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.
The three-step analgesic ladder for cancer pain treatment. (Reproduced by permission of World Health Organization. Cancer Pain Relief, 2nd ed. Geneva: Author; 1996.)
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.
Although there is no quantitative biochemical or neurophysiologic test for pain, tools have been devised to assess pain intensity4,5 (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 pain22,23 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).
Doses and Routes of Some Nonopioid Analgesics
||Download (.pdf) TABLE 55-1
Doses and Routes of Some Nonopioid Analgesics
First dose: 1000 mg
Choline magnesium trisalicylate
Liquid available; less dyspepsia and platelet dysfunction
Sustained release available
First dose: 500 mg
Frequent side effects
Lower dose for repeated use
Limit to 5 days (PO/IV)
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:
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.
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
Equivalent and Recommended Opioid Doses and Routes
||Download (.pdf) TABLE 55-2
Equivalent and Recommended Opioid Doses and Routes
Approximate Equianalgesic Dose
Usual Starting Dose
30 mg q3–4 h
10 mg q3–4 h
20–60 mg q3–4 h
10 mg q3–4 h
7.5 mg q3–4 h
1.5 mg q3–4 h
4–8 mg q3–4 h
1–2 mg q3–4 h
20 mg q6–8 h
10 mg q6–8 h
20 mg q6–8 h
10 mg q6–8 h
4 mg q6–8 h
2 mg q6–8 h
2–4 mg q6–8 h
1–2 mg q6–8 h
300 mg q2–3 h
100 mg q3 h
300 mg q2–3 h
100 mg q2–3 h
200 mg q3–4 h
130 mg q4 h
30–60 mg q3–4 he
60 mg q2 he
30 mg q3–4 h
5–10 mg q3–4 he
30 mg q3–4 h
5–10 mg q3–4 he
Cessation or reduction of opioid use may be appropriate when the patient is pain free after antitumor therapy or after a successful anesthetic or neuroablative procedure. Based on clinical observation, reduction of the daily dose by 50% every 3 days usually prevents symptomatic withdrawal. Withdrawal symptoms include yawning, nausea, vomiting, abdominal cramps, diarrhea, insomnia, anxiety, irritability, temperature instability, diaphoresis, and salivation. It is generally not considered a life-threatening event; however, patients describe the withdrawal syndrome as a severe, flulike experience.
The usual route of systemic opioid administration is oral. The peak effect is typically in 20 to 90 minutes, and the duration is 3 to 6 hours.51 Extended-release oral preparations are available for maintenance of steady analgesia, with the peak effect at 2 to 3 hours and a duration of 8 to 24 hours.52–54 The clear advantages of oral administration are the numerous drugs available and their ease of use. However, some patients may not be able to use oral medications, including those with oral mucositis, dysphagia, bowel obstruction, and severe nausea.55
Fentanyl is a highly lipid-soluble opioid available in transdermal form (a transdermal therapeutic system), which is especially important when the oral route is less preferred.56 Transdermal fentanyl might also be selected if patient compliance or adherence with oral analgesics is an issue. The onset of analgesia is about 12 hours after initial patch application and continues for 16 to 24 hours after removal. A comparative trial against extended-release morphine suggests that transdermal fentanyl is associated with less constipation.57 It should be noted that transdermal fentanyl is indicated for pain in patients who are opioid tolerant only. Fentanyl is also available in transmucosal forms (buccal, sublingual, intranasal) for severe breakthrough cancer pain in opioid-tolerant patients. Transmucosal fentanyl is characterized by a more rapid onset compared with oral opioid alternatives,58–60 partly related to bypassing hepatic first-pass metabolism.
Morphine, oxymorphone, and hydromorphone are manufactured for rectal use. Injectable methadone and sustained-release morphine have also been used rectally.55,61 A disadvantage of rectal administration is the interpatient variability in absorption and degree of first-pass metabolism. Partial avoidance of the portal circulation may result in slightly increased bioavailability compared with oral opioids. Whereas morphine suppositories are slowly absorbed,55 morphine microenemas (10 mg in 1 mL) have a more rapid onset and longer duration than the same dose given orally.62 Mucositis or transmucosal lesions, diarrhea, thrombocytopenia, and neutropenia contraindicate the rectal route.
Injected opioids may be useful for patients who cannot take opioids by the oral, sublingual, or rectal routes; for those who need rapid dose titration; and for those whose high opioid needs cannot be easily met by other routes. IV injection of most opioids provides peak effect in 5 to 15 minutes, with a similarly shortened duration of effect. Subcutaneous injection analgesia peaks at 30 minutes and is preferred over intramuscular injection because the latter is more painful. The usual conversion ratio between subcutaneous and IV is considered 1:1. Continuous infusion (subcutaneous or IV) or frequent redosing is usually necessary to maintain analgesia with injected opioids. Subcutaneous infusion volume should be limited, especially in cachectic patients, to permit stable absorption.63 Moulin et al.64 compared subcutaneous with IV opioid infusion in 15 patients with cancer pain in a double-blind, randomized, crossover trial. The mean bioavailability was 78% with subcutaneous infusion, but pain scores and the need for breakthrough medication were no different from IV infusion.
