Cancer Pain: Principles of Management and Pharmacotherapy
Dermot Fitzgibbon
In 2008, the International Association for the Study of Pain (IASP) launched a global year against cancer pain to focus attention on the pain and suffering affecting patients with cancer. In 2011, the Institute of Medicine1 recognized chronic noncancer pain management as a public health challenge. In spite of increased attention on assessment and management, pain continues to be a prevalent symptom in patients with cancer.2 The consequences of unrelieved cancer pain can be devastating and include functional impairment, social isolation, and emotional distress. Inadequate treatment of cancer pain persists despite decades of efforts to provide clinicians with information about analgesics and pain-relieving techniques. The problems associated with undertreatment of cancer pain are outlined in Table 43.1. Although the reasons for inadequate treatment of cancer pain are complex, certain barriers to adequate pain relief are identified. These barriers primarily relate to health care professionals; patients, families, and the public; health care implementation and reimbursement; and drug regulatory systems.3
Cancer pain management guidelines typically incorporate pharmacologic, anesthetic, neurosurgical, and behavioral approaches. The World Health Organization (WHO) developed the most widely accepted approach for the treatment of cancer pain. The WHO algorithm largely focuses on pain intensity and the use of pharmacotherapy.4 Some have questioned the current appropriateness of the WHO guidelines, which may be considered outdated and not specific to the pharmacologic and interventional options used in contemporary pain management practices.5 Although the amount and quality of evidence regarding the use of opioids for treating cancer pain is low,6 opioid therapy remains the cornerstone for pain management in oncology.7,8,9,10,11,12 In the United States, physicians’ concerns about regulatory scrutiny and the possibility of unwarranted investigation by regulatory agencies negatively affect their prescribing of opioid analgesics to treat pain.13 In addition, it is widely reported that the United States is experiencing an epidemic of drug overdose deaths particularly from the use of opioid medications.14,15,16,17 The past two decades have been characterized by increasing abuse and diversion of prescription drugs, including opioid medications (see “Substance Abuse in Oncology” section).18 In a study of malpractice claims associated with medication management for chronic pain, issues in care (including death) were noted when patients did not cooperate in their care and with inappropriate medication management by physicians.19 Factors associated with death in this study included the use of long-acting opioids, additional concomitant psychoactive medications, and the presence of three or more factors commonly associated with medication misuse. In 2016, the U.S. Drug Enforcement Administration indicated that prescription drugs, heroin, and fentanyl were the most significant drug-related threats to the United States.15 The misuse of prescription opioids is associated with misuse of illicit opioids and nonmedical use of prescription opioids is a significant risk factor for heroin use,20 emphasizing the need for continued prevention efforts around prescription opioids. Regardless of age, gender, or type of user, the majority who misuse prescription pain relievers obtained the drugs from a friend or relative with the second most common source from a doctor.21 Particularly for chronic noncancer pain, there is insufficient evidence to determine the effectiveness of long-term opioid therapy for improving pain and function, but there is increasing evidence to support the evidence for a dose-dependent risk for serious harm.22 Higher opioid doses (50 mg per day or more of morphine) are associated with increased risk of opioid overdose death or adverse drug-related events.23,24 Although the overall rate of overdose is lower among patients with cancer compared with other patients, there was a statistically significant association of prescribing patterns with overdose risk among patients with cancer receiving opioid therapy.23 In response to persistent public health concerns regarding prescription opioids, the U.S. Food and Drug Administration (FDA) developed a multipart action plan in response to the opioid epidemic,25 and many states and health care systems have implemented legislation and policies intended to regulate or guide opioid prescribing.26 Unfortunately, data on state policy and systems-level interventions are limited and inconsistent.27 Patients with cancer and other significant comorbidities have a higher prevalence for polypharmacy and greater risk for drug-drug interactions, adverse drug events, hospitalizations, and increased mortality.28,29,30,31 Concurrent sedative-hypnotic use even at low opioid doses poses substantially greater risk of opioid overdose.32,33 In spite of these concerns, clinicians have an ethical and professional responsibility for safe and appropriate pain management in cancer patients.
