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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 140Management of Cancer Pain

, MD and , MD.

The evaluation and treatment of pain in the patient with cancer have evolved to encompass a series of scientifically based guidelines that define a comprehensive approach to the management of this difficult clinical problem. Current knowledge in cancer pain includes a delineation of the common pain syndromes in this population as well as their postulated neurophysiologic mechanisms, 1, 2 a classification of the types of patients with pain and the psychological factors that contribute to and alter the pain complaint, 3– 5 and methodologies to measure pain, as well as pharmacokinetic and pharmacodynamic models that correlate drug distribution with pain relief. 6– 9 These advances have focused attention on the cancer patient as the clinical model of pain and have led to improved care for this serious symptom.

Pain management for the cancer patient has as its primary goal effective symptom control, allowing patients to participate in diagnostic and therapeutic interventions to achieve an acceptable quality of life and a relatively pain-free death.

Scope of the Problem

Cancer is a major world health problem. 10 Every year, about 17 million new cases are diagnosed, half in developing countries, and 5 million patients die from these diseases annually. Prevalence data indicate that there are currently about 14 million people worldwide with cancer. Published reports indicate that between 30 and 50% of such cancer patients are in active therapy, and that 70 to 90% of patients with far advanced disease suffer significant pain. 10 It is conservatively estimated by the World Health Organization (WHO) that 5 million people are currently suffering from cancer pain with or without satisfactory treatment. The prevalence of pain increases with disease progression and varies according to the primary site. Other contributing factors include the stage of disease, the presence of metastases, the tendency for bony involvement, the proximity of tumor to neural structures, the generation of pain-producing substances by the tumor, and patient variables such as anxiety and depression.

Several studies have demonstrated that cancer patients experience more than one type of pain. 11– 13 In one survey, 81% of patients reported two or more distinct pain complaints, and 34% of these patients reported more than three types. 13 Pain also has an enormous impact on the quality of life of patients with cancer. Several methods have been developed to assess this observation. 14 The public perception of pain has also been studied. Patients’ fear of cancer is directly related to their fear of severe pain. 15– 17 Sixty-nine percent of cancer patients surveyed reported that severe pain from cancer might lead them to consider suicide, and 57% perceive death from cancer as painful.

The importance of a comprehensive evaluation in the management of cancer pain cannot be overstated. In a study of 276 consecutive pain consultations at Memorial Sloan-Kettering Cancer Center (MSKCC) the consultation identified a previously undiagnosed etiology for the pain in 64% of patients. New neurologic diagnoses were made in 36% of patients, and 18% of patients received radiotherapy, surgery, or chemotherapy, based on the findings of the pain consultation. 18

Barriers to Cancer Pain Management

Despite the publication of numerous national and international guidelines on how to manage cancer pain effectively, 6, 10 undertreatment of pain remains a significant problem. Barriers include poor physician assessment, inadequate knowledge of pharmacologic and other management strategies, and negative physician and patient attitudes toward opioid use for pain. 15 The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT) showed that 50% of adults who die in the hospital experience moderate to severe pain in the immediate period prior to death. 19, 20 A large multicenter study to address knowledge and attitudes of physicians regarding cancer pain management demonstrated that 86% of physicians felt that the majority of patients were undermedicated. 21 Only 51% believed pain control in their own practice setting was good or very good, and 31% would wait until the patient’s prognosis was 6 months or less before they would start maximal analgesia. The study also identified critical barriers to effective pain management (Table 140.1). Poor pain assessment was rated by 76% of physicians as the single most important barrier to adequate pain management. Other barriers included patient reluctance to report pain and to take opioids, physician reluctance to prescribe opioids, and nursing reluctance to give opioids. Physicians expressed dissatisfaction with their training for pain management in medical school and in residency or fellowship.

Table 140.1. Barriers to Cancer Pain Management.

Table 140.1

Barriers to Cancer Pain Management.

A study of 4,000 elderly nursing home residents with cancer revealed that 24, 29, and 38% of those over the age of 85, 74 to 84, and 65 to 74 years, respectively, reported daily pain. Twenty-six percent in daily pain did not receive any analgesics, and those over age 85 who reported daily pain were the most likely to receive no analgesia. 22 Sixty percent of all outpatients seen at an oncology clinic in the Netherlands were in pain, and 20% of this group reported a score of 5 or greater on a scale of 1 to 10. 23 These data emphasize the need for broad educational programs that address the barriers, the fundamental principles of cancer pain management, and the importance of institutional commitment to provide improved pain management. 24– 26

Mechanisms of Cancer Pain

Pain associated with cancer most commonly results from tumor infiltration of pain-sensitive structures such as bones, soft tissue, nerves, viscera, and blood vessels. Pain may also be caused by surgery, chemotherapy, or radiation therapy. Although the cause of the pain and the type of injury vary, the mechanisms that underlie these different clinical problems are now becoming understood as complex neurophysiologic and neuropharmacologic phenomena. 27

Two broad categories of pain have been described and are referred to as nociceptive pain, which include both somatic and visceral pain, and neuropathic pain.

Neurophysiology of Pain

There are sensory receptors preferentially sensitive to noxious stimuli. These nociceptors are primary afferent nerves with peripheral terminals that respond differentially to noxious stimuli. These nociceptors serve two major functions, defined as transduction and transmission. A series of chemical, mechanical, or thermal factors can produce receptor activation, producing an electrochemical nerve impulse in the primary afferent. The information is then coded into a frequency of impulses that is relayed (transmission) to the central nervous system, where pain perception occurs. Both myelinated and unmyelinated nociceptors convey pain sensation to the central nervous system. The myelinated nociceptor responds to noxious mechanical stimuli almost exclusively and has a rapid conduction over A delta fibers, causing a sharp stinging pain. Unmyelinated nociceptors are polymodal, responding to mechanical, thermal, and chemical stimuli, have a slower rate of conduction in a C fiber range, and are associated with a dull, burning, or aching pain. Studies in man reveal that activation of a single myelinated nociceptor is sufficient to cause a sharp, stinging pain. Activation of unmyelinated nociceptors is associated with a dull, burning, or aching pain.

In general, nociceptors are not spontaneously active but become sensitized with any tissue injury. A variety of substances can mediate this sensitization, including potassium ions, adenosine triphosphate, bradykinin, prostaglandins (especially prostaglandin E2), and leukotrienes. Tumor infiltration and compression may cause both mechanical and chemical activation of nociceptors. Primary hyperalgesia occurs by nociceptor sensitization at the site of tissue injury. Secondary hyperalgesia refers to changes in the central nervous system due to the nociceptor activation and may be experienced clinically as an expansion of the area of cutaneous hyperalgesia beyond the area of injury. 27 Once activated, pain is transmitted over A delta and C fibers and enters the spinal cord laterally, synapsing in the superficial dorsal horn to activate ascending nociceptive systems.

Sensory transmission is mediated through neuropeptides, substance P, calcitonin gene-related peptides, and the excitatory amino acids (EAA) glutamate and aspartate. 28 Central sensitization occurs as a result of EAA binding to the N-methyl-D-aspartate (NMDA) receptor. On binding, influx of intracellular calcium results in secondmessenger activation and the generation of nitric oxide, among other compounds. The activation of the NMDA receptor and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor contribute to the establishment of central sensitization and neuronal windup that underlie in part secondary hyperalgesia and persistent pain states.

Two physiologically distinct pathways ascend in the anterolateral quadrant of the spinal cord. The neospinothalamic pathway projects to the ventrobasilar thalamic complex, and from there, axons project to the somatosensory cortex in the parietal lobe. This pathway mediates sensory-discriminative aspects of pain perception (stimulus localization and intensity). The paleospinothalamic tract ascends, projecting to the reticular formation, posterior thalamic nucleus, and intralaminar thalamic nuclear complex. From these areas, axons project diffusely to the cortex and specifically to the orbital frontal cortex. This pathway mediates the arousal, emotional, and affective/suffering components of pain. The existence of a specific nucleus in the posterior thalamus responsible for pain and temperature sensation has recently been elucidated. 29

There is an endogenous pain suppression pathway that arises in the periaqueductal gray (PAG) of the midbrain and descends to the nucleus raphe magnus (NRM) in the medulla. From the NRM, there are projections to the dorsal horn of the spinal cord through the dorsal longitudinal fasciculus. This pathway modulates afferent nociceptive impulses. Electrical stimulation of the PAG, NRM, or dorsal horn or microinjection of morphine at these sites produces analgesia without concomitant motor, sensory, or autonomic blockade. Serotonin and norepinephrine are the putative neurotransmitters in these areas. Endogenous opioid compounds are also involved as modulators in this pain suppression system. Enkephalin, β-endorphin, and dynorphin are the most potent inhibitors of nociceptive activity. These three peptides are derived from three precursor molecules: (a) pro-opiomelanocortin is the common precursor for β-endorphin, (b) pro-enkephalin A is the common precursor for met-enkephalin and leu-enkephalin, and (c) pro-enkephalin B is the precursor for dynorphin. Enkephalin is distributed in specific nuclei in the brain stem and spinal cord. β-endorphin is found in the arcuate nucleus of the hypothalamus and in the pituitary. These endogenous opioid peptides produce analgesia by binding to specific receptors that are found in high concentration in cortical, brain stem, and spinal cord sites. β-endorphin binds to the mu receptor, enkephalin to the delta receptor, and dynorphin to the kappa receptor. Morphine and the commonly used opioids mimic the action of endogenous opioid peptides.

Types of Pain

Somatic Pain

Somatic pain is the most common type of pain in patients with cancer and bone metastases are the most prevalent cause. Somatic pain is characterized as well localized, intermittent, or constant and is described as aching, gnawing, throbbing, or cramping. Such metastases are characterized by bone destruction with concurrent new bone formation. Both myelinated and unmyelinated afferent fibers are present in bone, and their density is greatest in the periosteum. Prostaglandins sensitize nociceptors and produce hyperalgesia and pain as osteolysis and osteoclast formation occur. 30 Other factors, such as osteoclast-activating factor, also sensitize nociceptors and produce increased sensitization to pain. 31 Drugs that interfere with prostaglandin synthesis and osteoclast formation inhibit bone pain by inhibiting this sensitization and may also inhibit tumor growth. The widespread use of bisphosphonates has resulted in improved analgesia and a significant reduction of skeletal complications in patients with malignant bone pain (see Adjuvant Drugs section).

Visceral Pain

Visceral pain is mediated by discrete nociceptors in the cardiovascular, respiratory, gastrointestinal, and genitourinary system, is usually described as deep, squeezing, or colicky, and is commonly referred to cutaneous sites, which may be tender. This referral pattern is thought to be related to the fact that somatic and visceral structures have dual innervation by common afferent fibers. These fibers converge in the dorsal horn in the spinal cord. The pain of a visceral site may be misrepresented as a cutaneous one. Shoulder pain, resulting from diaphragmatic irritation from a pleural disease, is an example of a cutaneous referral of a visceral pain. Visceral pain results from mechanical or chemical activation of nociceptors by tumor compression or visceral distension or obstruction and responds to a wide variety of pain management approaches including pharmacologic, anesthetic, and neurosurgical procedures. 31– 33 Recent experimental data in animals suggest that kappa-opioid receptor agonists are uniquely efficacious in the treatment of visceral pain. 34– 36 The role of such agents in the management of human cancer pain requires further investigation.

Neuropathic Pain

The second category of pain common in cancer patients is neuropathic pain, which results from injury to the peripheral receptor, afferent fiber, or central nervous system. Such injury is associated with spontaneous and ectopic firing in the peripheral nerve as well as at the level of the dorsal horn. Reorganization of the nervous system occurs, and spontaneous neural activity can be measured at the level of the thalamus. Neuropathic pain is clinically described as a burning, dysesthetic, squeezing sensation with paroxysms of shocklike pain.