Patient-controlled analgesia (PCA) may be useful for initiation of parenteral opioid therapy, rapid opioid titration with changing pain intensity, and treatment of incident pain.65 Because the patient controls the delivery of the opioid, individual differences in pain intensity, drug clearance, and effectiveness are less likely to interfere with therapy. In a study of 26 patients with oral mucositis after bone marrow transplantation, psychological dependence was no more likely, total opioid consumption and side effects were less, and analgesia was the same or better with PCA as with nurse-administered opioids.66 PCA devices are individually programmed for the size of the dose (demand dose), the minimum time between doses (lockout interval), and the cumulative dose allowed in 1 or 4 hours (several times higher than the anticipated need). In addition, an optional nursing bolus may be allowed. Continuous infusion (a basal rate) may be programmed in addition to the demand doses to allow sleep and to cover baseline pain. An important inherent safety feature of PCA is that the patient cannot self-administer additional medication if he or she is already overly sedated. Those attending to the patient must not circumvent this safety feature by pressing the demand button for the patient.
Recommended PCA settings for morphine, hydromorphone, and fentanyl are shown in Table 55-3. Much larger doses may be needed for opioid-tolerant patients. To limit the total volume of injectate, hydromorphone may be chosen over fentanyl and morphine because of its potency and solubility. Whereas fentanyl is commercially available only at 50 μg/mL, morphine and hydromorphone can be compounded to 50 mg/mL for injection.
Suggested Post–Controlled Analgesia Opioid Programming for an Opioid-Naïve Patient After a Loading Dose of the Opioid Is Given
||Download (.pdf) TABLE 55-3
Suggested Post–Controlled Analgesia Opioid Programming for an Opioid-Naïve Patient After a Loading Dose of the Opioid Is Given
Morphine 1 mg/mL
Hydromorphone 0.25 mg/mL
Fentanyl 25 or 50 μg/mL
Patient-controlled analgesia is an efficient means of determining a patient's opioid requirement when initiating or changing opioids. The pump records the amount of drug used, which is then converted to continuous infusion, transdermal fentanyl, or a sustained-release oral preparation. PCA is available for use in the home as well as the hospital. Patients without IV access may use subcutaneous PCA.65
CHANGING OPIOIDS AND ROUTES OF ADMINISTRATION
Dose-limiting side effects and the loss of the previous route of administration are the usual reasons for changing drugs or routes. Trials of several opioids should be considered before abandoning systemic opioids for treatment of cancer pain because patients may respond differently to different drugs. Incomplete cross-tolerance between opioids may account for the apparent decrease in required dose when changing analgesic drugs.40,67 When changing one opioid to another drug or route of administration, conversion is made with the assistance of opioid conversion charts (see Table 55-2).
All opioid doses can be expressed as equianalgesic doses. Typically, 10 mg of parenteral morphine is considered the unit dose, and doses of other drugs for oral or parenteral administration are listed in equianalgesic amounts. The conversion tables (see Table 55-2) contain approximations based largely on short-term use of smaller opioid doses. When converting large opioid doses, caution dictates dose reduction by one-third to half to account for incomplete cross-tolerance.40,67 When changing to methadone, a 75% to 90% initial dose reduction is indicated because of the greater potential for drug accumulation and the possibility of unexpectedly high potency.40 If inadequate analgesia necessitates the conversion and there are no significant side effects, the new drug may be started closer to the equianalgesic dose.50 Additional short-acting opioid is made available while titrating the new drug to achieve stable analgesia. When any change in opioid or route is made, frequent assessments are needed to keep pain controlled and to prevent side effects.
Optimal therapy may not be achieved in the cancer pain population with opioids alone. Often, opioids combined with nonopioid analgesics and adjuvant analgesics are necessary to achieve satisfactory relief.68 A number of adjuvant drugs are used in conjunction with opioids, especially to relieve the neuropathic component of the pain state, which is considered at times to be an opioid-resistant type of pain (or only partially responsive to opioids). An additional benefit of adding adjuvants is to provide an opioid-sparing effect, thus lessening opioid-related side effects.
The tricyclic antidepressants (TCAs) were used as analgesics shortly after their introduction.69,70 The mechanism of their analgesic action is not certain, but it probably includes enhancement of monoamine concentrations in the dorsal horn71 and stimulation of α2 receptors72 (see Chapter 62, Adjuvant Analgesics). They are useful in treating neuropathic pain and have been proven analgesic in well-designed trials for postherpetic neuralgia (PHN), diabetic neuropathy, atypical facial pain, migraine headache, fibrositis, and central poststroke pain.69,70 There have been few controlled trials of TCAs for the treatment of cancer pain, perhaps because cancer pain encompasses so many somatic, visceral, and neuropathic entities (see Chapter 44, Cancer Pain Syndromes). Amitriptyline has been shown effective, however, in a placebo-controlled study of 20 patients with neuropathic postmastectomy pain;73 however, in another randomized controlled trial (RCT), its effectiveness was not supported.74 The analgesic effect of the TCAs on neuropathic pain seems to be separate from their antidepressant or sedative effects.73,75–78
The TCAs are most appropriate for cancer patients with neuropathic pain, which is often described as burning, searing, aching, or dysesthetic, and occurs in the setting of known or probable nerve injury. The choice of drug is empiric; there is no clearly superior drug. A patient having difficulty with sleep may benefit from a more sedating drug, such as amitriptyline, imipramine, or doxepin. Nortriptyline is less sedating, and desipramine has the fewest side effects.75,79 Trazodone is not an effective analgesic for neuropathic pain but may be indicated in cancer pain patients with sleep disturbances. Probably fewer than half of patients with neuropathic pain achieve greater than 50% pain relief with an antidepressant,71 and a lack of complete relief should not be interpreted as treatment failure.