TABLE 43.1 Factors Contributing to Undertreatment of Cancer Pain in United States | ||||||
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Pain management and relief can be achieved by several means (Table 43.2). Successful pain management requires an accurate diagnosis of the etiology of the pain complaint(s) and
tailoring treatment to the individual patient: matching drug treatment, anesthetic, neurosurgical, psychological, and behavioral approaches to the patient’s needs. Successful management requires that the person or persons responsible for pain management be familiar with all these aspects of care and with the uniqueness and challenges of pain in oncology patients. Evidence-based medicine, systematic reviews, meta-analyses, and guidelines are increasingly incorporated into modern pain management. Scientific data and relevant evidence employing methodologic, rational judgments, analysis, and understanding of current knowledge can then be applied in clinical settings. In the areas of chronic noncancer and cancer-associated pain, evidence-based decision making for pharmacotherapy is lacking and decisions for pain management in oncology is frequently extrapolated or inferred from chronic pain situations. Often, practitioners must rely on clinical practice guidelines, limited clinical trial data, case reports, or anecdotal information for clinical decision making. Clinical practice guidelines are systematically developed statements that aim to help physicians and patients reach the best health care decisions. Guidelines and recommendations for management of cancer pain have largely focused on relieving acute pain or pain associated with advanced disease.34,35,36,37 Not all patients with cancer experience tumor-related pain, and management principles differ depending on the source of pain and these recommendations are not appropriate for oncology patients with nonmalignant sources of pain or for pain management in cancer survivors.38,39 However, pharmacotherapy remains the optimal and preferred modality for symptomatic pain management in oncology, but safe and effective drug prescribing practices must be observed and implemented. Since 1986, the focus of cancer pain treatment has been the use of strong opioids based on the WHO’s analgesic ladder. Changing societal factors in the last 15 years suggest changes in the distribution of drug use disorders in the general US adult population. Prescriptions for opioid analgesics and other psychoactive medications with addiction potential have increased greatly, with consequences such as drug overdoses.40 Comparisons of 12-month and lifetime Diagnostic and Statistical Manual of Mental Disorders (4th ed., DSM-IV) drug use disorder prevalence in the general adult population in 2001 to 2002 (2.0% and 10.3%, respectively)41 and 2012 to 2013 (4.1% and 15.6%, respectively)42 indicate that rates of 12-month drug use disorders more than doubled, whereas rates of lifetime drug use disorders increased by 50%. Using Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-5) criteria drug use in 2012 to 2013 disorder, prevalence of 12-month and lifetime drug use disorder were 3.9% and 9.9%, respectively.43 Drug use disorder was generally greater among men, white and Native American individuals, younger and previously or never married adults, and those with lower education and income. A lower prevalence of drug abuse has been reported in the cancer population, with 3% of psychiatry consultations in a single cancer center in 1990 being requested for managing issues related to drug abuse.44 Similarly, a low prevalence of drug abuse was reported by the Psychiatric Collaborative Oncology Group study in 1983, in which fewer than 5% of patients in ambulatory care met the criteria for a substance abuse disorder.45 This low prevalence may not be an accurate reflection of the true prevalence because of underreporting. The prevalence of substance abuse in cancer patients is largely understudied and needs clarification. Patients with cancer are known to have an increased risk of psychiatric symptoms and disorders, cardiovascular diseases, and suicide.46,47,48 Living or being diagnosed with cancer can induce severe psychological stress.49 In a retrospective review of 204 supportive care clinic oncology patients (with the majority having active cancer) considered to be at risk for substance abuse based on history or behaviors, 46% had evidence of use of nonprescribed opioids, benzodiazepines, or illicit drugs such as heroin or cocaine, and 39% had inappropriately negative urine toxicology, raising concerns for diversion.50
tailoring treatment to the individual patient: matching drug treatment, anesthetic, neurosurgical, psychological, and behavioral approaches to the patient’s needs. Successful management requires that the person or persons responsible for pain management be familiar with all these aspects of care and with the uniqueness and challenges of pain in oncology patients. Evidence-based medicine, systematic reviews, meta-analyses, and guidelines are increasingly incorporated into modern pain management. Scientific data and relevant evidence employing methodologic, rational judgments, analysis, and understanding of current knowledge can then be applied in clinical settings. In the areas of chronic noncancer and cancer-associated pain, evidence-based decision making for pharmacotherapy is lacking and decisions for pain management in oncology is frequently