Cancer pain is usually caused directly by neoplastic injury to pain-sensitive structures. For this reason, primary antineoplastic therapy, including radiation, chemotherapy, and palliative surgery, should be considered part of an analgesic strategy in some cases. When therapy directed at the tumor is inappropriate, is not feasible, is ineffective, or causes painful therapy-related syndromes, symptomatic analgesic therapies become the overriding concern. Opioid-based pharmacotherapy is the mainstay approach, but adjunctive anesthetic, surgical, psychiatric, and physical modalities may be essential as well (see Chapter 54, Cancer Pain Syndromes). Pharmacologic approaches may be systemic or regional (anesthetic).

The World Health Organization (WHO) proposed a three-step approach—the analgesic ladder—to the selection of drugs for the treatment of cancer pain (Fig. 55-1).¹ Step 1, for mild pain, uses nonopioid analgesics and adjuvant drugs. Adjuvant drugs can be either nontraditional analgesics or drugs added to manage the side effects of the primary analgesics. For more intense pain, an opioid is added. Some opioids are used conventionally for moderate pain, and others are used for severe pain. This approach is designed to be simple to understand and usable around the world. Uncontrolled field testing has found the WHO guidelines effective for 70% to 100% of patients with cancer.² The aim of this chapter is to provide an overview of the approach to medical management of cancer pain, particularly covering the use of systemic analgesics recommended by the WHO’s analgesic ladder for cancer pain.

Pain is often underrecognized in cancer patients. Cleeland et al.³ surveyed outpatients with metastatic cancer and physicians from 54 treatment centers. They found that 42% of 597 patients with pain were not receiving adequate analgesia by the WHO guidelines (see Fig. 55-1). Insufficient pain relief was particularly common among minorities, women, and elderly adults. An important barrier to effective pain management was a discrepancy between the patient’s and the physician’s assessment of the extent to which pain was interfering with daily activities. The data underscore the importance of accurate pain assessment in providing adequate cancer pain relief.

The assessment should allow inferences about the pain mechanisms, identification of the pain syndrome (see Chapter 44, Cancer Pain Syndromes), and classification of the relationship between the pain and the disease. The clinician must also assess the functional impact of the pain and psychosocial comorbidities. It is essential to accept the patient’s report of pain at face value. Pain should be assessed frequently and systematically, especially when a new pain is reported or a new analgesic treatment is initiated. The location, intensity, and quality of the pain; aggravating and relieving factors; pain impact or interference with daily activities; and the patient’s emotional and cognitive response to pain should all be noted.

PAIN MEASUREMENT TOOLS

Although there is no quantitative biochemical or neurophysiologic test for pain, tools have been devised to assess pain intensity^4,5 (see Chapter 6, Evaluating the Patient with Chronic Pain). Categorical scales, such as the verbal rating scale (VRS), which ask patients to rate pain intensity using adjectives such as “mild” and “excruciating,” are simple to use but assume an understanding of the adjectives. Pain relief may also be rated with a categorical or percentage scale. The numerical rating scale (NRS), rating pain from 0 for “no pain” to 10 for “the worst imaginable pain,” is easily implemented and recorded during frequent assessments. The use of numbers removes any linguistic misunderstanding of categorical descriptors. Similarly, a 100-mm visual analog scale (VAS) may be used, with or without intensity descriptors. Although a VAS score may not mean the same thing to different patients, it is reliable on repeated use with the same patient.⁶ This permits serial assessments by different clinicians, if necessary, over the course of treatment. Patients must be instructed in the use of these analog scales.

All of the pain scales just described are validated and reliable measures of pain intensity;⁷ however, they are unidimensional pain measures, so they do not reflect the complexity of the pain experience.^8,9 Nonetheless, they provide a score that can be recorded, as vital signs are.¹⁰ This is useful for tracking pain intensity and can prompt intervention when pain exceeds an acceptable level. Although there is inconsistency with translating between numerical and categorical scales, a recent systematic review suggested that a numerical score of 0 to 4 should represent mild pain, 5 to 6, moderate pain, and 7 to 10, severe pain.¹¹

When the patient cannot communicate, pain must be evaluated by other means. Next of kin are usually able to verify the existence of pain, but they cannot accurately describe its intensity, location, and treatment.¹² Non-English speakers need a translator or a pain scale with instructions in their language. Originally designed for use in children, the Wong-Baker Faces Pain Rating Scale might also be useful in some cognitively impaired adult patients.¹³