Suggested dosing for the TCAs is shown in Table 55-4. Because these drugs are usually sedating, they are best given in the evening. If the initial low dose is not effective, it should be increased every few days to weeks until an effect is seen or side effects become intolerable. As with opioids, greater analgesia is seen with higher doses.76
Doses of Some Tricyclic Antidepressants Used for Pain Management
||Download (.pdf) TABLE 55-4
Doses of Some Tricyclic Antidepressants Used for Pain Management
Dose Range (mg)
Sedation and hypotension are common; effective for insomnia
Sedating but less so than others tricyclics
May have an alerting effect; tachycardia
Adverse effects with TCAs are common.70 They are primarily anticholinergic, including sedation, constipation, urinary retention and overflow incontinence, tachycardia, dry mouth, blurred vision, dysphoria, and agitation. Antihistamine effects are responsible for sedation and weight gain and may exacerbate hypotension. α1 and α2 Blockade contributes to orthostatic hypotension and tachycardia. Most of these side effects are not life threatening and diminish with time. Dry mouth tends to persist. The side effects are troubling, however, and often result in discontinuation of the TCA. Cardiac conduction abnormalities and seizures are more concerning effects. A history of seizure is a relative contraindication to TCA use.80 An electrocardiogram should be obtained before TCA initiation to rule out bundle branch block and bifascicular block, which are also relative contraindications.81 Dose adjustment according to drug levels may help to prevent these consequences of antidepressant therapy.80 When a patient experiences unwanted side effects, it is wise to switch to another TCA because patient responses are variable and often idiosyncratic. Persistence in treatment is essential because analgesic response may take several weeks to become evident.69
Duloxetine is a serotonin-norepinephrine reuptake inhibitor approved for many indications, such as depression, painful diabetic neuropathy, fibromyalgia, chronic multisite musculoskeletal pain, and others. Matsuoka et al.82 performed a pilot study to determine the analgesic effects of duloxetine for neuropathic cancer pain. In this study, 15 cancer patients with neuropathic pain were administered duloxetine, and a retrospective analysis of the data revealed that 11 of these 15 patients benefitted either by a reduction in pain intensity as recorded on NRS or improvement of other symptoms, such as sleepiness and lightheadedness.
Carbamazepine has long been used for treatment of trigeminal neuralgia.83 Several anticonvulsants are now commonly used to treat lancinating and burning dysesthesias complicating nerve injury (see also Chapter 62, Adjuvant Analgesics). In addition to trigeminal neuralgia, glossopharyngeal neuralgia, tabes dorsalis, diabetic neuropathy, PHN, postamputation pain, migraines, central pain, and other conditions have been reported to respond to anticonvulsants in case reports, case series, and poorly controlled trials.84 Two randomized, double-blind, placebo-controlled studies support the use of gabapentin for diabetic neuropathy and PHN.85,86
Swerdlow studied 200 patients with lancinating pain in an open-label, uncontrolled trial of carbamazepine, phenytoin, valproate, and clonazepam.84 Patients were switched from one drug to another if they failed to obtain relief. Most patients did respond to one of the drugs, but there was no clearly superior medication in general or for any particular condition. McQuay et al.87 conducted a systematic review of 20 randomized, controlled anticonvulsant trials. Patients with trigeminal neuralgia responded to carbamazepine, and those with diabetic neuropathy responded to both carbamazepine and phenytoin. Valproate and carbamazepine were effective for migraine prophylaxis.
Although there have been few prospective, controlled trials of anticonvulsants for patients with cancer pain, individual patients may respond dramatically, and these medications should not be withheld from patients in pain pending definitive evidence of their efficacy. Yajnik et al.88 compared phenytoin with buprenorphine and the combination in three groups of 25 patients with cancer pain resulting from various causes. A low dose of phenytoin (100 mg twice daily) provided greater than 50% pain relief in most patients and enhanced the effect of buprenorphine without increasing side effects.
Carbamazepine is started at 100 mg twice daily and is escalated until toxicity occurs, pain is relieved, or the safe plasma level is exceeded (12 μg/mL). Bone marrow suppression often manifests as mild leukopenia or thrombocytopenia and rarely aplastic anemia. If bone marrow suppression is anticipated from radiation, chemotherapy, or tumor replacement, carbamazepine should be avoided. Patients receiving carbamazepine should have their complete blood counts and hepatic transaminases monitored. Reversible hepatotoxicity, resembling viral hepatitis, occurs rarely, and fatal hepatic necrosis is less common.89 Cutaneous reactions may also occur and require cessation of the medication. Sedation, vertigo, ataxia, hyponatremia, and nausea are more common effects.84 Oxcarbazepine is a structural derivative of carbamazepine with a safer side effect profile in that it is less likely to cause the above-mentioned hematologic and hepatic adverse effects. It should be noted, though, that both carbamazepine and oxcarbazepine have not been well studied for cancer-related pain.