extrapolated or inferred from chronic pain situations. Often, practitioners must rely on clinical practice guidelines, limited clinical trial data, case reports, or anecdotal information for clinical decision making. Clinical practice guidelines are systematically developed statements that aim to help physicians and patients reach the best health care decisions. Guidelines and recommendations for management of cancer pain have largely focused on relieving acute pain or pain associated with advanced disease.34,35,36,37 Not all patients with cancer experience tumor-related pain, and management principles differ depending on the source of pain and these recommendations are not appropriate for oncology patients with nonmalignant sources of pain or for pain management in cancer survivors.38,39 However, pharmacotherapy remains the optimal and preferred modality for symptomatic pain management in oncology, but safe and effective drug prescribing practices must be observed and implemented. Since 1986, the focus of cancer pain treatment has been the use of strong opioids based on the WHO’s analgesic ladder. Changing societal factors in the last 15 years suggest changes in the distribution of drug use disorders in the general US adult population. Prescriptions for opioid analgesics and other psychoactive medications with addiction potential have increased greatly, with consequences such as drug overdoses.40 Comparisons of 12-month and lifetime Diagnostic and Statistical Manual of Mental Disorders (4th ed., DSM-IV) drug use disorder prevalence in the general adult population in 2001 to 2002 (2.0% and 10.3%, respectively)41 and 2012 to 2013 (4.1% and 15.6%, respectively)42 indicate that rates of 12-month drug use disorders more than doubled, whereas rates of lifetime drug use disorders increased by 50%. Using Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-5) criteria drug use in 2012 to 2013 disorder, prevalence of 12-month and lifetime drug use disorder were 3.9% and 9.9%, respectively.43 Drug use disorder was generally greater among men, white and Native American individuals, younger and previously or never married adults, and those with lower education and income. A lower prevalence of drug abuse has been reported in the cancer population, with 3% of psychiatry consultations in a single cancer center in 1990 being requested for managing issues related to drug abuse.44 Similarly, a low prevalence of drug abuse was reported by the Psychiatric Collaborative Oncology Group study in 1983, in which fewer than 5% of patients in ambulatory care met the criteria for a substance abuse disorder.45 This low prevalence may not be an accurate reflection of the true prevalence because of underreporting. The prevalence of substance abuse in cancer patients is largely understudied and needs clarification. Patients with cancer are known to have an increased risk of psychiatric symptoms and disorders, cardiovascular diseases, and suicide.46,47,48 Living or being diagnosed with cancer can induce severe psychological stress.49 In a retrospective review of 204 supportive care clinic oncology patients (with the majority having active cancer) considered to be at risk for substance abuse based on history or behaviors, 46% had evidence of use of nonprescribed opioids, benzodiazepines, or illicit drugs such as heroin or cocaine, and 39% had inappropriately negative urine toxicology, raising concerns for diversion.50
TABLE 43.2 Approaches to Pain Management in Cancer Patients | ||||||||||||||
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Safe and appropriate medication prescribing practices are of paramount importance in the oncology pain population. The challenges presented to clinicians are numerous and include educational deficits, time restraints, and limited access to all types of care. New challenges to access are occurring as a result of interventions designed to combat the prescription drug abuse epidemic, with fewer clinicians willing to prescribe opioids, pharmacies reluctant to stock the medications, and payers placing strict limits on reimbursement.39 In the era of personalized medicine, Hui and Bruera51 suggested that pain management may be tailored to the individual need by use of a personalized pain goal, and this can be obtained by asking a patient to identify the maximal intensity of pain from 0 to 10 (0, no pain; 10, worst pain) that would still be considered comfortable. The concept is a personalized pain goal is attractive but managing pain by pain scores can be problematic,52,53,54 and more appropriate goals may be to identify a pain management plan that results in a reduction in interference in activities of daily living and improvement in quality of life and overall functional ability.
Cancer Pain Management Overview
Successful management of the cancer patient with pain ultimately depends on the ability of the clinician to accurately assess problems, identify and evaluate the components that contribute to the pain complaint, and formulate a plan for continuing care that is responsible for the evolving goals and needs of the patient and the patient’s family (see Chapter 42). In general, the goals of patient care in oncology are often complex, but they broadly include prolonged survival, and optimizing comfort and function with associated improved quality of life. Adoption of these goals logically leads to a multimodality treatment approach targeted to specific problems (Fig. 43.1).