Tumor infiltration of the brachial and lumbar plexus are the most common causes of neuropathic pain. 37 Such pain also results from injury to the peripheral nerve as occurs in postmastectomy and post-thoracotomy pain. Tricyclic antidepressants, selective serotonin reuptake inhibitors, anticonvulsants, opioids, local anesthetics, NMDA antagonists, and some neurostimulatory procedures have all been used successfully in the management of neuropathic pain. New anticonvulsants and new data on opioid-responsive neuropathic pain have significantly improved the outcome for these patients (see below).

Common Pain Syndromes in Patients with Cancer

Over the last 15 years, a series of well-defined pain syndromes have been described in patients with pain and cancer. Many of these pain syndromes are unique to cancer and are often misdiagnosed because health-care professionals are unfamiliar with their clinical presentation. 1, 2, 38 In each of these syndromes, pain is the overriding symptom that prompts medical attention. Knowledge of the common pain syndromes facilitates assessment and treatment and supports the need for training in cancer pain management as an integral part of the oncologist’s training. The three major categories of pain syndromes are listed in Table 140.2.

Table 140.2. Cancer Pain Syndromes.

Table 140.2

Cancer Pain Syndromes.

Strategy for Assessment and Treatment

At the current time, a series of algorithms (Figure 140.1) have been developed for the management of this population of patients. 39, 40 A randomized, controlled clinical trial implementing a treatment algorithm based on the Agency for Health Care Policy and Research Guidelines for Cancer Pain Management revealed that patients randomized to the algorithm group experienced a significant reduction in pain intensity compared to the control group. 41 Furthermore, the patients with greater adherence to opioid and analgesic therapies in the algorithm group experienced better pain scores, which emphasized the critical value of the implementation of guidelines in cancer pain management.

Figure 140.1. The World Health Organization Three-step Analgesic Ladder for Cancer Pain.

Figure 140.1

The World Health Organization Three-step Analgesic Ladder for Cancer Pain.

In developing a strategy to manage the patient with pain and cancer, identification of the nature of the pain (somatic, visceral, neuropathic) and the specific pain syndrome can facilitate the development of an approach for pain relief. It is well recognized that pharmacologic approaches represent the mainstay of therapy, but any therapeutic strategy must also recognize the importance of psychological, behavioral, anesthetic, and neurosurgical approaches.

The guiding principles of a therapeutic strategy for cancer pain must include: (a) detailed assessment of the patient’s pain, (b) individualization of the therapeutic approach, (c) assurance of available expertise to provide therapeutic strategies to patients, (d) continual reassessment of the degree of pain relief and impact on mood, functional status, patient and family acceptance, and the patient’s overall quality of life, (e) choosing the simplest approach prior to the use of complicated and extensive techniques, (f) ongoing communication between the physician and patient in defining the options for therapy and the potential risk/benefit ratios of any of the therapeutic approaches, and (g) defining the goals of pain management in dying patients.

Assessment of Pain

Critical to the development of a successful therapeutic strategy is the physician’s ability to establish a trusting relationship with the patient (Table 140.3). This requires a complete history of the pain complaint, including the patient’s description of the site of pain; its quality, exacerbating, and relieving factors, its radiation if any; its exact onset and temporal pattern and to what extent the pain interferes with activities of daily living, work, and social life; and the degree to which the pain has had a psychological impact. Multiple pain complaints, particularly common in patients with advanced disease, need to be prioritized and classified. In some instances, verifying the history from a family member may be necessary because the patient is either unable or unwilling to detail the pain symptom appropriately. Some patients may well deny their pain, and family members may be more objective in assessing the disability of patients who underreport their symptoms. After a careful history, a medical and neurologic examination helps to provide the necessary data to substantiate the clinical history. The importance of a neurologic assessment is supported by data from Clouston and colleagues, who reported that back pain was the most common symptom for neurologic referral in a review of neurologic consultations at MSKCC. 42 This study emphasized the need for the treating physicians to have sufficient knowledge of the neurologic complications of cancer especially because cancer patients with back pain are at such high risk for epidural spinal cord compression with resultant paraplegia. 40 Knowledge of referral patterns of pain in the common cancer pain syndromes can direct the examination. For example, the pain symptoms in patients with postmastectomy pain syndrome are so characteristic that they can help to define the diagnosis of nerve injury by their temporal relationship to the surgery, the site of pain in the distribution of the intercostobrachial nerve, and the pain description. 2 Of greatest importance, no patient should be inadequately evaluated because of an inadequately controlled pain. Early management of the pain while investigating the cause will markedly improve the patient’s ability to participate in the necessary diagnostic procedures.

Table 140.3. Algorithm for the Clinical Assessment of Pain.

Table 140.3

Algorithm for the Clinical Assessment of Pain.

At the time of the initial assessment, the patient’s psychological state should be evaluated, including the patient’s psychiatric history, current level of anxiety or depression, suicidal ideation, and degree of functional incapacity. Numerous studies support the significance of psychological factors in accounting for differences in pain experiences in patients with cancer. 3, 43, 44 Psychiatric symptoms in patients with cancer pain must be viewed initially as a consequence of uncontrolled pain. This has been documented in both adults and children with pain. 44 Uncontrolled pain is a major factor in cancer-related suicide. 45 In one study, the desire for death was positively correlated with low family support and with depression. 46 A series of psychiatric syndromes have been described in patients with cancer, with depression occurring in as many as 25% of patients. 44 In a study of the incidence of psychiatric disorders in patients with cancer, 39% of those patients who received a psychiatric diagnosis had significant pain. In contrast, only 19% of patients who did not receive a psychiatric diagnosis had significant pain. The psychiatric diagnoses included adjustment disorders with depressed or mixed mood and major depression. 43 As depression is often a treatable disorder, patients may experience significant pain relief if their psychiatric symptoms are promptly recognized and managed appropriately. The National Comprehensive Cancer Network has provided important guidelines for the management of psychiatric symptoms in the cancer population. 47

Personality factors that have been quite distorted by the presence of pain often disappear with adequate pain relief. Pain is recognized as one of the patient-related factors that predicts for potential psychiatric morbidity, along with disease and treatment-related variables, interactions between patient and illness, and factors relating to the patient’s environment. 5 Closely allied to these psychological factors is the concept of the meaning of pain. It is not uncommon for patients during active therapy to endure significant pain for the promise of a successful outcome. With advanced disease, when active antitumor therapy is no longer effective, it is common for patients and families to request that if nothing else can be done, at least their pain should be adequately managed. 48– 50

The use of several scales such as the Brief Pain Inventory, the McGill Pain Questionnaire, the Memorial Pain Assessment Card (MPAC), and the Memorial Symptom Assessment Scale (MSAS) allow for repetitive valid measurement of pain and mood and clearly facilitate the health-care professional in determining the degree of physical pain and emotional distress in the individual patient. 7, 8 We commonly request that patients understand these distinctions to help distinguish physical pain from psychological distress to allow us to direct appropriate therapy. Using the MPAC, pain relief and mood can be evaluated in 20 seconds. The use of such a scale provides a format for communication between the patient and health-care professional and can be used in choosing the appropriate therapy. Recording pain intensity on the daily chart of each inpatient at MSKCC not only establishes pain intensity as a fifth vital sign but also underscores a critical institutional commitment to pain management. 51

Pharmacologic Approaches

Pharmacologic approaches are the most commonly used method for managing cancer pain. The WHO has recognized that analgesic drug therapy is the mainstay of pain treatment for cancer patients as part of the Cancer Pain and Palliative Care Program, advocating the three-step approach shown in Figure 140.1. 10, 52 Validation studies of the WHO guidelines reveal successful treatment of cancer pain in 69 to 100% of patients. 53– 57 Such an approach advocates the use of non-opioid, opioid, and adjuvant analgesics alone and in combination, titrated to the needs of the individual patient. The Agency for Health Care Policy and Research has developed guidelines for the treatment of cancer pain, 6 and the Joint Commission on Hospital Accreditation has established pain assessment and treatment as an important priority in the delivery of high-quality inpatient care. The effective use of these analgesic drugs should be a major part of every physician’s armamentarium in managing patients with pain.

The specific guidelines for the use of pharmacologic approaches are detailed in Table 140.4. The fundamental concept that underlies this approach is individualization of pharmacotherapy. The selection of the right analgesic administered in the right dose on a regular schedule to maximize pain relief and minimize adverse effects begins with the use of non-opioids for mild pain. In patients with moderate pain that is not controlled with non-opioids such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and adjuvant medications (WHO step 1), the so-called weak opioids (codeine, hydrocodone, oxycodone, and tramadol) alone or in combination are prescribed (step 2). In patients with severe pain, a strong opioid (morphine, hydromorphone, fentanyl, methadone, oxycodone, oxymorphone, or levorphanol) is the drug of choice (step 3). At all levels, certain NSAIDs and adjuvant drugs may be used for specific indications. It is critical that patients presenting in severe pain should generally be treated with a strong opioid immediately.

Table 140.4. Guidelines for the Use of Analgesic Drugs in Cancer Pain Management.

Table 140.4

Guidelines for the Use of Analgesic Drugs in Cancer Pain Management.

Non-opioid Analgesics

The non-opioid analgesics include acetaminophen and NSAIDs, of which aspirin is the prototypic agent. These compounds are most commonly used orally, but their analgesia is limited by a ceiling effect so that increasing the dose beyond a certain level (e.g., 900–1,300 mg per dose of aspirin and 300–400 mg of acetaminophen) will produce no increase in peak effect. Tolerance and physical dependence do not occur with repeated administration. Aspirin and the other NSAIDs have analgesic, antipyretic, anti-inflammatory, and antiplatelet actions. Within this group, some NSAIDs lack the antiplatelet effects of aspirin, (e.g., choline magnesium trisalicylate), and others appear to produce fewer gastrointestinal side effects than aspirin (e.g., ibuprofen). Acetaminophen, which is as potent as aspirin, is an analgesic and antipyretic but is much less effective as an anti-inflammatory agent and does not interfere with platelet function. As a group, these compounds have an analgesic effectiveness that is equal to or greater than that of aspirin. These drugs produce analgesia by inhibiting the formation of prostaglandin E2, following nociceptive stimulation from tissue injury.

Nonsteroidal Anti-inflammatory Drugs

The drugs in this group have a higher analgesic potential than aspirin and serve as an important first step in the management of patients with pain and cancer (Table 140.5). They differ from each other both in duration of analgesic action and in pharmacokinetic profile. These drugs may have a special role to play in the management of bone pain because numerous studies have shown that aspirin inhibits tumor growth in an animal model of metastatic bone tumors. However, a meta-analysis of NSAIDs in bone pain did not demonstrate them to be more effective than weak opioids. 58, 59

Table 140.5. Non-Opioid Analgesics Commonly Used for Mild to Moderate Pain.

Table 140.5

Non-Opioid Analgesics Commonly Used for Mild to Moderate Pain.

NSAIDs inhibit cyclooxygenase, which results in decreased prostaglandin synthesis. In addition to this peripheral action, a recent study indicates that they may also interfere with the action of glutamate and substance P in the central nervous system when cyclooxygenase is inhibited. 60 Two isoforms of the cyclooxygenase enzyme have been identified. cyclooxygenase-1 is a normal constituent of blood vessels, stomach, and kidney. Cyclooxegenase-2 (Cox-2) is induced in the setting of peripheral inflammation and acts as an attractant of inflammatory mediators. The Cox-2 inhibitors have been shown to reduce inflammation without the gastrointestinal and hematologic toxicity typically associated with other NSAIDs. 61

In clinical experience, some patients respond better to one NSAID than to another, and each patient should therefore be given an adequate trial of one drug on a regular basis before switching to another. Survey data from WHO demonstration projects suggest that between 20 and 40% of patients obtain pain relief with the use of non-opioid analgesics alone. 10, 62, 63 Intravenous ketorolac is the only NSAID available in the United States for IV use. Although very useful as an opioid-sparing or opioid-reducing agent in cancer patients who are difficult to manage with morphine alone, its use is limited to a 5-day course due to gastrointestinal toxicity. 64

Numerous studies have elucidated the major risk factors for gastrointestinal toxicity associated with NSAID use. 65, 66 While all of the NSAIDs may be associated with gastrointestinal (GI) toxicity, a recent meta-analysis demonstrated that ibuprofen in doses less than 1,600 mg/d was associated with the least risk of hemorrhage; aspirin, indomethacin, naproxen, and sulindac had intermediate risk; and ketoprofen and proximcam were associated with the highest risk. 67 Although nausea and upper abdominal pain may be produced by NSAIDs and raise concern about more serious toxicity when they occur, dyspepsia is a poor predictor of ulceration, and two-thirds of NSAID users have absolutely no symptoms before bleeding or perforation. Various factors contribute to the high risk of ulcer complications, including advanced age, use of higher doses, concomitant administration of corticosteroids, and a history of either ulcer disease or previous GI complications from NSAIDs. 68, 69 Although the use of prophylactic therapies remains controversial, misoprostol has been shown to be highly effective in the management of GI side effects. In patients who fail to receive adequate relief with non-opioids or are unable to tolerate them, the use of opioid analgesics is considered as the next step.