Phenytoin and valproate are available in oral and IV forms. A new form of phenytoin, fosphenytoin, may be administered intramuscularly. Treatment with phenytoin begins with an oral loading dose, and maintenance therapy, starting at 100 mg three times daily, is adjusted to control pain with a plasma concentration of less than 20 μg/mL. Side effects may include anemia, anorexia, nausea, somnolence, and ataxia. Bone marrow suppression is less likely with phenytoin than carbamazepine. The potential for hepatotoxicity mandates periodic monitoring of liver function tests.84 Hypersensitivity to phenytoin is rare but potentially fatal and manifests with rash, fever, and hepatitis. Up to 19% of patients taking phenytoin develop cutaneous reactions, usually without hypersensitivity.90 Oral valproate therapy is usually started at 125 mg twice daily. The most common side effects are nausea and epigastric pain, which are reduced by taking it with food and with enteric-coated tablets. Hepatotoxicity is rare.84
Gabapentin has received considerable attention in pain management, and there is evidence to support its use in diabetic neuropathy and PHN.85,86 Several studies support the effectiveness of gabapentin as an adjuvant for cancer-related neuropathic pain,91–93 and a recent literature review corroborates this finding.94 It is usually started at 300 mg at bedtime and increased as high as 3600 mg/day in divided doses. The dosage should be reduced in patients with renal impairment because it is eliminated unchanged in the urine. Side effects (somnolence, ataxia, peripheral edema, and dizziness) are not life threatening, and plasma concentrations are not monitored, making this an easy anticonvulsant to use.95
Pregabalin is a structurally similar anticonvulsant to gabapentin, with similar indications for use. The use of pregabalin for cancer pain has not been extensively studied; however, there is some evidence in the literature to support its use for cancer-related bone and neuropathic pain. For example, Sjolund et al.96 performed a randomized trial on pregabalin's effect on cancer-induced bone pain. A total of 152 patients enrolled in this study were assigned either to pregabalin or placebo. The endpoint was the duration-adjusted average change from baseline in the daily worst pain. The study had to be discontinued after interim review because of an insufficient sample size to make meaningful statistical analyses, yet descriptive analyses of the data suggested that pregabalin could be helpful in reducing metastatic bone pain. Several studies support pregabalin use in neuropathic cancer pain,97,98 although a systematic review was not able to draw any conclusions because of the limitations for comparison of the available studies.99
SYSTEMIC LOCAL ANESTHETICS
Systemic local anesthetics are often used to treat neuropathic pain (see also Chapter 62, Adjuvant Analgesics). IV lidocaine (5 mg/kg over 30 minutes) has been found effective for PHN and diabetic neuropathy.100,101 A small number of case reports and higher level evidence in the literature demonstrate the effectiveness of IV lidocaine for refractory cancer pain with a neuropathic component. For instance, Sharma et al.102 conducted an RCT to evaluate the use of IV lidocaine in cancer pain refractory to opioid therapy. Fifty eligible patients enrolled in this study received both IV lidocaine and IV placebo 2 weeks apart. There was a significant difference in the degree of pain relief after lidocaine infusion, and more patients reported reduced analgesic requirements afterward compared with placebo infusion.
Ketamine is a dissociative anesthetic with a number of pharmacodynamic properties useful for pain, including its antagonism of the N-methyl-D-aspartate (NMDA) receptor and its agonist activity at the opioid receptor, among other mechanisms of action. Common side effects of ketamine include sedation, somnolence, sensory illusions, dissociative feelings, and visual disturbance. Transaminitis has been reported in those undergoing continuous ketamine infusion.103 Ketamine has been shown to be effective in treating refractory cancer pain as supported by a recent systematic review and synthesis of available data by Bredlau et al.104 One of the studies included in this review, for example, was a randomized, double-blind, crossover trial105 of IV ketamine at two doses (0.25 or 0.50 mg/kg) or saline as a control performed in ten participants with various cancer diagnoses. Each participant received each intervention, with a 2-day washout between interventions. Compared with saline, ketamine administration provided significantly improved analgesia, and there was no significant difference in pain scores between the two ketamine doses. It should also be noted that ketamine as an infusion is suggested to be no more than 0.5 mg/kg/h. In the oral route, 0.2 to 0.5 mg/kg (maximum, 50 mg/dose) two or three times daily has been suggested.104
Several compounded agents are used to create an oral topical solution for mucositis-related pain, which can occur with chemotherapy, radiation therapy, and hematopoietic stem cell transplant. These compounded agents may consist of local anesthetics, antimicrobials, analgesics, anti-inflammatories, adjuvants, and others. A survey was conducted to compare the ingredients used in 40 U.S. institutions’ compounded oral solutions (known as “magic mouthwash”) for chemotherapy-induced oral mucositis,106 finding that diphenhydramine, viscous lidocaine, magnesium hydroxide–aluminium hydroxide, nystatin, and steroids were the most commonly used ingredients.