Comprehensive cancer care encompasses a continuum that progresses from disease-oriented, curative, life-prolonging treatment through symptom-oriented, supportive, and palliative care extending to terminal-phase hospice care. Pain management is, and should be, an integral component of comprehensive cancer care.55,56,57,58,59 Designing an effective pain control
strategy for the individual patient requires knowledge of the ways in which a patient’s cancer, cancer therapy, and pain therapy can interact. Collaboration with different health care providers (such as medical oncologists and radiation oncologists) is essential to successful pain management.
strategy for the individual patient requires knowledge of the ways in which a patient’s cancer, cancer therapy, and pain therapy can interact. Collaboration with different health care providers (such as medical oncologists and radiation oncologists) is essential to successful pain management.
 FIGURE 43.1 Multimodality therapeutic management of cancer pain. Others include psychosocial interventions, nursing care, alternative pain management strategies, and end-of-life issues. |
Two important aspects of cancer affect management and include the oncologist’s ability to treat the cancer and the ability to assess the components of the tumor pathophysiology that of themselves do not cause pain (the cancer’s “nonpain” pathophysiology).60 The ability to treat cancer modifies the need for pain management (successful treatment reduces the likelihood of persistent tumor-related pain) and the appropriateness of invasive pain procedures. Cancer nonpain pathophysiology can interfere with the oral administration of medications, narrow the patient’s therapeutic window for analgesic drugs, limit the effectiveness of psychological pain therapies, and complicate or preclude invasive pain-reducing procedures. In addition, cancer therapy can interfere with, or enhance, pain therapy and vice versa. Antineoplastic treatment can interfere with pain therapy by causing additional pain or by producing other adverse effects such as fatigue and gastrointestinal (GI) disturbances. Cancer treatment can enhance pain therapy by reducing the extent of tumor burden, by acting as an adjuvant analgesic, and, often times, by providing intravenous access for parenteral drug administration to patients who require it. Pain therapy can sometimes interfere with cancer therapy by increasing or complicating the adverse effects of cancer therapy, for example, opioid-related bowel dysfunction. It can enhance cancer therapy by improving patient function or sense of well-being, and certain palliative surgical procedures may have the ancillary effect of improving organ function.
The basic principles of tumor-directed pain control include:
Modifying the source of pain by treating the cancer and the inflammatory effects of cancer
Altering the central perception of pain, for example, by the use of analgesics, antidepressants, anxiolytics, and psychotherapy
Interfering with nociceptive transmission outside of and within the central nervous system (CNS), for example, with anesthetic techniques (e.g., neurolytic celiac plexus block, neuraxial analgesia, and spinal neurolysis) or neurosurgery procedures (e.g., cordotomy and myelotomy)
The pain experienced by most cancer patients responds to direct and indirect modification of the source of the pain combined with pharmacologic and nonpharmacologic alteration of the central perception of pain.37,61,62,63 The guiding principle in developing pain management goals is to individualize the approach to the patient’s needs. Part of the process of developing treatment goals is to take into consideration the burdens (adverse effects; opportunity costs) and benefits of different treatment options.63 Clinicians may find that patient treatment goals differ from their own, either because patients feel that pain is inevitable or because patients expect pain to be relieved with minimal effort on their part. Issues that physicians should discuss with patients include expected lifestyle; cost and reimbursement issues; and concerns about opioid tolerance, addiction, and side effects. Discussing these issues in advance may uncover and address potential barriers to treatment. Moreover, treatment goals may change during the course of the patient’s illness, and all health care providers interacting with the patient during the course of the illness need to keep abreast of such changes. Medication adherence has major implications for the effective treatments of different diseases.64,65,66,67 Inadequate adherence with an analgesic regimen is problematic in oncology68,69 and adherence rates for scheduled around-the-clock (ATC) regimens better than for as needed regimens.70 Most interventions to improve cancer pain outcomes rely on psychoeducational approaches which focus on knowledge transfer to address attitudes and barriers to opioid use.71,72,73,74 However Bennett et al.75 found that patient-based educational interventions resulted in modest benefits in the management of cancer pain and did not have significant benefit on medication adherence or on reducing interference with daily activities. A large variety of approaches have been used with varying effect, and attempts to understand the reasons for heterogeneity between results have so far been unsuccessful.76 A patient-centered approach that includes good communication between health providers and patients can promote adherence and improve outcomes.74,77
PRIMARY ANTICANCER TREATMENT
Pain produced by tumor infiltration may respond to antineoplastic treatment with radiation treatment and chemotherapy. These approaches to pain control are elaborated in Chapters 42 and 48.
