioid are required for IV and subcutaneous (SC) administration.

Side Effects.

The most common side effects of opioids include constipation, nausea, vomiting, and sedation; less commonly, these agents produce delirium, pruritus, myoclonus, dry mouth, and urinary retention. Significant respiratory depression, a dreaded side effect in the treatment of acute pain, is extremely rare and not a concern when chronic pain is treated carefully according to accepted guidelines such as those of the WHO.

Constipation (and, occasionally, nausea and vomiting) should be treated prophylactically while monitoring carefully for other side effects. Although tolerance to many side effects (including nausea, sedation, and respiratory depression) typically occurs over 1 to 5 days, constipation persists and should be managed with regularly scheduled laxative regimens (see Chapter 91).

Tolerance.

Opioid tolerance is defined as the need for an increasing amount of drug to achieve the same analgesic effect. Tolerance develops with regular opioid use and is manifested by a shortened duration of pain control and an overall increase in the perception of pain. The addition of a nonopioid analgesic (see prior discussion) or an adjuvant drug (see later discussion) can compensate for tolerance, but the simplest means of overcoming tolerance is to increase the dose or dose frequency. Cross-tolerance among opioids is common but not complete after prolonged opioid administration, so that it may be possible to boost analgesia by switching to another opioid, starting at as low as 50% to 75% of the equianalgesic dose.

Dependence.

Physical dependence presents as the development of opioid withdrawal symptoms upon abrupt discontinuation or if opioid antagonists are administered. The withdrawal syndrome can be avoided by tapering slowly, no faster than 25% every 3 days. If withdrawal symptoms appear, the dose should be increased to the immediately preceding dose, and the taper should proceed more slowly.

Psychological dependence (addiction) is an abnormal behavior pattern in which a person becomes overwhelmingly involved in the acquisition and use of a drug. Addiction is rare in cancer patients who take opioids for pain relief and have no personal or family history of substance abuse. Such patients and their families should be counseled and reassured about the low risk for addiction; misconceptions often result in the avoidance of pain medications or the underreporting of pain. Likewise, health care professionals should not hesitate to prescribe opioids for such patients when an opioid is indicated. However, an increasing prescription drug abuse problem in the United States warrants close attention to risk factors for addiction.

Pseudoaddiction is drug-seeking behavior that resembles psychological dependence but occurs because of an inadequate pain regimen. Examples include “only-as-needed” dosing for continuous pain, dosing intervals that exceed duration of action, and inappropriately low doses. This drug-seeking behavior disappears if an appropriate analgesic regimen is prescribed.

Choice of Opioid Agent.

Choice should be dictated by the patient’s needs. For patients with moderate to severe pain, hydrocodone, morphine, or oxycodone are reasonable initial short-acting oral agents.

Hydrocodone is more potent than codeine but less potent than morphine and is generally commercially available in combination form with acetaminophen. Morphine is the prototype opioid analgesic for severe cancer pain. It is effective both orally and parenterally with a duration of action of approximately 3 to 4 hours. The use of sustained-release preparations (e.g., MS
Contin, Oramorph SR, Kadian, Avinza) provides prolonged analgesia (8 to 24 hours) with less frequent dosing, but the cost can be high. These long-acting formulations cannot be crushed or chewed, but Kadian and Avinza capsules can be broken open and the contents sprinkled into food or liquid for patients who cannot swallow pills easily or are receiving tube feedings. Oxycodone is available in a long-acting, slow-release formulation (OxyContin) with an effect lasting 8 to 12 hours.

TABLE 90-3 Approximate Equianalgesic Doses of Short-Acting Opioids for Chronic Pain^a,b

Oral Dose (mg)	Usual Oral Dosing Interval	Analgesic	Parenteral Dose (mg)	Usual Parenteral Dosing Interval
200	q3-4h	Codeine	130	q3-4h
30	q3-4h	Hydrocodone (Vicodin, Zydone)
20-30		Oxycodone (Percodan, Percocet, Tylox, Roxicet, Roxicodone, Roxiprin)^c,^d
30	q4h	Morphine^c,^e,^f	10	q3-4h
7.5	q3-4h	Hydromorphone (Dilaudid)^e	1.5	q3-4h
4	q4-6h	Levorphanol (Levo-Dromoran)	2	q4-6h
Fentanyl (Duragesic) patch or other long-acting opioid preparations should be considered for patients with a relatively stable basal dose and relatively well-controlled pain. According to the manufacturer, a 10-mg IM or SC or IV dose or 60-mg oral dose of morphine every 4 h for 24 h (total 60 mg/d IM/SC/IV or 360 mg/d oral) is approximately equivalent to transdermal fentanyl 100 µg/h. Palliative care clinicians generally divide the 24-hr oral morphine dosage by 3.8 to get the roughly equivalent dose per hour of fentanyl. Patches should be replaced every 48 to 72 h. ^aAll doses and intervals are approximate and should be adjusted according to the patient’s response. When a patient has been on a particular opioid for weeks or months, conversion to a relatively lower dose of another opioid is often adequate, especially with methadone, which has occasionally been reported to be 5 to 30 times as potent as predicted by this kind of table when used after prolonged or high-dose treatment with other opioids. ^bThis table does not include meperidine (Demerol) or pentazocine (Talwin), which generally should not be used for chronic cancer pain. ^cOxycodone is available as a long-acting preparation (OxyContin). Morphine is also available in long-acting preparations—MS Contin or Oramorph SR, lasting 8 to 12 h, or Avinza or Kadian, lasting 24 hours. Sustained-action tablets should not be crushed or chewed, but Kadian and Avinza capsules can be broken and suspended in a liquid. ^dSome oxycodone preparations are compounded with acetaminophen or aspirin. Acetaminophen should not exceed 4,000 mg/d for prolonged periods. ^eMorphine and hydromorphone (Dilaudid) are available as suppositories. Rectal dose and intervals are generally the same as with oral administration. ^fLiquid morphine preparations can be administered by the sublingual or buccal route. Dose and intervals are similar to those for oral administration. h, hours; q, every.