Attention to nonverbal pain manifestations is also important. Autonomic changes may be present, including hypertension, tachycardia, and diaphoresis. Patients with organic brain disease may show agitation or confusion, or they may be apathetic, inactive, or irritable. They may also refuse to eat without explanation, protect the painful part, and show facial grimacing. Although these manifestations are not specific for pain, empiric analgesic treatment in such situations, after ruling out more serious acute illness, often confirms the assessment. The Behavioral Pain Scale (BPS) is a clinical tool developed to assess pain in sedated, critically ill patients. The BPS score is calculated as the sum of three observer-based behavioral categories (each rated from 1 to 4): facial expression, upper extremity movement, and compliance with ventilation.¹⁴

Several multidimensional assessment instruments incorporate pain quality, intensity, location, emotional and functional impact, and effectiveness of coping skills.¹⁵ Among the most well-known of these are the McGill Pain Questionnaire (MPQ)¹⁶ and its short form (MPQ-SF).¹⁷ The MPQ-SF is more appropriate for the time-restricted clinical setting. It consists of 15 descriptors, 11 of which are sensory items (throbbing, shooting, stabbing, sharp, cramping, gnawing, hot-burning, aching, heavy, tender, splitting); the remaining four (tiring-exhausting, sickening, fearful, punishing-cruel) are affective items. These items are rated using a 4-point VRS. The MPQ-SF also contains a VAS and a VRS for intensity of pain. A recent systematic review of the MPQ in the cancer population supported its utility as a valid, reliable, and sensitive measure for cancer pain.¹⁸

The Brief Pain Inventory (BPI) and its short version (BPI-SF) are scales that assess the severity of pain and its impact on the patient’s daily function¹⁹—the sensory and reactive dimensions of pain, respectively. The BPI-SF is more widely used in the clinic setting because of its brevity. The BPI-SF contains front and back body diagrams for the patient to label the site(s) of pain, four items on pain severity (worst, least, average, and current pain over the past 24 hours), and seven items on pain interference (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). Each item is scored using an NRS. There is also a question regarding pain response to analgesics.

The MD Anderson Symptom Inventory (MDASI)²⁰ is based on the BPI and is used as a single tool to measure 13 of the most common cancer-related symptoms. The following symptoms are included in the MDASI: pain, fatigue, nausea, disturbed sleep, emotional distress, shortness of breath, lack of appetite, drowsiness, dry mouth, sadness, vomiting, memory difficulties, and numbness/tingling. The patient rates each of these symptoms with an NRS. The MDASI also includes a section on interference caused by pain.

The Edmonton Symptom Assessment System (ESAS) and a recent revision (ESAS-r) assess nine symptoms common in advanced cancer patients.²¹ The symptoms are rated using an NRS and are as follows: pain, nausea, tiredness, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath. There is also an optional tenth symptom that the patient may add to the questionnaire. The revised version was designed to improve ease of use by providing definitions for each symptom and by rearranging the order of the symptoms, among other updates.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are routinely used in the treatment of cancer pain (see Chapter 61, NSAIDs). In general, they should be used on an around-the-clock schedule for patients with mild pain before advancing to Step 2 of the WHO analgesic ladder.¹ At that step and beyond, nonopioid analgesics may be continued in addition to starting opioids. NSAIDs may be especially effective for neoplastic bone pain^22,23 and in cancer patients experiencing arthralgias associated with aromatase inhibitor therapy,^24,25 but they are probably useful in all types of pain because they provide at least additive analgesia. They can act synergistically with opioids in the spinal cord²⁶ and allow reduction of opioid dose, lessening the likelihood of opioid-related side effects (opioid sparing). When one NSAID is ineffective or poorly tolerated, another NSAID should be tried. When the oral route is not available, as in patients with unremitting nausea, some NSAIDs and acetaminophen may be given rectally. Ketorolac is available for intramuscular and intravenous (IV) use in the United States but is not recommended for prolonged use because of potential renal toxicity (Table 55-1).

Before initiating NSAID or acetaminophen therapy, the potential for toxicity must be considered (see Chapter 61, NSAIDs).²⁷ Nonselective NSAIDs inhibit cyclooxygenase-1 and -2 enzymes (COX-1 and COX-2, respectively) and can produce gastroduodenal irritation and ulceration, renal cortical ischemia from reduced renal blood flow, hepatotoxicity, and platelet dysfunction. These toxicities are believed to be related more so to inhibition of COX-1, the constitutive enzyme.²⁸ COX-2 is induced by injury or inflammation, and it is therefore likely that analgesia is related mainly to inhibition of this particular enzyme. Certain NSAIDs, including choline magnesium trisalicylate, meloxicam, nabumetone, diclofenac, and etodolac, may be less likely to cause gastrointestinal (GI) toxicity because they show relative selectivity for COX-2.²⁹ Celecoxib inhibits only COX-2, so it causes less GI toxicity than most NSAIDs.³⁰