Opioid Analgesics

The opioid analgesics as a class consist of heterogeneous compounds whose pharmacologic effects are derived from their interaction with multiple central nervous system opiate receptors. 70 The morphine agonist drugs bind to discrete opiate receptors and produce analgesia. The opioid antagonists also bind to opioid receptors but block the effects of morphine-like agonists and do not have analgesic properties of their own. The agonist drugs, with morphine as the prototype, are most commonly used in the management of cancer patients with pain. A series of opioid analgesics is available and is listed in Table 140.6.

Table 140.6. Opioid Analgesics Commonly Used for Moderate to Severe Pain.

Table 140.6

Opioid Analgesics Commonly Used for Moderate to Severe Pain.

Drugs such as codeine and tramadol have a limited analgesic efficacy. These drugs are used for the management of mild to moderate pain and have been included in step 2 of the analgesic ladder because of the wide availability of these compounds in most countries and because of their acceptability to patients for mild to moderate pain. Codeine is commonly used for patients with mild to moderate pain. 71 However, at the higher doses required to treat severe pain, it is poorly tolerated by patients because it produces significant nausea. Approximately 15% of the population cannot convert codeine to morphine because of the lack of a specific enzyme. 72 This factor should be taken into consideration in patients who do not obtain effective analgesia from codeine. Tramadol was recently approved in the United States for the treatment of mild to moderate pain. Although not scheduled as an opioid, tramadol binds weakly to the mu-receptor and inhibits reuptake of serotonin and norepinephrine. It is 10-fold less potent in mu receptor binding than codeine and 6,000-fold less potent than morphine. 73 Given its low affinity for opioid receptors, it does not cause significant dependence or respiratory depression. It has been compared favorably to morphine and buprenorphine in European trials and was shown to be safe and effective in a double-blind randomized placebo-controlled trial for the treatment of diabetic neuropathic pain. 74, 75

Oxycodone is included in both step 2 and step 3 of the analgesic ladder. Oxycodone is available in combination with acetaminophen (Percocet, Tylox) or alone in tablet form and liquid form. When used in a 5-mg dose combined with acetaminophen, it has a higher analgesic efficacy than codeine and propoxyphene. When used alone in doses of 15 mg parenterally or 30 mg orally, it is equipotent to morphine and can be used to treat moderate to severe pain. Oxycodone is now available in a controlled-release oral preparation, which in a randomized double-blind cross-over trial was found to be as safe and effective as controlled-release morphine. 76 Given its lack of active metabolites, oxycodone may be useful as an alternative to morphine, particularly in elderly patients or when the development of side effects precludes the use of morphine. The new controlled-release form of oxycodone has also been shown to be as effective as the immediate-release preparation. 77

Because of its place on the essential drug list of the WHO, its familiarity to physicians, and its wide oral use in the management of cancer pain, a WHO expert consensus panel named morphine as the drug of choice for the management of patients with pain and cancer. 10 Morphine, the prototypic drug, has an oral bioavailability that varies from 35 to 75% and a plasma half-life of 2 to 3 hours, which is somewhat shorter than its duration of analgesia of 4 to 6 hours. With repeated administration, the pharmacokinetics of morphine and its metabolites remain linear, and there does not appear to be autoinduction or biotransformation, even following large chronic doses. 78 These properties contribute to the safe use of morphine. As judged by single-dose studies in both acute and chronic pain, the relative potency of intramuscular (IM) morphine to oral morphine is 1:6, that is, 10 mg IM produce equianalgesia to 60 mg of oral morphine. On the basis of a series of survey studies in clinical practice, Twycross and others have suggested that the relative potency of morphine with repeated administration is 1:2 or 1:3. 79, 80 Several explanations have been offered to explain the differences, including metabolic and/or pharmacokinetic factors, the use of adjuvant analgesics in the hospice setting, and the fact that pain relief is maintained with repetitive doses. 80 In clinical practice, the 1:2 or 1:3 ratio is most commonly used in titrating a patient with morphine.

Morphine is predominantly metabolized at the three and six positions by hepatic glucuronidation to morphine-3-glucuronide (M-3-G, 55%) and morphine-6-glucuronide (M-6-G, 15%). 81 M-6-G binds to the opiate receptor, and in animal studies, when injected either by the ventricular or intrathecal route, is approximately 90- to 650-fold more potent as an analgesic than morphine. 82 M-3-G does not bind to opiate receptors and makes little if any contribution to the analgesic potency of morphine. Conflicting data has been reported on the role of M-3-G and the development of tolerance. 83 Some studies suggest that the accumulation of M-3-G may be associated with the side effects of central nervous system excitation (e.g., myoclonus and delirium) whereas M-6-G accumulation may result in the depressive side effects (e.g., drowsiness and respiratory depression). 81 Children under the age of 10 years have significantly lower concentrations of these metabolites whereas patients over the age of 70 years have higher plasma metabolite concentrations, which may partly explain the increased sensitivity to morphine side effects commonly observed in elderly patients. 81 In man, M-6-G occurs in higher levels following oral administration and accumulates in renal failure. 84, 85 Recent surveys suggest that there is a large interindividual variability in the relationship between renal impairment and the degree of M-6-G accumulation, and the impact on patient side effects of a relatively increased M-6-G/morphine ratio therefore remains unclear. Tiseo and colleagues noted an overall positive correlation between serum creatinine level and M-6-G/morphine ratio but no association between this ratio and either the occurrence of encephalopathy or myoclonus. 86 In short, morphine doses should be adjusted in patients with renal insufficiency and carefully titrated to the needs of the individual. Morphine is now available in a wide variety of preparations, including immediate-release tablets, oral solutions, controlled-release tablets (for 8, 12, or 24 hours), buccal tablets, rectal suppositories, and parenteral forms (intravenous, subcutaneous, epidural, and intrathecal). 87

Hydromorphone (Dilaudid) is a strong opioid (1.5 mg of IV hydromorphone is equipotent to 10 mg of morphine) and a useful alternative to morphine in the treatment of moderate to severe cancer pain. Although myoclonus has been described in the setting of continuous high-dose infusion, possibly due to accumulation of other metabolites (e.g., 3-0 methyl or a glucuronide 88 ), hydromorphone may be a suitable alternative to morphine in the setting of toxicity. Given its water solubility, availability in a high-potency formulation (10 mg/ml), and 87% bioavailability, hydromorphone is the drug of choice for chronic subcutaneous administration. It is also available in a suppository form and a controlled-release tablet. In a double-blind trial comparing morphine and hydromorphone patient-controlled analgesia, no differences were found with respect to analgesia or side effects. 89 Although cognitive performance was somewhat poorer in the hydromorphone group of patients, they reported better mood compared with the patients who received morphine.

Oxymorphone is only available in parenteral and suppository forms and is used for severe pain in patients who are unable to tolerate oral analgesics. It has less histamine-release effects compared to the other morphine cogeners and can be used in patients who develop histamine-induced headache or itch.

The choice of any one of these drugs is empiric. In patients who are unable to tolerate morphine or who have excessive side effects of nausea or sedation, switching to one of these congeners is often helpful. In the elderly patient, hydromorphone, oxycodone, and fentanyl may be better tolerated with fewer side effects than morphine. Levorphanol should be considered a second-line drug and used cautiously because drug accumulation associated with its long half-life may produce adverse effects.

Advantages to the use of methadone in cancer pain include 85% bioavailability, lack of active metabolites, low cost, long half-life resulting in larger intervals between doses, and improved patient compliance. Its plasma half-life averages 24 hours but may range from 13 to 50 hours whereas the duration of analgesia is only 4 to 8 hours. Methadone is a useful alternative to morphine but requires greater sophistication in its clinical use, and for that reason, it is a second-line drug for patients who have had a prior opioid exposure and who are tolerant. Repetitive analgesic doses of methadone lead to drug accumulation because of the discrepancy between its plasma half-life and its duration of analgesia. Sedation, confusion, and even death can occur when patients are not carefully monitored and dosages adjusted during the accumulation period, which can last from 5 to 10 days. In the opioid-naive patient, doses should be titrated carefully. Several groups have reported a broad experience in the use of methadone and have further confirmed the need for careful dose titration. 90, 91 Although commonly believed that it can be used as a drug on an 8- or 12-hour basis, its duration of analgesia is so variable that more frequent doses are commonly necessary. 90 Most equianalgesic opioid tables suggest a dose ratio of 1:1 between oral morphine and oral methadone. However, recent studies of interindividual differences in responses to opioid analgesics demonstrate the dramatically reduced doses of methadone that provide analgesia in patients who are switched from morphine or hydromorphone. 92– 94 In rotating patients from morphine to methadone, Ripamonti and colleagues used a dose ratio of 4:1 for patients who received 30 to 90 mg of morphine daily, 6:1 for patients who received 90 to 300 mg daily, and 8:1 for patients who received 300 mg or more. As little as one-tenth the equianalgesic dose of methadone can provide effective analgesia in patients tolerant to other opioid analgesics. 95 Bruera and colleagues demonstrated that the hydromorphone/ methadone ratio is correlated with total opioid dose, and that in switching from hydromorphone to methadone, much lower doses than expected may provide satisfactory analgesia. In patients receiving more than 330 mg of hydromorphone prior to the switch, the dose ratio was 1.6:1 whereas in patients receiving less than 330 mg of hydromorphone daily, the dose ratio was 0.95:1. 95 In general, caution should be taken when switching patients to methadone. Mercandante recently reported that in comparing the use of methadone versus morphine in pain management of advanced cancer at home, those who received methadone required fewer dose escalations, supporting a definite role for methadone in the hands of an experienced clinician. 96

Fentanyl is now available for intravenous use, in a transdermal patch, and in an oral transmucosal preparation. Fentanyl is 20 to 30 times more potent than morphine and has a variable half-life of 6 to 20 hours. Advantages of the transdermal patch include excellent patient compliance (as it only needs to be replaced every 72 hours), continuous controlled-release analgesia, and lack of an oral first-pass effect. There is a delay in the onset of analgesia, however, taking up to 12 to 15 hours for peak plasma levels to occur after a patch is applied, and therefore, patients need to have their pain controlled during this titration phase. Pharmacokinetic studies of repeated doses show a linear drug dose level. Four mg of intravenous morphine is approximately equivalent to 100 μg of intravenous fentanyl. Transdermal fentanyl was reported to be effective and safe in the long-term management of patients with advanced cancer of the GI tract and the head and neck 97 and with other malignancies. 98 Steady state is generally achieved within 12 to 24 hours following application of the patch. Several studies now suggest that patients who receive transdermal fentanyl may be more satisfied and less troubled by side effects compared with those who receive sustained-release morphine. 99– 101

Breakthrough pain has been defined as a transient increase in pain to moderate or severe intensity in conjunction with a baseline pain that is well controlled. The prevalence of breakthrough pain among inpatients with cancer has been reported as 64%. 102 Oral transmucosal fentanyl citrate (OTFC) is a new and valuable option for the treatment of cancer-related breakthrough pain. 103 There are two formulations of OTFC currently approved for use in the United States (Table 140.7). Fentanyl Oralet is approved as an anesthetic premedication in children and for procedure-related pain in adults and children. It is available in 100, 200, 300, and 400 mg and is indicated for opioid-naive patients, who generally require lower doses than opioid-tolerant patients requiring relief for breakthrough pain. Fentanyl Actiq is available in a wider range of dosages (200–1,600 micrograms) and is indicated for the management of breakthrough pain in opioid-tolerant adults. Twenty-five percent of both preparations are absorbed transmucosally over a 15-minute period, and an additional 25% is absorbed via the gastrointestinal tract over the following 90 minutes. Onset of relief may occur within 5 minutes. 103 In dose-titration trials, OTFC has been shown to be safe and effective in comparison with other agents used for breakthrough pain. 104, 105 In multi-center dose-titration trials, the effective OTFC dose did not correlate with the prior opioid requirements. The optimal dose needs to be determined by titration in approximately 75% of patients. 104

Table 140.7. Oral Transmucosal Fentanyl Citrate.