Corticosteroids are used as co-analgesics when inflammation or the mass effect of vasogenic edema causes pain.107 They reduce inflammation by inhibiting phospholipase activity and thus prostaglandin synthesis. In addition, they may reduce axonal sprouting and neurokinin concentration in sensory fibers near injured tissue.108 Regenerating axons in neuromas discharge spontaneously or with minimal tactile stimulation because of high sodium channel expression;109 locally injected corticosteroids reduce neuroma discharge in animal models and appear to be effective in humans as well. Acute neural compression (e.g., in spinal cord compression), intracranial hypertension (from brain metastases), bony and soft tissue infiltration, and visceral distention cause pain that may respond to steroids.110 Dexamethasone is probably the most commonly prescribed corticosteroid for cancer-related symptoms, including pain. For bone or neuropathic pain, the typical oral dose of dexamethasone is 4 to 8 mg/day (which can be in divided doses).111
Corticosteroids have numerous toxicities when taken chronically.107 These include fluid retention and electrolyte disturbances, hypertension, proximal myopathy, osteoporosis and aseptic necrosis, insomnia, psychosis, gastritis, hyperglycemia, and impaired cellular immunity. These adverse effects may be undesirable in cancer patients who are expected to survive for more than several months. Mood elevation, antiemesis, and appetite stimulation are often desirable side effects of corticosteroids, but they may diminish with prolonged use.107
The term skeletal-related events (SREs) describes a constellation of clinical complications from bone metastases, including bone pain, hypercalcemia of malignancy, pathologic fracture that may result in cord compression, need for radiotherapy, or need for surgery. Bone-modifying agents can be used to reduce SREs, and evidence supports the use of bisphosphonates to reduce metastatic bone pain and induce healing of lytic lesions.112 Body and colleagues113 studied the effect of oral ibandronate on bone pain and quality of life in patients with metastatic breast cancer to bone. A total of 564 patients enrolled in these two double-blind randomized studies received either oral ibandronate at 50 mg/day or placebo for up to 96 weeks. There was a significant reduction and maintenance of pain scores below baseline in the ibandronate group through the length of the study. There were also improved scores for quality of life in the ibandronate group compared with the placebo group. The authors of this study concluded that the results were suggestive of a clinically useful co-analgesic property of ibandronate.
Clonidine, an α2 receptor agonist, may contribute to analgesia by stimulating presynaptic or postsynaptic receptors in the superficial dorsal horn, decreasing sympathetic outflow, and enhancing noradrenergic inhibitory fibers from the brain stem.114 These mechanisms may make clonidine a useful analgesic adjuvant for opioids, especially in the setting of neuropathic pain.115,116 Max et al.114 found a single dose of oral clonidine (0.2 mg) superior to placebo, ibuprofen (800 mg), and codeine (120 mg) in the treatment of PHN. Oral clonidine has not been well studied, however, for cancer pain. The epidural route appears to be more effective than the systemic route for clonidine,116 and spinal delivery of clonidine has demonstrated effectiveness in a number of reports in cancer-related pain.117,118 Side effects associated with clonidine include orthostatic hypotension, sedation, dry mouth, and constipation. Clonidine does not appear to aggravate opioid-induced respiratory depression.
MANAGEMENT OF ANALGESIC SIDE EFFECTS
Many of the analgesics described in the earlier sections produce dose-limiting side effects, particularly the opioids. Tolerance to opioid side effects generally occurs after repeated use for at least 1 week; however, many patients may continue to experience intolerable side effects, particularly with repeated titration of opioid dosages. Achieving a balance between analgesia and tolerable side effects can be aided by adjuvants as described in the text below.
Opioids have three emetogenic mechanisms: a direct effect on the chemoreceptor trigger zone, an enhancing effect on vestibular sensitivity, and a slowing effect on gastric emptying. Although nausea is common with opioids, tolerance to this effect occurs quickly. Treatment is therefore given as needed.50 When evaluating opioid-induced nausea, refractory constipation and impaction of stool must be considered and treated first. If nausea follows meals or is accompanied by postprandial vomiting, metoclopramide is an appropriate choice to stimulate GI motility. If nausea occurs with movement, meclizine may be more effective as an antihistamine and anticholinergic for vertigo or motion sickness. In the absence of these associations, a phenothiazine, antihistamine, or serotonin antagonist is appropriate (Table 55-5). If these are ineffective, a corticosteroid107 or benzodiazepine may also be useful.
Opioids bind to specific receptors in the CNS as well as in the GI system to produce constipation by direct and anticholinergic effects.119 An increased GI transit time causes excessive water and electrolyte reabsorption from the feces. Decreased biliary and pancreatic secretion further dehydrates the stool. The TCAs, clonidine, dehydration, surgical procedures, and bowel obstruction by tumor contribute to constipation as well. Elderly patients are particularly susceptible to constipation and impaction of stool.120
Opioid-induced constipation is so common that cathartic and stool-softening medications should be routinely initiated alongside around-the-clock opioid orders. The coadministration of docusate (a stool softener) and sennosides (a stimulant laxative) is appropriate for most patients. Adequate hydration, physical activity, and proper nutrition are also helpful. If constipation develops or persists with this bowel regimen, then an osmotic laxative, such as lactulose (15–30 mL) or magnesium citrate (200 mL), is added after ruling out fecal impaction. Bisacodyl suppository or sodium phosphate–biphosphate enemas are used for patients who are too nauseated to take oral cathartics. Disimpaction may be facilitated with mineral oil or saline enemas. Refractory constipation may respond to oral naloxone (1–12 mg), which antagonizes enteric opioid receptors. Because naloxone is only about 3% bioavailable, systemic opioid withdrawal and recrudescence of pain may be avoided with low doses. Oral naloxone should be avoided in patients with bowel obstruction.121,122 Methylnaltrexone, a peripherally acting opioid antagonist, is FDA approved for opioid-induced constipation. The dosage is weight based and administered subcutaneously, and it produces a rapid, robust, and consistent response usually within 4 hours of administration.123 Caution is suggested in the patient population at risk for bowel perforation, such as those with history of bowel obstruction or abdominal or pelvic malignancy.