NSAID-induced dyspepsia is best managed prophylactically by taking the drugs with food. If this is insufficient, addition of a histamine-2 (H₂) receptor blocker, coating agent, proton pump inhibitor (PPI), or antacid may be necessary. NSAID-induced ulcers may be prevented with H₂ blockers, misoprostol (a prostaglandin E analog), or PPIs. Yeomans et al.³¹ showed that omeprazole, a PPI, is somewhat more effective in preventing and healing gastric and duodenal ulcers than ranitidine, an H₂ blocker. The same group also found that omeprazole is better than misoprostol in healing gastric and duodenal ulcers and in preventing their reappearance during NSAID therapy.³² The risk of ulceration during NSAID therapy increases with age, previous NSAID intolerance, history of peptic ulcer disease, and smoking.³³ In these patients, prophylactic use of an H₂ blocker, PPI, or misoprostol is warranted.

Most NSAIDs interfere with platelet aggregation, thereby creating possible bleeding risk associated with their use. For instance, despite its short elimination half-life, aspirin irreversibly inhibits platelet aggregation for the lifetime of the platelet (4–7 days). The platelet effect of other NSAIDs lasts about 2 days after the drug is discontinued. Choline magnesium trisalicylate, however, does not prevent normal platelet aggregation, as measured experimentally, and appears to be associated with less occult GI bleeding.³⁴ COX-2 inhibitors have less or no platelet effect.³⁰

The renal side effects of NSAIDs include reversible renal insufficiency, interstitial nephritis, and predisposition to acute tubular necrosis in patients with low renal perfusion. NSAIDs should be prescribed with caution for patients with hypertension, renal insufficiency, or congestive heart failure.

Other toxicities are also possible; both acetaminophen and NSAIDs may cause hepatotoxicity, even at normally recommended doses.³⁵ Confusion and inability to concentrate are possible central nervous system (CNS) effects of NSAIDs. Patients who are allergic to aspirin or to an NSAID may have a cross-reactive allergy to other NSAIDs.

Opioids are indicated for the treatment of cancer pain because of their effectiveness, reliability, safety, and ease of administration (see Chapter 58, Opioid Pharmacology). Although neuropathic pain may be more difficult to treat with opioids, its presence does not preclude a favorable response to opioid-based analgesia.³⁶

Steps 2 and 3 of the WHO analgesic ladder advocate the addition of opioids for moderate to severe pain, with or without an adjuvant drug.¹ “Weak” and “strong” opioids are not inherently different in their ability to control pain but are customarily used in amounts appropriate for milder and stronger pain, respectively. The so-called weak opioids (e.g., codeine and hydrocodone) for Step 2 are commonly prepared in combination with co-analgesics (acetaminophen, aspirin, or an NSAID). The co-analgesic limits dose escalation, necessitating a change to another opioid or preparation as pain increases.

THE CONCEPTS OF TOLERANCE, PHYSICAL DEPENDENCE, AND ADDICTION

Opioids can induce tolerance and physical dependence. Addiction—defined as loss of control over drug use, compulsive use, and use despite harm—is rare in cancer pain patients with no history of substance abuse.³⁷ Although demands for opioids and dramatic pain behavior are commonly interpreted as markers of addiction, undertreatment of pain is an alternative explanation (a phenomenon known as pseudoaddiction).³⁸

Although tolerance to opioid analgesia occurs, disease progression is usually to blame for increasing analgesic requirements.³⁹ Tolerance to adverse effects, such as respiratory depression and somnolence, also occurs and thus allows for dose escalation to satisfactory analgesia. Physical dependence is another pharmacologic effect of opioids and is defined solely by the development of withdrawal symptoms (an “autonomic arousal”) after abrupt cessation of therapy or after administration of an opioid partial agonist or antagonist in an opioid-tolerant individual. Physical dependence is not a clinical problem if this aforementioned abstinence syndrome is avoided. It should be mentioned, of note, that many patients confuse the concept of physical dependence with the state of addiction; therefore, the difference should be explained to them for reassurance purposes.

The U.S. Food and Drug Administration (FDA) defines “opioid tolerant” as follows:

CHOOSING AN OPIOID

Few comparative clinical trials exist to differentiate opioids according to responsiveness. Hence, they are usually chosen on the basis of familiarity by the prescriber. Other factors to consider are their potency, route of administration, cost, convenience, and availability. Individual patients vary greatly in their response to different opioids, supporting the practice of sequential opioid trials (opioid rotation) to find the most acceptable balance between analgesia and side effects (see the Changing Opioids and Routes of Administration section later in this chapter).⁴⁰ There is ongoing research, however, in applying pharmacogenomics testing to patients, with the idea being to identify specific genetic polymorphisms in each patient that could affect response to opioids.^41–43 This information would allow tailored treatment, which in turn could translate to better prediction and monitoring of analgesic response.