Table 140.7

Oral Transmucosal Fentanyl Citrate.

Meperidine is a drug that should not be administered for chronic cancer pain. Studies have demonstrated that repetitive dosing can lead to accumulation of a toxic metabolite, normeperidine, which results in central nervous system hyperexcitability. This adverse effect is characterized by subtle mood changes followed by tremors, multifocal myoclonus, and occasionally, seizures. This complication occurs more commonly in patients with renal disease but can occur following repeated administration in patients with normal renal function. 106

The role of opioids in the management of neuropathic pain has been controversial. Several recent placebo-controlled trials have demonstrated the use of opioids in the management of neuropathic malignant and nonmalignant pain. 107– 110 Patients with neuropathic pain should be given a trial of an opioid to assess the degree of opioid responsiveness. 111

Start with a Specific Drug for a Specific Type of Pain

Choosing an analgesic regimen requires knowledge of the pharmacokinetic and pharmacodynamic properties of these drugs as well as the type of pain (nociceptive versus neuropathic). Each physician should become familiar with several drugs in each of these groups and adapt them to the needs of his or her clinical practice. Cherny and colleagues have documented the strategies used by pain physicians for the selection of analgesic drugs and routes of administration. In a prospective study, 80 of 100 patients referred to the Memorial Sloan-Kettering Cancer Center Pain Service required changes in either opioid or route of administration to obtain adequate analgesia with tolerable side effects. Many patients experienced significantly better analgesia and a reduction in side effects with the substitution of one opioid for another. 112 This process of opioid substitution or rotation is a common clinical practice. The major reasons to switch opioids are to maximize analgesia or minimize side effects. Cherney demonstrated that the most common reasons for requesting a pain consultation were either because of uncontrolled pain despite analgesic therapy or excessive side effects without adequate analgesia. 112 Ashby and colleagues demonstrated that substituting fentanyl or oxycodone for morphine in patients in his series produced improved cognitive function, less sedation, and better pain relief. 113 Bruera and Ripamonti have used opioid rotation to maximize analgesia and have demonstrated the use of significantly lower doses of methadone in switching patients from morphine and hydromorphone (see above).

A common approach is to start a patient on a non-opioid, followed by the use of codeine or oxycodone alone or in combination with the non-opioid. If with repeated doses the patient does not obtain effective pain relief, switch him or her to morphine, hydromorphone, fentanyl, levorphanol, or methadone. We commonly choose morphine, but in patients intolerant to morphine, we use hydromorphone as our first-line drug. In the elderly patient, we often choose oxycodone, hydromorphone, or fentanyl before morphine because our clinical empiric data suggest that they may produce fewer central nervous system side effects than morphine. 114 Levorphanol and methadone tend to be second-line drugs, particularly in the elderly patient where their long half-lives present a potential risk of producing adverse effects. The dose is then titrated to the individual needs of the patient.

In choosing a dose, it is most useful to start with one that is equivalent to one-half the equianalgesic dose of the previous drug used and dose the patient to analgesia. Recent studies in opioid rotation suggest that the published equianalgesic guidelines may require modification on an individual patient basis according to prior opioid exposure and the specific opioid selected for the substitution. We first order the medication on a regular basis, usually every 3 to 4 hours, and instruct the patient to take the medication on this fixed schedule. If the patient has had no prior opioid exposure and presents with severe pain, start the medication on an as-needed basis, requesting that the patient ask for medication when he feels his pain beginning to return. This may be every 2 to 3 hours. Within one or two doses, it is possible to assess the needs of the individual patient and to adjust the timing of the doses accordingly.

Rescue medications equivalent to one-half of the standing dose should be made available to patients and ordered on a regular dosing schedule in case their pain is not adequately relieved or if they have breakthrough pain. 102 The next scheduled dose should be given on time without regard to the intervening rescue doses.

Recent work in drug interactions commonly seen in the pain and palliative care setting suggest extensive genetic polymorphism in the cytochrome P-450 family of enzymes. 115 Pharmacokinetic interactions, which involve the CYP 2D6 isozyme and result in poor or rapid opioid metabolism, may result in undertreatment or overtreatment if not recognized. For example, if haloperidol is added to a patient’s drug regimen that already includes codeine, the patient’s metabolism of codeine is slowed, which could result in toxicity and further problems if switched to another opioid. 115 Since 15% of Caucasians lack the CYPD211 enzyme required to metabolize codeine to morphine they may require higher doses than others for optimal analgesia. 116

Choose the Route of Administration to Fit the Needs of the Individual Patient

Recent studies have demonstrated that the majority of cancer patients require at least two routes of administration of analgesic drugs, and that 30% of patients require three routes of administration during the course of their pain management. 117

Oral Route

The oral route is convenient and preferable. Numerous studies have led to the use of oral opioid analgesics in chronic cancer pain and have demonstrated that these drugs work effectively when used in the appropriate equianalgesic doses for the intended route of administration. 78, 79 When given orally, the opioids differ substantially with respect to their presystemic elimination, i.e., the degree to which they are inactivated as they are absorbed from the gastrointestinal tract and passed through the liver into the systemic circulation. As indicated in Table 140.6, morphine and hydromorphone have parenteral/oral potency ratios of 1:3 and 1:5, respectively, and methadone and levorphanol are subject to less presystemic elimination, resulting in an intravenous/oral potency ratio of at least 1:2. The failure to recognize these differences often results in a substantial reduction in analgesia when changing from the parenteral to the oral route. In general, orally administered drugs have a slower onset of action and a longer duration of effect; drugs administered parenterally have a more rapid onset of action but a shorter duration of effect.

Intranasal, Sublingual, Buccal, Rectal, and Transdermal Routes

The intranasal, sublingual, buccal, rectal, and transdermal routes of administration provide alternative approaches for patients who cannot take oral drugs. These routes obviate the need for parenteral administration and offer the advantage of eliminating the first-pass effect through the liver because they are rapidly taken up into the systemic circulation.

Intranasal butorphanol, a mixed agonist-antagonist, provides adequate analgesia for patients with acute postoperative pain but is not commonly used for chronic cancer pain management. Sublingual buprenorphine, a partial opioid agonist, is widely used outside of the United States in the second step of the WHO analgesic ladder. It provides adequate pain relief for patients with mild to moderate pain. Both fentanyl and methadone are well absorbed sublingually, as demonstrated in a study of normal volunteers. 118 An oral transmucosal formulation of fentanyl (see above) has been demonstrated to be efficacious in treating breakthrough pain in cancer patients. Morphine is poorly absorbed sublingually but has been reported anecdotally to be effective. 119 Buccal tablets of morphine are effective but require prolonged exposure. Such absorption requires that the tablet remain in contact with the gum for a prolonged period (1 to 2 hours), making this approach less practical for most patients.

Oxymorphone, hydromorphone, and morphine are available as rectal suppositories and are effective in managing chronic cancer pain. Studies of sustained-release morphine rectal suppositories in normal volunteers reported no significant differences in morphine absorption between the oral and rectal methods except that rectal absorption was delayed. 120 The available pharmacokinetic data do not clearly define whether rectal administration of morphine does avoid the first-pass effect through the liver.

The transdermal fentanyl patch offers a unique route of opioid administration (see above). In the setting of GI malignancy, this route may be especially desirable.

Intravenous Boluses and Infusions

The common use of permanent central catheters to provide intravenous access for patients receiving chemotherapy has expanded the use of this route of administration to manage the patient with chronic cancer pain who is unable to tolerate drugs by the oral route. Intravenous bolus doses of opioids provide the most rapid onset and shortest duration of analgesia. The time to peak effect correlates with the lipid solubility of the opioid and can range from 2 to 5 minutes for methadone to 10 to 15 minutes for morphine. 121 This mode of administration allows for complete systemic absorption. Intravenous bolus injections are used to titrate opioid doses in the patient with rapidly escalating pain. 122 This approach is most useful in the patient in an acute painful crisis for rapid escalation or for the patient with far advanced disease in the terminal stages of his or her illness. In patients requiring frequent repeated intravenous boluses to maintain analgesia, a continuous infusion often is a more practical approach. Continuous infusions provide more stable analgesia without the peak and trough effects seen with repeated boluses. Specific guidelines for the use of continuous infusions have been developed and are summarized in Table 140.8. 122

Table 140.8. Guidelines for the Management of Continuous Intravenous Infusion (CII) of Opioids.

Table 140.8

Guidelines for the Management of Continuous Intravenous Infusion (CII) of Opioids.

In a study of 46 infusions in 36 patients with pain and cancer, continuous IV infusion provided effective pain control in the majority. In this series of patients who were stabilized on an intravenous dose of opioid and who then developed increasing sedation, obtundation, and coma, the intravenous infusions were not decreased prior to death. The goal for intravenous infusions in the dying patient needs to be clearly delineated to both families and staff to avoid any concern that such an approach is a form of “slow euthanasia.” 123, 124 The intent of continuous intravenous infusions in this setting is to provide patients with continuous relief of pain and suffering. However, continuous infusions should not be limited to use in only the dying patient. This approach has been widely used to manage patients with acute postoperative pain as well as chronic cancer pain in the home setting. 125 It is often used with patient-controlled pumps as an effective method. Patientcontrolled analgesia (PCA) and the development of tolerance are discussed in the following sections.

Intermittent or Continuous Subcutaneous Infusions

This approach has been particularly useful in obviating the pain management problems of patients who cannot take oral opioids because of nausea or vomiting, gastrointestinal intolerance, or obstruction. 126– 128 In patients with lack of available venous access with pain requiring continuous treatment and with adverse effects from bolus injections, the use of continuous subcutaneous infusions obviates these practical problems and allows patients to be maintained in a hospital or discharged home with adequate pain control. Using a portable infusion pump attached to a 27-gauge butterfly needle, and rotating the subcutaneous sites, this approach has been useful in patients for periods of 24 hours to 12 months in chronic cancer pain management. 126 The intraclavicular and anterior chest sites provide the greatest freedom of movement for patients. The infusion site is changed every 5 to 7 days, and a wide variety of opioid analgesics, including morphine, hydromorphone, levorphanol, oxymorphone, heroin, and fentanyl, have been used safely and effectively by this approach. Methadone use has been complicated by the development of cutaneous rashes and inflammatory lesions thought to be a hypersensitivity response. 90 Limited pharmacokinetic studies have demonstrated that the bioavailability of drug from subcutaneous sites at steady state varies from 78 to 100%. 127, 128 Guidelines for the use of this approach have been well described in the literature. 127, 128

Epidural and Intrathecal Infusions

Although the vast majority of cancer patients receive adequate analgesia with oral opioids, patients who experience intolerable side effects or who are unable to take medication by mouth may receive significant relief from epidural and intrathecal infusions. 129 Opioid receptor agonists bind to selective sites within the substantia gelatinosa of the spinal cord and produce analgesia without motor or sensory dysfunction. 130 Data suggest that approximately 10% of cancer patients require this approach to provide adequate analgesia. 131, 132 The combination of low doses of local anesthetics with opioids has expanded the usefulness of this technique in patients with neuropathic pain. 133 The use of clonidine alone or in combination has demonstrated efficacy in neuropathic cancer pain (see Adjuvant Drugs section).