Somnolence and mental clouding are common complaints when opioids are initiated or escalated. Some patients continue to have these problems, especially when certain co-analgesics (antidepressants, anticonvulsants, benzodiazepines, antihistamines, and phenothiazines) with similar drowsiness side effect profile are being used. After ruling out primary CNS abnormalities and metabolic derangement, unnecessary sedative medications should be gradually eliminated. If symptoms persist and analgesia is adequate, the opioid dose may be reduced or the opioid drug may be changed. If analgesia is unsatisfactory, co-analgesics may be initiated or increased to achieve an opioid-sparing effect. An anesthetic or neuroablative procedure may be necessary if the patient finds sedation particularly troubling.50
Psychostimulants, such as caffeine (100–200 mg orally per day), dextroamphetamine (2.5–10 mg orally twice daily), and methylphenidate (5–10 mg orally twice daily), are commonly used to offset fatigue or the sedative effects of opioids.124 Bruera et al.125 studied the cognitive effects of methylphenidate versus placebo in a double-blind, crossover trial involving 20 patients with cancer pain who were receiving continuous infusions of opioids. Cognitive function was improved by methylphenidate, and most patients preferred it to placebo. Amphetamines, similar to antidepressants, have mood-elevating and analgesic properties.124
Respiratory depression occurs with sedation when opioids are given systemically, and tolerance to this effect occurs quickly. All opioids affect the medullary respiratory center directly. No pure opioid agonist is less likely to cause respiratory depression than another when given at an equianalgesic dose. For most patients, mild respiratory depression (respiratory rate, 8–12 breaths/min) is well tolerated. For those with limited ventilatory or respiratory reserve, it may be problematic. If a low respiratory rate and moderate sedation occur after the expected peak of opioid activity, it is best to withhold further opioids until the respiratory rate rises or pain returns. If necessary, ventilatory support and a small dose of dilute naloxone (20–80 μg intravenously) may be given and repeated as necessary. Because naloxone's reversal effects are shorter than the sedation and respiratory depressant effects of most opioids, continued close monitoring for recurrence of respiratory depression is necessary50 and may require continuous naloxone infusion.
MYOCLONUS AND HYPERALGESIA
Myoclonus (uncontrollable spasms of certain muscle groups) and hyperalgesia (excessive sensitivity to mildly noxious stimuli) are sometimes seen at very high doses of opioids. Their occurrence, separately or together, may limit the ability of opioids to control pain at the end of life.126 The mechanisms of these conditions are not certain but may include the inhibition of nonopioid CNS inhibitory systems127 and the potentiation of glutamate activity at NMDA receptors.106 A change to another opioid (to take advantage of incomplete cross-tolerance) and the addition of co-analgesics and adjuvants (to exploit opioid dose-sparing effects) may allow a reduction in total opioid dosage, thereby possibly relieving both complications.67 Clonazepam (0.5–2 mg orally three times daily) and perhaps other anticonvulsants may also be used to suppress myoclonus.67,128 Finally, an anesthetic or neuroablative procedure may be indicated for refractory cases.
Refractory pain is a symptom that can lead to a cancer diagnosis and everything that diagnosis entails. Cancer pain relief engenders hope that disease is stabilized or in remission or cured. Recurrent pain may signal recurrent disease. Worsening pain may indicate failure of curative therapy and herald progression of disease and portend the end of life.
Pain experienced by patients with cancer may be from primary or metastatic tumor. It may be an aftereffect of treatments—surgery, chemotherapy, or radiation therapy. Or cancer patients may suffer from pain unrelated to their cancer diagnosis. Similar to many of us, patients with cancer have various acute and chronic pain issues.
Pain in a patient with cancer does not exist in isolation from other problems. Instead, it is part of a complex constellation of concurrent symptoms that burden the patient. These issues can be bothersome enough by themselves. When they are intertwined with each other, they each contribute to suffering individually, and they synergize to yield a potentiated level of discomfort. This gestalt of misery requires multidisciplinary assessment and multimodal management to achieve best outcomes. In addition to various nonmedication approaches, rational polypharmacotherapy is key to a balanced analgesic strategy.
When pharmacotherapy is the basis of treatment, opioids are often the cornerstone of that foundation. Adjuvant co-analgesics serve as the mortar that facilitates the strength of the regimen. Additional help comes from psycho-social-spiritual support, rehabilitation therapy, integrative strategies, and procedural interventions ranging from simple injections to advanced neuromodulation.
In addition, cancer pain may respond to palliative cancer therapies such as surgery, chemotherapy, or radiotherapy. Indeed, a palliative mindset enables the health care team to provide comprehensive care at any stage of the disease experience, even parallel to curative efforts. Palliative care strategies use a team approach to provide patient-centered care focused on relief of pain and symptom distress that negatively impacts the patient and family. This extra layer of support has an ultimate goal to provide patients with the best possible quality of life for as long as they live.
World Health Organization. Cancer Pain Relief. Geneva: Author; 1996.
AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med
D. Pain assessment in cancer. In: Effect of Cancer on Quality of Life. Boca Raton, FL: CRC Press; 1991.
CL. Cancer pain assessment—can we predict the need for specialist input? Eur J Cancer
MI. The reliability of a linear analogue for evaluating pain. Anaesthesia
DF, et al. Studies comparing Numerical Rating Scales, Verbal Rating Scales, and Visual Analogue Scales for assessment of pain intensity in adults: a systematic literature review. J Pain Symptom Manage
JJ. Bonica's Management of Pain. Baltimore, MD: Lippincott, Williams & Wilkins; 2010.