In general, the initial opioid should be a short-acting drug when the patient (1) has severe pain and requires rapid dose titration, (2) has intermittent pain, or (3) is opioid naïve and there is concern about delayed toxicity from a long-acting preparation. In other cases in opioid-tolerant patients, however, a long-acting drug or extended-release drug may be the initial opioid. Long-acting opioids include methadone and levorphanol, and extended-release preparations include hydrocodone, morphine, oxycodone, oxymorphone, hydromorphone, tapentadol, and fentanyl.

There are differences among opioids in relative toxicities. Meperidine, for instance, should be avoided for cancer pain treatment, especially in patients with renal failure.⁴⁴ Its active metabolite, normeperidine, has a long half-life and causes CNS excitability that can result in seizures. It can accumulate with high doses, prolonged use, and renal dysfunction. Morphine is hepatically biotransformed into its metabolites of morphine- 3-glucuronide (M3G) primarily, and morphine-6-glucuronide (M6G), the latter being an active metabolite that is much more potent than the parent compound. These metabolites do not tend to cause problems in patients with normal renal function, but they could accumulate and lead to toxicity in those with renal insufficiency.

Partial opioid receptor agonists (e.g., buprenorphine) and mixed agonist–antagonists (e.g., pentazocine, nalbuphine, and butorphanol) should also be avoided. They may precipitate both withdrawal symptoms and pain in patients who are opioid tolerant. When used alone, increasing amounts provide less incremental analgesia, a phenomenon known as a “ceiling effect.” Some of the mixed agonist–antagonists also have relatively greater toxicity than the pure µ agonists.⁴⁵

Combination analgesics, which often contain acetaminophen, should be used with caution because of the possibility of acetaminophen toxicity, as previously mentioned. Daily acetaminophen intake should not exceed 3 g, per recent FDA guidelines. Alcohol use, coexisting hepatic disease, and starvation (which may be present in debilitated cancer patients) predispose to acetaminophen hepatotoxicity at even lower doses.³⁵

Methadone and levorphanol have long half-lives and may be considered in place of extended-release preparations for baseline opioid requirements. One advantage of these drugs is that they are absorbed easily by the gut and may be effective in patients with bowel pathology who are unable to completely absorb the aforementioned extended-release preparations⁴⁶ or in patients who have feeding tubes that preclude the use of most extended-release pills. Methadone may be difficult to titrate, however, because the initial duration of action (~6 hours) is shorter than its elimination half-life, leading to potentially fatal drug accumulation with repeated dosing over 2 to 5 days.⁴⁷ Furthermore, methadone pharmacokinetics are highly variable among patients owing to differences in protein binding, urinary excretion, and induction of metabolism by other drugs.^46–48 Methadone’s elimination half-life is usually about 24 hours, but it may be as short as 12 hours or longer than 50 hours.

OPIOID DOSING

The appropriate opioid dose and interval should control pain without end-of-dose failure and unacceptable side effects at peak concentration (i.e., without bolus effects). The required dose varies with the severity of pain, the type of pain, preexisting opioid exposure, psychological distress, and other factors.³⁶ Elderly adults are more sensitive to opioid-induced analgesia but may also be more susceptible to its side effects.⁴⁹ Large doses may be necessary as the disease progresses. Although there is no theoretical limit to the dose, a practical limit is imposed by the occurrence of intolerable side effects, a large injectate volume, numerous pills or suppositories, or excessive skin surface required for transdermal applications.

When initiating opioid therapy, a short-acting drug may be given on an as-needed basis every 2 or 3 hours (Table 55-2). After 5 or 6 half-lives (1 day for morphine), the basal daily opioid requirement is determined, and a long-acting opioid preparation may be substituted. Alternatively, a long-acting opioid may be used initially when pain is constant and not severe or progressive. Long-acting opioids should be provided regularly to prevent most pain. An additional short-acting opioid (5%–15% of the basal daily requirement) is made available for breakthrough pain every 1 to 3 hours.⁵⁰ If the short-acting opioid is needed more than three times per day, the amount of long-acting opioid is usually increased. It is inconvenient and unnecessary to increase the dosing frequency of long-acting oral preparations when increasing the total daily dose. Dose changes should be in increments of one-third to half of the preceding dose or according to the patient’s usage of breakthrough opioid. If side effects prevent dose escalation, switching to another opioid should be considered before changing to another route of administration or abandoning opioids.⁴⁰