The availability of patient-controlled devices that can be attached to subcutaneous reservoirs to which the epidural catheter is attached has allowed patients to be fully ambulatory using this technique. 134 The pharmacokinetics of epidural opioids suggest that a substantial amount of opioid (10 to 100 times the amount that would be there from a systemic injection) diffuses into cerebrospinal fluid from the epidural space. There is concurrent systemic uptake of the drug comparable to an intramuscular injection. Therefore, the epidural route is associated with both cerebrospinal fluid as well as systemic uptake of the drug. In contrast, intrathecal administration is associated with significantly less systemic uptake of drug. 135, 136 The advantage of both these routes of administration is that smaller doses of opioids can be used, and the undesirable central effects (e.g., somnolence and respiratory depression) of the opioids can be minimized. However, in a recently published 3-year retrospective outcomes study on the use of epidural catheters in the management of chronic cancer pain, technical problems and infections, including epidural abscesses, occurred in a significant number of patients, suggesting that the epidural route may be most useful in patients with limited life expectancy. 137 In Cherney’s study, cited above, of the 12% of patients who received an epidural or intrathecal catheter for cancer pain, the infusion was continued in only 4%. 112

Patient-Controlled Analgesia

This method of opioid administration employs the concept of individualization of analgesic dose, in which the patient can titrate the analgesic doses to provide adequate relief. Patients taking oral medications and who are instructed in how to titrate their dose are in fact using PCA. This term has been more selectively used to describe the use of specifically designed infusion pumps that can deliver a continuous infusion with bolus doses by the intravenous, subcutaneous, or epidural routes. Each pump can be programmed to the needs of the individual patient with a set “lock-out time” to prevent patients from overdosing themselves. This approach is most useful for managing the patient with continuous as well as incident pain who requires a bolus dose of opioid prior to movement. The wide variety of PCA pumps, from simple devices to sophisticated computerized systems, combined with the use of intravenous or subcutaneous administration has been a major advance in cancer pain management for the dying patient. 138 In such patients with intractable nausea and gastrointestinal obstruction, antiemetics can be combined with the opioids to manage bowel obstruction in the terminal phase.

Use Equianalgesic Doses When Switching to Alternative Routes

For patients who are stabilized on a continuous or subcutaneous route and who need to be converted to the oral dosing route, this is best done by slowly reducing the parenteral dose and substituting equianalgesic oral doses on a fixed schedule over a 2- or 3-day period. This obviates the problems that arise from changing from a route with a rapid onset of action (IV) to one with a slower onset (PO). When converting a patient from the intramuscular to the intravenous route, we have assumed that the equianalgesic dose is the same for these two routes. When switching from high doses of morphine or hydromorphone to methadone, conversion rations suggested by Ripamonti and Bruera, respectively, should be used. 92, 95

Adjuvant Drugs

There is a series of adjuvant drugs that are used in patients with pain and cancer. 139, 140 These drugs have been developed and approved for clinical indications other than analgesia, including nausea, vomiting, anxiety, mania, depression, and seizures. Moreover, there are specific adjuvant drugs for the treatment of neuropathic pain and bone pain. The choice of the drugs must be individualized using the simplest but most potent of combinations.

Antidepressant Drugs

This class of drugs appears to be the most useful in the management of patients with neuropathic pain. 141 Their analgesic effects are thought to be mediated in part by serotonergic and noradrenergic activity in the central nervous system. Controlled studies in migraine, postherpetic neuralgia, and diabetic neuropathy have demonstrated their efficacy. They appear to be equally useful in controlling chronic burning pain, continuous dysesthesia, and lancinating or shocklike pain common in patients with peripheral nerve injury. Amitriptyline is the most commonly used drug, but imipramine, desipramine, and paroxitene have also been reported to be effective. 142, 143 For amitriptyline, the suggested dosing schedule is to start at 10 to 25 mg in a single dose at bedtime, with dosing increments of the same amount. Doses can be increased every 1 to 2 days, particularly when using 10-mg tablets. Compliance with the regimen as well as the establishment of a therapeutic level can be facilitated by the assessment of plasma levels. Upward titration should be considered if the levels are below a therapeutic range. However, there is no therapeutic window for analgesia with amitriptyline. The majority of patients will note some response within a week, but it may take 2 to 3 weeks to see an analgesic effect. Of interest, analgesia with amitriptyline is often achieved earlier and at lower dosages in the treatment of neuropathic pain compared with its use as an antidepressant. Of all of the selective serotonin reuptake inhibitors on the market in the United States, paroxetine has demonstrated efficacy in postherpetic neuralgia, with fewer side effects than amitriptyline. 144 One study suggests that it may be particularly helpful in managing pruritus in the advanced-cancer patient. 145

Anticonvulsant Drugs

Carbamazepine and gabapentin are anticonvulsant drugs that suppress spontaneous neuronal firing and represent the drugs of choice for treating trigeminal neuralgia and other neuropathic pain. In cancer patients, carbamazepine has been used specifically in managing the acute shocklike neuralgic pain in the cranial or the cervical distribution caused by tumor infiltration or surgical injury. This drug has also been effective in patients with stump pain secondary to traumatic neuroma and patients with lumbosacral plexopathy reporting acute lancinating pain. Patients should commonly start at 100 mg at bedtime, slowly titrating up to 400 to 800 mg per day. The minimal effective concentration for analgesia is not known, but evaluation of plasma levels of carbamazepine are helpful in determining compliance and evaluating drug absorption in the individual patient. Carbamazepine is contraindicated in patients with leukopenia because of its independent ability to produce leukopenia.

Gabapentin has been shown in controlled trials to be very useful in the treatment of neuropathic malignant and nonmalignant pain. Its excellent side-effect profile, lack of hepatic metabolism, and lack of any known drug-drug contraindications make it a prime choice. While small numbers of patients report bothersome gastrointestinal side effects and mental clouding, it is generally well tolerated up to 4,800 mg per day. Patients start on 100 mg three times a day and titrate upward as warranted. Gabapentin has been shown to be highly effective for neuropathic pain in randomized double-blind controlled trials. 146 The clinical experience with phenytoin in the management of patients with neuropathic pain suggests that it is a useful approach in some patients with escalating neuropathic pain associated with brachial and lumbosacral neuropathies. 147 Both clonazepam and valproic acid have been reported to be effective in a series of anecdotal case reports and may be considered as alternative agents in patients who are unable to benefit from carbamazepine, gabapentin, or phenytoin. 139

Phenothiazine Drugs

Methotrimeprazine has been shown to have definitive analgesic properties in single-dose studies in patients with postoperative pain and chronic cancer pain. 148, 149 A dose of 15 mg parenterally is equivalent to 15 mg of morphine parenterally. This drug is most useful in the patient who is opioid tolerant, providing temporary analgesia by a non-opioid receptor mechanism. It is most commonly used in the patient with bowel obstruction and pain to avoid the constipating effects of opioid drugs. In patients with pain and opioid-induced nausea and vomiting, it acts as both an analgesic and an antiemetic. In patients who are highly anxious, it is reported to have anxiolytic properties as well. Long-term administration of this drug in patients with cancer pain has not been fully assessed.

Haloperidol is the drug of choice in the management of patients with acute psychosis and delirium. Its role in pain management is to treat drug-induced psychosis, which may result from opioid drugs. Its specific indications are for the treatment of confusional states and hallucinations in patients receiving opioids. Animal studies demonstrate that haloperidol potentiates morphine analgesia. The doses of haloperidol in patients with acute delirium or acute psychotic reaction start with 0.5 to 1 mg orally at bedtime or 1 to 3 times a day, depending on the patient’s symptomatology and ability to tolerate the drug. 3, 150 Risperidone may be useful as an alternative agent as it is associated with fewer parkinsonian side effects in some patients.

Antihistamine Drugs

Hydroxyzine has been shown to have analgesic effects when combined with morphine or meperidine in doses of 100 mg parenterally. 151 Hydroxyzine also has antiemetic and sedative properties, both of which can be desirable in patients with nausea, vomiting, and acute anxiety. Common practice is to use hydroxyzine at doses of 25 mg in combination with opioids to control these other effects.

Corticosteroids

Corticosteroids are the most widely used general-purpose adjuvant analgesics. They may ameliorate pain and produce beneficial effects on appetite, nausea, and mood. They provide analgesia from pain syndromes associated with raised intracranial pressure, acute spinal cord compression, superior vena cava syndrome, metastatic bone pain, neuropathic pain due to infiltration or compression by tumor, and hepatic capsular distension. 40 Patients with advanced cancer who experience pain and other symptoms that may respond to steroids are usually given relatively small doses (dexamethasone, 1 to 2 mg twice daily). In patients with epidural spinal cord compression, high doses (dexamethasone, 100 mg IV, followed by a slow taper) can be used to manage an acute episode of severe pain. 40 Eighty-five percent of patients receiving 100 mg of dexamethasone as a part of a radiotherapy protocol reported significant relief associated with marked reduction in analgesic requirements within 24 hours of administration of this dose. Several studies demonstrate prolonged survival times and reduced opioid doses in terminal cancer patients receiving steroids. In patients with prostate cancer, 30 mg of prednisone on a regular basis improves patients’ quality of life and reduces their pain symptomatology. 40, 152– 154 In a controlled study of oral methylprednisolone, patients with pain due to advanced cancer reported analgesic effects that seemed to stabilize following the introduction of this treatment. 155 Pain resulting from tumor infiltration of the brachial and lumbosacral plexus is often improved by the use of steroids. Steroids also improve the headache and radicular pain commonly seen in leptomeningeal disease. Corticosteroids may be particularly helpful in the patient who is admitted to the hospital with far advanced disease and diffuse pain in an acute painful crisis. We often use a large dose of steroids in this setting (100 mg of dexamethasone IV) to stabilize the patient and provide rapid symptom control. However, steroid psychosis can complicate steroid use and can occur during dose escalation and withdrawal. Steroid-induced psychosis is frequently responsive to haloperidol.

Neurostimulant Drugs

Dextroamphetamine has been demonstrated to provide additive analgesia in patients receiving morphine for postoperative pain. 156 In a controlled repeated-dose trial, oral methylphenidate reversed opioid-induced sedation and provided supplemental analgesia in a population of patients with cancer pain. 157, 158 Recent anecdotal evidence suggests that pemoline in starting doses of 18.5 mg per day may also be useful to counter opioid-induced sedation, but controlled studies are lacking. Pemoline is rarely associated with significant hepatic dysfunction and should be used with appropriate caution.

Topical and Systemic Local Anesthetics

Topical drugs are most useful in the management of painful cutaneous and mucosal lesions and as a premedication prior to skin puncture. Controlled studies have demonstrated the effectiveness of a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA) in reducing pain associated with venipuncture, lumbar puncture, and arterial puncture. 159, 160 Viscous lidocaine is frequently used in the management of oropharyngeal ulceration. 161

Oral local anesthetic drugs have been studied in the management of neuropathic pain. Mexiletine is the safest of these drugs, with doses starting at 100 to 150 mg per day. One open label study demonstrated efficacy in patients with diabetic neuropathy. 162 If side effects do not occur, the dose can be increased by 100 mg every few days until a maximum dose of approximately 300 mg three times per day is reached. Cardiac monitoring should be used during dose escalation.