LS. Cancer pain assessment. Curr Opin Support Palliat Care
CL. Pain ratings: the fifth vital sign. Am J Nurs
WH, de Raaf
PJ, de Klerk
C, van der Rijt
CC. Cut points on 0-10 numeric rating scales for symptoms included in the Edmonton Symptom Assessment Scale in cancer patients: a systematic review. J Pain Symptom Manage
A. The use of next-of-kin to estimate pain in cancer patients. Pain
GD, et al. The Faces Pain Scale for the self-assessment of the severity of pain experienced by children: development, initial validation, and preliminary investigation for ratio scale properties. Pain
A, et al. Validation of a behavioral pain scale in critically ill, sedated, and mechanically ventilated patients. Anesth Analg
S. New developments in the assessment of pain in cancer patients. Support Care Cancer
R. The McGill Pain Questionnaire: major properties and scoring methods. Pain
R. The short-form McGill Pain Questionnaire. Pain
L, et al. The McGill Pain Questionnaire as a multidimensional measure in people with cancer: an integrative review. Pain Manag Nurs
KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore
XS, et al. Assessing symptom distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer
M. Validation of the Edmonton Symptom Assessment Scale. Cancer
RL. Painful boney metastases. Am J Ther
T, et al. Aromatase inhibitor-associated arthralgia and/or bone pain: frequency and characterization in non-clinical trial patients. Clin Breast Cancer
M, et al. Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations. Cancer Treat Rev
K. Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Pain
PB. NSAIDs revisited: selection, monitoring, and safe use. Postgrad Med
. 1997;101:257–260, 263–257, 270–251.
K, et al. Distribution of COX-1 and COX-2 in normal and inflamed tissues. Adv Exp Med Biol
M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med
C. An evidence-based evaluation of the gastrointestinal safety of coxibs. Am J Cardiol
L, et al. A comparison of omeprazole
for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine
for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med
prevents duodenal ulcers associated with non-steroidal anti-inflammatory drug therapy. Aliment Pharmacol Ther
EJ. Choline magnesium trisalicylate does not impair platelet aggregation. Pharmatherapeutica
toxicity in an urban county hospital. N Engl J Med
CE. The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions. Pain
KM. Patterns of narcotic drug use in a cancer pain clinic. Ann N Y Acad Sci
JD. Opioid pseudoaddiction—an iatrogenic syndrome. Pain
KM. The impact of a comprehensive evaluation in the management of cancer pain. Pain
RK. Individual variability in the response to different opioids: report of five cases. Pain
NC. Pain management in the 21st century: utilization of pharmacogenomics and therapeutic drug monitoring. Expert Opin Drug Metab Toxicol
JR. Opioid genetics: the key to personalized pain control? Clin Genet
J. Opioid genetics in the context of opioid switching. Curr Opin Support Palliat Care
GR. Effects of renal insufficiency on the pharmacokinetics and pharmacodynamics of opioid analgesics. Drug Intell Clin Pharm
RW. Analgesic effectiveness of the narcotic agonist-antagonists. Br J Clin Pharmacol
. 1979;7(Suppl 3):297s–308s.
in the management of cancer pain: a review. Pain
Y, et al. Fatal methadone
toxicity: potential role of CYP3A4 genetic polymorphism. J Anal Toxicol
MJ. Estimation of methadone
clearance: application in the management of cancer pain. Pain
AG, et al. Narcotics in the elderly. Med Clin North Am
NI. The management of cancer pain. CA Cancer J Clin
. 2000;50:70–116; quiz 117–120.
A. Steady-state kinetics and analgesic effect of oral morphine
in cancer patients. Eur J Clin Pharmacol
K. Review of a controlled-release morphine
preparation. In: Advances in Pain Research and Therapy
. New York: Raven Press; 1990:191–202.
W, et al. Comparison of a once-a-day sustained-release morphine
formulation with standard oral morphine
treatment for cancer pain. J Pain Symptom Manage
RD, et al. Pharmacokinetic-pharmacodynamic relationships of controlled-release oxycodone
. Clin Pharmacol Ther
C, et al. Rectal methadone
in cancer patients with pain. A preliminary clinical and pharmacokinetic study. Ann Oncol
KA, et al. Transdermal fentanyl
in the long-term treatment of cancer pain: a prospective study of 50 patients with advanced cancer of the gastrointestinal tract or the head and neck region. Pain
D. Transdermal fentanyl
versus sustained-release oral morphine
in cancer pain: preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group. J Pain Symptom Manage
JG. Intranasal fentanyl
spray: a novel dosage form for the treatment of breakthrough cancer pain. Ann Pharmacother
L. A randomized, placebo-controlled study of fentanyl
buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain
buccal tablet for the treatment of breakthrough pain in opioid-tolerant patients with chronic cancer pain: a long-term, open-label safety study. Cancer
WI. Rectal controlled-release morphine
: plasma levels of morphine
and its metabolites following the rectal administration of MST Continus 100 mg. J Clin Pharm Ther
L, et al. Role of rectal route in treating cancer pain: a randomized crossover clinical trial of oral versus rectal morphine
administration in opioid-naive cancer patients with pain. J Clin Oncol
RN. Continuous Sc infusion of narcotics for the treatment of cancer pain: an update. Cancer Treatment Rep. 1987;71:953–958.
AI. Comparison of continuous subcutaneous and intravenous hydromorphone
infusions for management of cancer pain. Lancet
E. Current status of patient-controlled analgesia in cancer patients. Oncology (Williston Park)
. 1997;11:373–380, 383–374; discussion 384–376.