Adjuvants for Bone Pain

Bisphosphonate drugs (pamidronate, clodrinate, and etidronate) bind to bone hydroxyapatite, inhibiting osteoclast activity, and are highly effective in the management of metastatic disease to the bone and in managing multiple myeloma. Recent large randomized double-blind studies have demonstrated their efficacy not only in relieving bone pain but also in reducing skeletal complications. 163, 164 Pamidronate, given as a 90 mg monthly infusion, has recently been shown to be safe and effective for up to 2 years. 165 While the currently available bisphosphonates do not appear to affect overall survival, they are very useful palliative agents. As pamidronate is 100 times and 10 times more potent than etidronate and clodronate, respectively, it is now the bisphosphonate most commonly used. Third-generation bisphosphonates (e.g., zoledronate and ibandronate) that may be significantly more potent than pamidronate are now in clinical trials. 166 Recent studies suggest that bisphosphonates also may inhibit bony attachment of cancer cells, decrease cytokine production, and induce apoptosis of tumor cells. 167, 168 The new generation of bisphosphonates may be useful not only for pain and reduction of skeletal complications but also for improved survival.

Strontium-89, among other radiopharmaceuticals, has been reported to be effective in patients with bone pain secondary to widely metastatic disease. 169– 171 Since this treatment can compromise marrow reserve and irreversibly lower platelet counts, its use is not recommended if future myelosuppressive chemotherapy is under consideration or if significant thrombocytopenia is present. Typically, pain relief develops within 6 weeks and is sustained for a median duration of 6 months.

Other Adjuvants

The oral antitussive dextromethorphan is an NMDA receptor antagonist as well as a calcium channel blocker. In experimental models, dextromethorphan prevents and reverses the development of tolerance. 172, 173 In a cancer population, however, dextromethorphan given at 30 mg three times a day was found to be ineffective in providing analgesia when compared with conventional therapies based upon the WHO Analgesic Ladder. 174

Octreotide, a somatostatin analogue with analgesic and palliative effects, inhibits pancreatic, gastric, and intestinal secretions and facilitates water and electrolyte absorption. 175, 176 It may be useful for pain, particularly in the setting of bowel obstruction.

Epidural clonidine may be useful in cancer patients with severe pain who cannot be optimally managed on opiates, due to side effects. 177 In a randomized placebo-controlled trial in the setting of intractable cancer pain, 45% of patients received analgesia versus 21% in the placebo group. 178 Clonidine was especially useful in patients with neuropathic pain. Given its properties as an alpha-2-adrenergic agonist, blood pressure and heart rate must be continuously monitored.

Treatment of Side Effects

A number of side effects associated with opioid analgesics can, depending upon the circumstance, be characterized as desirable or undesirable. Respiratory depression, sedation, confusion, nausea, vomiting, constipation, and multifocal myoclonus are the most common side effects encountered in the clinical use of opioids.

Respiratory Depression

Respiratory depression is potentially the most serious adverse effect. The morphine-like agonists act on brain stem respiratory centers to produce, as a function of dose, increasing respiratory depression to the point of apnea. In man, death from an overdose of a morphine-like agonist is nearly always due to respiratory arrest. Therapeutic doses of morphine may depress all phases of respiratory activity: rate, minute volume, and tidal exchange. However, as carbon dioxide accumulates, it stimulates central chemoreceptors, resulting in a compensatory increase in respiratory rate, which masks the degree of respiratory depression. At equianalgesic doses, all the morphine-like agonists produce an equivalent degree of respiratory depression. Respiratory depression most commonly occurs in opiate-naive patients after acute administration of an opioid and is typically associated with other signs of central nervous system (CNS) depression, including sedation and mental clouding. Tolerance develops rapidly to this effect with repeated drug administration, allowing the opioid analgesics to be used in the management of chronic cancer pain without significant risk of respiratory depression. If respiratory depression does occur, it can be rapidly reversed by the administration of the specific opioid antagonist, naloxone. The use of naloxone should be based on the prior opioid exposure of the patient. In patients chronically receiving opioids who develop respiratory depression, the standard naloxone dose, 0.4 mg/mL, should be diluted in 10 cc of saline and slowly titrated in the patient to reverse respiratory depression. This approach prevents the patient from experiencing excruciating pain with reversal of the analgesic effects of the current opioid while providing improved respiratory function. Cancer patients receiving opioids chronically are very sensitive to naloxone’s effects, and patients who have been taking drugs with a long half-life, such as methadone or levorphanol, or who have been taking a slow-release morphine preparation or using a transdermal patch will require a continuous infusion of naloxone to maintain a stable respiratory pattern. The dose of naloxone used continuously should be calculated from the initial dose used to reverse depression. Commonly, 1.2 mg of naloxone is diluted in 250 mL of saline and slowly titrated to the needs of the individual patient. Before administering naloxone to a comatose patient, an endotracheal tube should be placed to prevent aspiration given the possibility of respiratory compromise, excessive salivation, and bronchial spasm. In patients receiving meperidine chronically, naloxone may precipitate seizures by blocking the depressant action of the meperidine and allowing the convulsant activity of the active metabolite, normeperidine, to be manifest. Therefore, in respiratory depression from meperidine, naloxone must be administered with extreme caution, and diazepam or lorazepam should be available for intravenous injection to treat any potential seizures.

Sedation

This side effect is particularly bothersome for patients who are trying to maintain their normal daily work and social activities. Tolerance develops to this effect within several days. In patients who are excessively sedated but who are obtaining adequate analgesia, the use of caffeine, dextroamphetamine, or methylphenidate as described above may counteract this effect (Table 140.9).

Table 140.9. Algorithm for the Management of Persistent Opioid-induced Sedation.

Table 140.9

Algorithm for the Management of Persistent Opioid-induced Sedation.

Confusion and Hallucinations

Cognitive impairment can result from opioid administration and should be clearly defined and separated from opioid sedative effects. Confusion, hallucinations, and acute psychosis may result from single or multiple opioid doses although in a recent study of naloxone administration at a large cancer center, opiates were found not to be the cause of cognitive changes in the majority of cases. 179 All patients with mental status changes on opiates must receive a complete medical and neurologic evaluation to ascertain the etiology of the problem. If opiates are the culprit, tolerance develops to these effects. Dose adjustment and rotation to another opioid may be useful (Table 140.10).

Table 140.10. Algorithm for the Management of Confusion/Delirium in Cancer Patients Receiving Opioids.

Table 140.10

Algorithm for the Management of Confusion/Delirium in Cancer Patients Receiving Opioids.

Nausea and Vomiting

Nausea and vomiting can occur from the action of opioid analgesics on the medullary chemoreceptor trigger zone (CTZ). The incidence of nausea and vomiting is markedly increased in ambulatory patients, suggesting that the opioid drugs also alter vestibular sensitivity. The ability of an opioid analgesic to produce nausea and vomiting appears to vary with the drug and the patient, so that some advantage may result from switching to an equianalgesic dose of another opioid. Alternatively, an antiemetic may be useful in combination with the opioid. Commonly used drugs for control of nausea and vomiting associated with opioids include prochlorperazine, metoclopramide, scopolamine, lorazepam, dexmethasone, and the 5-HT3 antagonists, ondansetron and granisetron. Tolerance to this side effect generally develops within 2 to 3 days.

Constipation

Constipation is the most common adverse effect of the opioid analgesics. These drugs act at multiple sites in the gastrointestinal tract and spinal cord to produce a decrease in intestinal secretions and peristalsis, resulting in a dry stool and constipation. Tolerance develops slowly if at all to the smooth-muscle effects of opioids, so that constipation usually persists when these drugs are used for chronic pain.

Provision for a regular bowel regimen including cathartics and stool softeners should be instituted to diminish this effect. A wide number of approaches have been suggested. 180 A high-fiber diet alone or in combination with a bulk laxative containing bran, methylcellulose, or psyllium should be tried. If ineffective in 2 to 3 days, and depending upon the patient’s medical status, the use of an osmotic cathartic or the daily administration of a laxative should be the next step. Whatever approach is taken, it should be used regularly and aggressively to prevent the onset of bowel obstruction and secondarily induced pain.

Multifocal Myoclonus

High doses of all the opioid analgesics can produce multifocal myoclonus. This complication is most prominent with the repeated administration of large parenteral doses of meperidine (250 mg or more per day) but can occur from escalating doses of morphine, hydromorphone, and methadone. 116 One approach is to switch the patient to an alternative opioid. If myoclonus is a complication of high-dose opioids in a dying patient, the use of anxiolytics to suppress the myoclonic jerks offers an alternative approach. The use of intravenous benzodiazepines, barbiturates, and anticonvulsants has been reported anecdotally to be of some value in managing this symptom. 181– 183

Tolerance

Tolerance is a pharmacologic effect characterized by the fact that with repeated administration, increasing doses are necessary to provide the same effect. Dose escalation in the cancer patient most often is a sign of disease progression and should prompt a thorough medical investigation. 184 Tolerance develops at different rates for the various opioid effects. Tolerance to respiratory depression, as discussed above, develops rapidly in contrast to slow tolerance to the constipating effects. The first sign of analgesic tolerance is the patient’s report that the duration of analgesic effect is reduced from its initial interval. The patient who reports the shorter duration of pain relief is often labeled as a clock-watcher, and that patient’s report is often misinterpreted by health-care professionals as an early sign of addiction. From studies in cancer patients, it is now well recognized that although tolerance does occur, it is not the sole or even overriding factor in the dose escalation that occurs in the use of opioids in patients with pain and cancer. Rather it is often progression of disease that dictates the need for escalating doses of drugs, which implies that there is a change in the pain stimulus, requiring an increase in the dose of the drug. It is common for patients to increase their dose of opioid analgesic during the titration phase until they have reached steady state and are stabilized on a dose. This stabilized dose may increase over a 2- to 4-week period, but the increase tends to be slow, by one-tenth to one-fifth of the daily dose of the drug. When the pain stimulus changes, either increasing or decreasing, there is a rapid change in the patient’s requirements for analgesics. It is critical to remember that in patients with increasing pain, the degree of relief of pain and its analgesic effect are based on a log-dose relationship, and doubling the dose may therefore be necessary to provide adequate analgesia. In patients who have effective pain control, it is always useful to try to expand the time interval between the doses to see if the patient can reduce his or her analgesic requirements.

In the clinical realm, it is important to recognize that there is no limit to tolerance. A wide range of opioid requirements in individual patients has been reported, with average requirements of patients with advanced disease in the last 4 weeks of life between 400 and 600 mg of morphine equivalents per 24 hours. 117 Up to 10% of patients require large doses of opioids in the range of > 5,000 morphine quivalents per 24 hours. 117 There are several ways to manage the tolerant patient, including switching to an alternative analgesic, using adjuvant drugs and epidural local anesthetics, and employing a neurosurgical approach such as cordotomy.

In their 1991 landmark study, Trujillo and Akil demonstrated that the NMDA receptor antagonist MK-801 attenuated the development of morphine-associated tolerance and dependence without affecting morphine analgesia. 185 Other noncompetitive NMDA antagonists have also inhibited the development of opioid tolerance, suggesting a possible role in the treatment of chronic pain. 186 Through the release of substance P and glutamate, NMDA receptors facilitate and prolong nociceptive impulses and may participate in critical functions of the central nervous system including memory and long-term potentiation, neuronal degeneration, and excitotoxic injury. 187 Both the d and l isomers of methadone, unlike the other available opioids, bind as noncompetitive antagonists to the NMDA receptor, and in animal studies, d-methadone has been shown to provide analgesia through a non-opioid mechanism. 188

Differentiate Physical Dependence from Psychological Dependence

Physical dependence is the term used to describe the phenomenon of withdrawal when an opioid is abruptly discontinued or when a opioid-mixed agonist-antagonist or antagonist (e.g., naloxone) is administered. The severity of this withdrawal is a function of the dose and duration of prior opioid administration. Prior exposure to an opioid agonist can greatly increase a patient’s sensitivity to an antagonist. To prevent acute withdrawal, patients receiving opioids should be tapered off their drug. Twenty-five percent of the previous daily dose will prevent signs and symptoms of withdrawal. This dose is also referred to as the detoxification dose and is given in four divided doses. The initial dose is given for 2 days and then decreased by one-half, administered in four divided doses for 2 days, until the total daily dose of 10 to 15 mg/day (for morphine) is reached. After 2 days on this dose, the opioid can be discontinued. The degree of physical dependence is related to the opioid dose and the time of opioid exposure.

In contrast to physical dependence, psychological dependence is a term used to describe a behavioral pattern of drug use characterized by continued craving for an opioid for effects other than pain relief. An overwhelming involvement with drug use and procurement as compulsive traits are the salient features of this type of dependence. Cancer patients chronically receiving opioids become physically but not psychologically dependent on their drugs. Patients’ and physicians’ fears of addiction are the major barrier to adequate cancer pain management. 189– 191 Patients with poorly managed and/or undertreated pain may mimic the signs of psychological dependence, displaying a behavioral pattern known as pseudoaddiction. 192 The prevalence of true psychological dependence among patients receiving opioids for chronic medical illness is extremely rare. The Boston Collaborative Drug Surveillance Study reported an incidence of 0.4%. 193 A better understanding of the legal restrictions to opioid use, coupled with broad educational programs beginning with governmental initiatives as part of the WHO Cancer Pain Relief Program, has helped to clarify some of these issues and identify the proper role of opioid analgesics in cancer pain management. 52, 194

Psychological and Behavioral Approaches

Psychological management of cancer pain includes the use of psychotherapeutic, cognitive-behavioral, and psychopharmacologic interventions. The use of short-term supportive psychotherapy based on a crisis intervention model allows patients to receive emotional support, continuity, information, and skills to assist in adapting to a pain crisis. 3 Psychiatrists and psychologists need to be specially trained in psycho-oncology. Their role can be pivotal in managing patients who have significant psychological morbidity associated with their cancer pain. 44

Cognitive-behavioral techniques are helpful in promoting an increased sense of control, thus reducing the sense of hopelessness and helplessness common to many cancer pain patients. 195, 196 These techniques are most useful in three clinical situations: (a) in the management of patients with intermittent predictable pain (such as pain associated with procedures), (b) in the management of incident pain (e.g., in the patient with pain on movement), and (c) in the management of chronic cancer pain.

A series of cognitive-behavioral approaches used with cancer patients are listed in Table 140.11. The goal of such interventions is to enhance a pain patient’s sense of personal control or self-efficacy. Some techniques are primarily cognitive, focusing on perceptual and thought processes, and others are predominantly behavioral, directed at developing modulation of behavior to help patients cope with pain and cancer. Focused psychological interventions can facilitate patients’ coping with acute exacerbations of cancer pain and can help patients with chronic cancer-related pain syndromes achieve functional adjustments to living. 3

Table 140.11. Cognitive-Behavioral Techniques for Cancer Pain.

Table 140.11

Cognitive-Behavioral Techniques for Cancer Pain.

In general, cognitive-behavioral therapy can be implemented by all members of the pain team. Many of the specific techniques can be learned and practiced by the clinician, nurse, social worker, and psychologist. These approaches are used concurrently with analgesic drug therapy and anesthetic and neurosurgical approaches.

Anesthetic Approaches

Anesthetic approaches can be divided into five major types: (1) myofascial trigger-point injections, (2) peripheral nerve blocks, (3) autonomic nerve blocks, (4) epidural and intrathecal nerve blocks, and (5) ketamine and nitrous oxide. The techniques for each of these procedures have been described in detail in standard textbooks. 132 Short-acting and long-acting anesthetics are used for temporary and diagnostic nerve blocks (e.g., trigger-point injections) whereas phenol, alcohol, and freezing are the common agents used for permanent blocks. Anesthetic agents temporarily depolarize nerves via an increase in sodium permeability through membrane lipoprotein channels. Neurolytic agents produce a permanent conduction block by disrupting neural tissue.

Trigger-Point Injections

Patients with significant musculoskeletal pain often describe specific tender trigger-point areas that are associated with significant pain relief when injected with either saline or local anesthetic. 197 Effective relief, however, is not diagnostic of musculoskeletal pain alone, and evaluation of the cause of pain is still necessary to rule out the specific etiology.

Peripheral Nerve Blocks

Peripheral nerve blocks can be used both diagnostically, to localize the nerve distribution, and therapeutically, to interrupt pain transmission within a determined nerve distribution. The usefulness of this technique is limited to areas of the body in which interruption of both motor and sensory function will not interfere with the patient’s functional status. This approach is most commonly used in patients who have pain in the head, chest, or abdomen. The technique is also limited by the fact that each peripheral nerve subserves sensory function over multiple levels, and multiple nerves usually must be blocked to provide adequate analgesia. These techniques are most useful in patients with nociceptive pain. Neuropathic pain is rarely if ever effectively controlled by such peripheral nerve blocks. 198 Examples of such blocks in the cancer patient include the gasserian ganglion block for cranial and facial pain, intercostal blocks for chest wall infiltration from tumor, and paravertebral blocks for radicular pain. 198– 201 In those patients with somatic pain who demonstrate effectiveness of a local anesthetic block, neurolytic blockade with phenol may provide more prolonged (2 to 3 months’) relief. The most common peripheral nerve neurolytic block is a paravertebral block performed under fluoroscopic guidance for localized intercostal pain.

Neurolytic blocks are most suitable for patients with localized pain or a short life expectancy. 202 They are most useful in patients in whom the pain is either unilateral in the chest or abdomen, or midline in the perineum. This approach is less useful in managing upper and lower limb pain associated with brachial and lumbosacral plexopathy because of the high risk of associated motor weakness with effective neurolytic blockade. Epidural phenol blocks are most useful in managing patients with chest wall pain over several dermatomes. Such an approach obviates the need to perform multiple paravertebral injections. Phenol is injected in small increments, 1 to 2 mL per segment over 2 to 3 days via an epidural catheter. The selection of patients for management with either epidural or intrathecal neurolytic agents should be based on the following criteria: (a) exhaustion of the appropriate antitumor approaches, (b) clear clinical and radiologic definition of the cause of pain, (c) poor candidacy for percutaneous cordotomy, (d) failure of opioid analgesics to produce adequate analgesia without significant side effects, (e) a favorable response to local anesthetic diagnostic epidural or intrathecal blocks, producing at least 75% pain relief, and (f) magnetic resonance imaging performed before the procedure to rule out epidural tumor infiltration.

Specific Autonomic Nerve Blocks

Sympathetic block is effective in conditions where there is vasomotor or visceromotor hyperactivity. This hyperactivity accompanies many of the cancer-related pain syndromes such as visceral pain or neuropathic pain from a plexopathy. The most rewarding sympathetic block is that of the celiac ganglion for pain due to abdominal neoplasms including carcinoma of the pancreas, stomach, duodenum, liver, gallbladder, adrenal gland, and colon. 203, 204 Nociceptive fibers of the splanchnic, sympathetic, vagal, phrenic, and somatic nerves converge upon the celiac ganglia, which are amenable to a regional block. The major side effect of the procedure is transient hypotension. Patients must be well hydrated and monitored carefully during the procedure and for 4 to 6 hours afterward. Significant neurologic complications such as paraparesis and renal hemorrhage occur in less than 1% of patients if proper technique is used. The procedure should only be performed under radiologic guidance to avoid such complications.

The lumbar sympathetic ganglia convey visceral nociceptive afferents from the pelvic viscera in men and women from the urogenital organs, colon, and rectum. Pain caused by cancer of the sigmoid colon or rectum may be relieved by bilateral lumbar sympathetic blockade, particularly if the disease is confined to those viscera. Pain caused by cancer of the bladder or prostate can sometimes be relieved by bilateral lumbar sympathetic block. However, because of the broad innervation of the pelvis and pelvic viscera, lumbar sympathetic blocks are often limited in the management of patients with disease that extends to involve the lumbosacral plexus and that involves structures with innervation as high up as T12. In the management of pain due to unresectable pancreatic carcinoma, a recent prospective randomized study demonstrated the benefit of intraoperative chemical splanchnicectomy with 50% alcohol as compared with placebo. 205

Stellate ganglion block has been used to manage pain in patients with tumor involving the head and neck region most commonly associated with the syndrome of postherpetic neuralgia in the V1 trigeminal distribution and with pain associated with brachial plexopathy. This procedure can be done readily on an outpatient basis by identifying the anatomy of the stellate ganglion and injecting local anesthetic. The appearance of Horner’s syndrome is a reversible effect of this type of block. This represents a temporary maneuver, but it may provide the patient with some transient analgesia.

Chemical hypophysectomy has been reported to relieve pain in 60 to 90% of breast and prostate cancer patients, regardless of whether it is carried out surgically by transcranial or open microsurgical technique, by transnasal cryoprobe, or by transnasal alcohol injection. 206 Rapid and persistent pain relief may be achieved independent of tumor regression or progression and without alteration in pituitary function. The mechanism by which analgesia is produced is not clear, but analgesia may result from the tracking of alcohol up the pituitary stalk into the hypothalamus, with consequent disruption of the hypothalamic-thalamic endorphinergic pain pathway. The side effects include diabetes insipidus, cranial nerve palsies, cerebrospinal fluid leakage, and rarely, meningitis. The major indication for this procedure is for pain that is widespread and due to multiple metastases, but it is rarely performed.

Nitrous Oxide

Nitrous oxide has analgesic properties and has been used in the management of patients with far advanced disease to provide additive analgesia. It is administered with oxygen through a nonrebreathing face mask, with concentrations varying from 25 to 75%. Its use in combination with systemic opioid analgesics is associated with improvement of symptoms of pain and anxiety and a demonstrable improvement in alertness. Although long-term nitrous oxide use has been associated with the development of pancytopenia, its short-term use is relatively safe. Its role is in the management of patients undergoing procedures that are associated with a significant amount of mechanical pain and for patients with severe incident pain, allowing them to change position or participate in diagnostic or therapeutic procedures without pain. 207

Ketamine

Ketamine has been shown to produce analgesia via infusion in cancer patients in doses much lower than those required for anesthesia (typically 0.1 to 1.5 mg/kg/h. A double-blind cross-over study evaluating the effect of intrathecal ketamine on spinal morphine analgesia revealed that ketamine enhanced the analgesic effect and reduced the amount of morphine required. 203 By acting as a noncompetitive NMDA antagonist, ketamine in animal studies prevents the development of tolerance and neuropathic pain. Oral, subcutaneous, and intravenous administration of ketamine in cancer patients has been reported, but no controlled studies define appropriate dosages and the full spectrum of side effects.

Neurosurgical Approaches

Neurosurgical approaches to the management of pain in patients with cancer can be readily divided into two major categories: antitumor procedures, specifically designed to treat the cause of pain (e.g., vertebral body resection for epidural spinal cord compression), and antipain or analgesic procedures directed at treating the specific type of pain 204 (Table 140.12). Included in the latter category are neuroablative procedures designed to interrupt pain pathways in either the peripheral or central nervous system (e.g., cordotomy), neurostimulatory procedures designed to produce analgesia by activating specific sites in the nervous system that modulate pain (e.g., dorsal column stimulation), and neuropharmacologic procedures designed to deliver drugs to specific sites in the nervous system (e.g., epidural, intrathecal, or intraventricular opioid administration).

Table 140.12. Neurosurgical Procedures for Cancer Pain.

Table 140.12

Neurosurgical Procedures for Cancer Pain.

Critical to these procedures is an understanding of the nature of the pain and the specific pain syndrome. Patients with nociceptive pain of a somatic or visceral type commonly respond to any one of these neuroablative and neuropharmacologic approaches. In contrast, patients with neuropathic pain, in which injury of the peripheral or central nervous system has occurred, may respond better to neurostimulatory procedures. Cancer patients commonly have somatic, visceral, and neuropathic components to their pain. In such instances, the combination of a series of procedures is often the most effective method for pain control.