HF. Prolonged morphine
self-administration and addiction liability. Evaluation of two theories in a bone marrow transplant unit. Cancer
P. Opioid hyperexcitability: the application of alternate opioid therapy. Pain
C, et al. Adult cancer pain. J Natl Compr Canc Netw
G. The use of antidepressants in the treatment of chronic pain. A review of the current evidence. Drugs
BA, et al. A systematic review of antidepressants in neuropathic pain. Pain
GW. Analgesic activity of tricyclic antidepressants. Ann Neurol
TL. Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacol Biochem Behav
effectively relieves neuropathic pain following treatment of breast cancer. Pain
W, et al. Amitriptyline
in neuropathic cancer pain in patients on morphine
therapy: a randomized placebo-controlled, double-blind crossover study. Tumori
SC, et al. Desipramine
relieves postherpetic neuralgia. Clin Pharmacol Ther
SC, et al. Amitriptyline
relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology
GA. Tricyclic antidepressant-induced seizures and plasma drug concentration. J Clin Psychol. 1992;53:160–162.
M. The effect of nortriptyline
in elderly patients with cardiac conduction disease. J Clin Psychol
A, et al. Pilot study of duloxetine
for cancer patients with neuropathic pain non-responsive to pregabalin
. Anticancer Res
M. Anticonvulsant drugs and chronic pain. Clin Neuropharmac. 1984;7:51–82.
AR, et al. Anticonvulsant drugs for management of pain: a systematic review. BMJ
as a coanalgesic in cancer pain. J Pain Symptom Manage
WJ. Dilantin hypersensitivity reaction. Cutis
C, et al. Gabapentin
for neuropathic cancer pain: a randomized controlled trial from the Gabapentin
Cancer Pain Study Group. J Clin Oncol
significantly improves analgesia in people receiving opioids for neuropathic cancer pain. Cancer Treat Rev
MD. Beyond neuropathic pain: gabapentin
use in cancer pain and perioperative pain. Clin J Pain
M. Randomized study of pregabalin
in patients with cancer-induced bone pain. Pain Ther
MC, et al. Post hoc analysis of pregabalin
vs. non-pregabalin treatment in patients with cancer-related neuropathic pain: better pain relief, sleep and physical health. Clin Transl Oncol
I. [Retrospective evaluation of pregabalin
for cancer-related neuropathic pain]. Masui
B, van Litsenburg
for the management of neuropathic pain in adults with cancer: a systematic review of the literature. Pain Med
HL. Both intravenous lidocaine
reduce the pain of postherpetic neuralgia. Neurology
P, et al. Treatment of chronic painful diabetic neuropathy with intravenous lidocaine
infusion. Br Med J
G, et al. A phase II pilot study to evaluate use of intravenous lidocaine
for opioid-refractory pain in cancer patients. J Pain Symptom Manage
LP, et al. Drug-induced liver injury following a repeated course of ketamine
treatment for chronic pain in CRPS type 1 patients: a report of 3 cases. Pain
for pain in adults and children with cancer: a systematic review and synthesis of the literature. Pain Med
A. Analgesic effect of intravenous ketamine
in cancer patients on morphine
therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage
RJ. Survey of topical oral solutions for the treatment of chemo-induced oral mucositis. J Oncol Pharm Pract
R. The risks and benefits of corticosteroids in advanced cancer. Drug Saf
treatment reduces sensory neuropeptides and nerve sprouting reactions in injured teeth. Pain
P. Corticosteroids suppress ectopic neural discharge originating in experimental neuromas. Pain
M. Steroids as pain relief adjuvants. Can Fam Physician
. 2010;56:1295–1297, e1415.
T. The role of corticosteroids in the treatment of pain in cancer patients. Curr Pain Headache Rep
DJ. Should bisphosphonates be part of the standard therapy of patients with multiple myeloma or bone metastases from other cancers? An evidence-based review. J Clin Oncol
R, et al. Oral ibandronate
improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Pain
M, et al. Association of pain relief with drug side effects in postherpetic neuralgia: a single-dose study of clonidine
, and placebo. Clin Pharmacol Ther
D, et al. Synergistic antinociceptive interactions of morphine
in rats with nerve-ligation injury. Anesthesiology
JC, De Kock
W. alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine
DR. The control of severe cancer pain by continuous intrathecal infusion and patient controlled intrathecal analgesia with morphine
D. Epidural clonidine
analgesia for intractable cancer pain. The Epidural Clonidine
Study Group. Pain
SL. Constipation as a side effect of opioids. Oncol Nurs Forum
RK. Pain management in the older cancer patient. Oncology (Williston Park)
RK, et al. Treatment of opioid-induced constipation with oral naloxone
: a pilot study. Clin Pharmacol Ther
NP. An investigation of the ability of oral naloxone
to correct opioid-related constipation in patients with advanced cancer. Palliat Med
Jr, et al. Efficacy and tolerability of subcutaneous methylnaltrexone
in patients with advanced illness and opioid-induced constipation: a responder analysis of 2 randomized, placebo-controlled trials. Pain Pract
. 2014 May 10. doi:10.1111/papr.12218. [Epub ahead of print].
P. Psychomotor and cognitive functioning in cancer patients. Acta Anaesthesiol Scand
N. Neuropsychological effects of methylphenidate
in patients receiving a continuous infusion of narcotics for cancer pain. Pain
HE. Barbiturates in the care of the terminally ill. N Engl J Med
AH. Mechanisms of the analgesic actions of opiates and opioids. Br Med Bull
treatment of myoclonic contractions associated with high-dose opioids: case report. Pain