Antitumor Approaches

Tumor resection with or without prior tumor embolization is a useful procedure to treat back pain in patients with a vertebral body metastasis from a radioresistant tumor. 204 Pain is dramatically reduced, and the patient’s spine is stabilized to limit further mechanical pain. In some patients with vertebral body collapse from metastasis, pain may persist following radiation therapy because of mechanical segmental instability. This pain problem can be identified by the presence of a localized kyphosis (gibbus) or posterior subluxation of the superior portion of the vertebral body, which is best evaluated on magnetic resonance imaging (MRI). Sundaresan and colleagues 208 have advocated the use of anterior vertebral body resection and stabilization with the use of Sternman pins and methacrylate. In his study of 200 patients, 80% reported excellent relief of pain. In the setting of postradiation spinal stenosis secondary to bony overgrowth with compression of the spinal canal and neural foramina, decompressive laminectomy can alleviate pain and improve neurologic deficit. 204

In the patient with severe headache secondary to leptomeningeal disease and increased intracranial pressure, ventricular shunts provide dramatic and immediate relief of pain, preventing worsening neurologic dysfunction. Similarly, in patients with large cortical or cerebellar hemispheric mass lesions, surgical resection is associated with relief of headache and overall improvement in quality of life.

Of a more controversial nature is resection of tumors compressing the brachial and lumbar plexus region. Without question, debulking procedures may be beneficial to reduce tumor load, but whether they truly reduce pain is not well documented. In Pancoast’s tumor, resection of the lower brachial plexus, commonly C8-Tl, is associated with decreased pain; 209 however, patients may develop a burning dysesthetic pain (neuropathic pain) secondary to nerve injury at the time of resection.

Antipain or Analgesic Procedures

Neuroablative Approaches

For the patient with cancer pain, the decision to have a neuroablative procedure is complicated by several concerns: each procedure has a certain, albeit minor, risk of producing greater neurologic deficit; such procedures are only useful for localized pain, and the procedure removes pain sensation and deprives the patient of a sensation that they have viewed as a marker, however unwelcome, of their disease. Patients are often reticent to consider these procedures early on in the course of their illness because they want first to exhaust the available antitumor approaches before considering a primary pain procedure. Patients will rarely give up neurologic function for improvement in pain, particularly if the neurologic deficit may be associated with incontinence or leg weakness.

The role of cordotomy is emphasized because it offers a practical, relatively simple approach to managing patients with localized pain. For the present, it remains the neurosurgical treatment of choice in the management of patients with predominantly refractory somatic pain.

Peripheral Neurectomy

Neurectomy, or peripheral nerve resection, is rarely used because it sacrifices significant motor as well as sensory function and because pain from cancer is rarely confined to the distribution of one or a few nerve roots. It is most useful in patients with tumor infiltration of the chest wall, where intercostal neurectomy is performed using a curved needle electrode inserted under the edge of the appropriate rib. This procedure is also considered an antitumor procedure because it is often part of a resection of the chest wall for both treatment of tumor and pain management.

Cranial Neurectomy

Trigeminal neurectomy is useful in managing facial pain secondary to tumor infiltration of the base of the skull. Using a percutaneous radiofrequency approach with physiologic location, a controlled lesion size can be facilitated. Siegfried and Broggi reported good relief in 10 of 20 patients with trigeminal pain caused by cancer. Glossopharyngeal radiofrequency lesions have also been used to reduce pain originating in the neck and pharyngeal region.

Dorsal Rhizotomy

This procedure involves cutting the dorsal roots. It can be performed as an open surgical procedure following laminectomy or by a percutaneous radiofrequency technique through the intervertebral foramina under radiographic control. For cancer pain, variable reports suggest that 43 to 76% of patients report significant pain relief with this approach. It has been used most commonly in managing of patients with pain in an edematous, useless upper extremity and in managing chest wall pain. 210

Cordotomy

This procedure can be performed as an open unilateral or bilateral surgical procedure or as a unilateral percutaneous one (Figure 140.2). A percutaneous unilateral cordotomy remains the neurosurgical treatment of choice for patients with refractory cancer pain. 211 The procedure is performed using radiographic visualization. A fine, sharpened electrode with a 2-mm bare tip is introduced into the spinal canal, guided by control usually in the C1-C2 interspace. Penetration of the cord is monitored by electrical impedance, using 100 Hz stimulation. The spinothalamic tract is identified by the patient reporting contralateral, topically organized perception of warm, cold, or occasionally burning sensation in the absence of any accompanying motor changes, and a graded radiofrequency lesion is made. The ability to complete the procedure technically varies from 70 to 99% of attempts. In some cases, the spinothalamic tract is not readily identified and/or the patient is unable to tolerate the procedure. Numerous series support the usefulness of this approach in patients with unilateral pain below the T1 region. 212, 213 Pain relief reports vary from 70 to 95%. Several authors have described unmasking of pain in patients undergoing unilateral lesions. Ischia and colleagues reported that 81% of 36 patients had pain relief in their painful site, but that 63% recognized or developed pain on the other side and 14% developed or continued to suffer pain because of an inadequate level of analgesia. 214 Patients need to be told in advance that unmasking of pain may occur. In an MSKCC series, good-to-excellent pain relief was characterized by the patient’s ability to reduce opioid requirements by greater than 50%. 215

Figure 140.2. Cross-section of the spinal cord showing sites of neuroablative procedures for pain control.

Figure 140.2

Cross-section of the spinal cord showing sites of neuroablative procedures for pain control. (Reprinted with permission from Sundaresan et al.

From series published in the literature and from our experience, complications including respiratory compromise occur in less than 2 to 4% of patients who undergo percutaneous cordotomy. Prior to the procedure, a clear understanding of the patient’s pulmonary function and diaphragmatic movement is necessary to prevent any inadvertent paralysis of the phrenic nerve ipsilateral to the site of the procedure. With successful cordotomy, the duration of pain relief varies but can be anywhere from 3 weeks to upwards of 6 months in 50% of the patients, making this a procedure of particular value in patients with advanced disease and a relatively short life expectancy. For patients with bilateral pain below the waist or for paraparetic or paraplegic patients, an open bilateral cordotomy can be performed, providing them often with sufficient pain relief to sit up in a chair when they had been previously restricted to lying prone because of severe mechanical sacral or pelvic pain. 216

Dorsal Root Entry Zone (DREZ) Lesion

This procedure was developed to manage predominantly neuropathic pain by producing a surgical lesion in the dorsal root entry zone at a depth of about 2 mm and at a 45° angle, just lateral to the entry of the dorsal rootlets. In a group of patients with Pancoast’s tumor infiltration of the brachial plexus, Sindou and Lapras reported that 65% obtained pain relief. 217 The procedure can also be performed as a radiofrequency lesion and requires a laminectomy. Its general practicality for the management of cancer patients remains undefined.

Cingulotomy

Cingulotomy has recently received new attention in the treatment of some patients with cancer pain. The development of a stereotactic procedure using MRI for guidance to place a radiofrequency lesion has led to new interest in this procedure. In a group of patients recently reported by Hassenbusch and colleagues, four patients with pain from widely metastatic diffuse bone disease and who were receiving opioid analgesics reported immediate pain relief with bilateral cingulate lesions. 218 The pain relief persisted in this group of patients until death in 2 to 6 weeks. This procedure has previously been used to treat patients with psychiatric illness and has a long history of use for patients with severe chronic pain from a variety of neuropathic syndromes. The literature suggests that up to 50% of cancer patients have had moderate, marked, or complete relief for 3 months after the procedure.

Neurostimulatory Procedures

All of these procedures are based on the Gate Theory of Pain, which suggests that a neurophysiologic gating mechanism exists in the spinal cord, probably within the substantia gelatinosa. Noxious sensation is conducted via smalldiameter peripheral nerve fibers whereas non-noxious sensation is transmitted via large-diameter fibers, and both send collaterals to the substantia gelatinosa and dorsal columns. Stimulation of the small fibers tends to promote pain or open the gate whereas stimulation of large fibers tends to inhibit pain or close the gate.

Transcutaneous Electrical Nerve Stimulation (TENS)

The use of TENS has developed as a clinical tool in managing patients with mild pain, most typically of a musculoskeletal or neuropathic nature. By using a small battery-operated device with superficial electrodes that can be placed over the painful area, both low- and high-intensity stimulation have been reported to be effective in controlling mild pain in a peripheral nerve distribution.

Peripheral Nerve Stimulation

Stimulation of peripheral nerves by implantation of electrodes was proposed on the basis of the concept of selectively activating large nerve fibers to suppress activity in small, presumably pain, fibers. Such stimulation produces paresthesias in the area of pain and has been used in the management of patients with brachial and lumbosacral plexopathies. 219 Experience to date suggests a 30 to 50% incidence of relief, with a general falloff in efficacy within the first 2 years. The complications include a 1% risk of nerve damage, a 3 to 5% risk of infection, a 3% risk of tissue reaction or technical failure, and a 16% failure of pain relief despite continued effective technical performance of the device.

Dorsal Column Stimulation

As the large nerve fibers ascend in a compact bundle through the dorsal column, they are accessible to selective electrical stimulation. The dorsal column stimulating technique involves the introducing an electrode into the epidural or intrathecal space and advancing it to the appropriate level overlying the dorsal columns. Retrograde firing of the large fibers ensues, with resulting inhibition of pain sensation at multiple levels of the spinal cord below the level being stimulated. Parameters that can be controlled include frequency, amplitude, and duration of the stimulatory cycles. The main indication for placement of a dorsal column stimulator is intractable dysesthetic or neuropathic pain of the limbs or trunk, such as occurs in patients with radiation-induced brachial or lumbosacral plexopathy. This procedure is effective in 43 to 75% of patients and carries a low morbidity rate. 220, 221 The most common complication is failure of the device itself, which occurs in approximately 10% of patients annually. Other complications include infections, cerebrospinal fluid (CSF) fistula, allergy or rejection response to the device material, and changes in stimulation over time, which may be related to cellular changes around the electrode or shifts in its position.

Thalamic Stimulation

The stereotactic insertion of stimulating electrodes into the medial thalamus has been most commonly used to manage pain characterized by a predominantly neuropathic component described as a steady, tingling, burning element of pain. 222 This is a procedure more commonly used in patients with nonmalignant neuropathic pain, but it has been reported to have been useful in the management of certain patients with head and neck cancer who had a predominantly neuropathic component to their symptomatology. 223 Complications with this procedure include infection in 2 to 15% of patients, electrode migration in 2 to 27%, and worsening neurologic dysfunction in 2 to 15%.

Adrenal Medullary Implants

The role of adrenal chromaffin cell transplants in neuropathic pain following spinal cord injury is now under investigation. The role of this procedure in the management of cancer pain is as yet undefined. 224

Sedation in the Imminently Dying

Close adherence to established pain management guidelines produces effective and satisfactory analgesia in 70 to 100% of cancer patients. Ventafriddaand colleagues reported that up to 50% of patients in his home-care palliative service had uncontrolled symptoms in the last days of life and required sedation for adequate control. 225 Hospice programs report the use of sedation uncommonly in only 5 to 10% of patients. 226 Recent attention has focused on the notion that opioid drugs are a form of “slow euthanasia” although The U. S. Supreme Court has defined sedation as appropriate care of the dying and not as physician-assisted suicide. 227– 229 In those patients whose pain cannot be relieved without cognitive impairment, the use of sedation is an acceptable strategy when the intent is to relieve suffering. Of note, there are few data to suggest that opioids hasten death and some data to suggest that they may prolong life. 230, 231 In patients who are sedated for symptom control, such an approach should include an open discussion with the patient’s family, a do-not-resuscitate order, the appropriate use of drugs for symptom control, and dose escalation only to manage clearly defined signs and symptoms. By invoking the principle of double effect, pain medication may be provided in doses that may risk respiratory depression to the point of death if required for symptomatic relief. The primary intention must always be pain relief although the foreseen but unintended result may be sedation or death. Such practices are considered an important part of appropriate and compassionate care of the dying at cancer centers worldwide. 48, 232, 233

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