Surgery
The surgeon treating a patient with newly diagnosed cancer must meet several responsibilities: biopsy for tissue diagnosis, adequate staging, consultation with medical and radiation oncologists for adjuvant therapy, and surgical resection. Surgery may also play a role in the relief of symptoms caused by specific problems, such as obstruction of a hollow viscus, unstable bone structures, and compression of neural tissues. A variety of surgical disciplines (e.g., general surgery, orthopedic, neurosurgical, plastic, and reconstructive) may participate in the care of the cancer patient.
Although the development of metastatic cancer usually indicates incurable disease, curative surgical resection is possible in rare instances. These instances must meet several criteria before the surgeon can operate: the primary lesion must be controlled, there must be the potential for complete resection of the metastases, there must be no other equally effective or better antitumor therapy available, metastases should involve only one organ, one should anticipate reasonable postoperative function, expected survival should be better than if left untreated, and the patient must be able to tolerate the surgical procedure. Sometimes, excision of the primary tumor is indicated in the presence of unresectable metastatic disease. Locally advanced
tumor can be very painful and unsightly, can interfere with vital functions such as breathing and swallowing, and produce complications such as bleeding and local infection. Resection of isolated metastatic colorectal cancer, GI stromal tumors, neuroendocrine cancers, renal cell cancer, and sarcoma is associated with longer survival or even cure.78 Most of the available information on metastasectomy relates to disease involving the liver, lung, and brain. Resection of primary renal cell cancer localized to the kidney has a 5-year survival rate approaching 95%.79 However, the presence of metastasis reduces the median survival to only 10 months. At the time of diagnosis of primary renal cell cancer, about 20% of individuals will have metastases. The benefit of resection of isolated colorectal cancer metastases to the liver and lung and results in a 5-year survival reported in the range of 27% to 58%.80,81,82 Surgical interventions for osseous (nonvertebral) disease depend on the severity of symptoms, location of tumor, expected associated morbidity if a fracture occurred, and availability of alternative or adjuvant treatments. The goal is primarily to decrease pain and to improve mobility and quality of life. The most obvious indication for surgery is the presence of a pathologic fracture in a weight-bearing long bone. Asymptomatic lesions may be followed clinically and radiographically. For metastatic spinal tumors, surgery can improve mechanical stability, cord compression, and pain. Complications may occur in up to 25% of patients who undergo surgery for spinal metastases, the most common being wound infection.83,84 Life expectancy is usually determined by the overall extent of disease and, to be of benefit, surgery must improve quality of life.85
tumor can be very painful and unsightly, can interfere with vital functions such as breathing and swallowing, and produce complications such as bleeding and local infection. Resection of isolated metastatic colorectal cancer, GI stromal tumors, neuroendocrine cancers, renal cell cancer, and sarcoma is associated with longer survival or even cure.78 Most of the available information on metastasectomy relates to disease involving the liver, lung, and brain. Resection of primary renal cell cancer localized to the kidney has a 5-year survival rate approaching 95%.79 However, the presence of metastasis reduces the median survival to only 10 months. At the time of diagnosis of primary renal cell cancer, about 20% of individuals will have metastases. The benefit of resection of isolated colorectal cancer metastases to the liver and lung and results in a 5-year survival reported in the range of 27% to 58%.80,81,82 Surgical interventions for osseous (nonvertebral) disease depend on the severity of symptoms, location of tumor, expected associated morbidity if a fracture occurred, and availability of alternative or adjuvant treatments. The goal is primarily to decrease pain and to improve mobility and quality of life. The most obvious indication for surgery is the presence of a pathologic fracture in a weight-bearing long bone. Asymptomatic lesions may be followed clinically and radiographically. For metastatic spinal tumors, surgery can improve mechanical stability, cord compression, and pain. Complications may occur in up to 25% of patients who undergo surgery for spinal metastases, the most common being wound infection.83,84 Life expectancy is usually determined by the overall extent of disease and, to be of benefit, surgery must improve quality of life.85
 FIGURE 43.2 Patient with metastatic prostate cancer who presented with large bowel obstruction. Endoscopy revealed extrinsic tumor compression of the proximal sigmoid colon that required placement of a 10-cm metal stent (red arrows) with complete relief of obstruction. Patient has also bilateral percutaneous nephrostomies (yellow arrows) for relief of bilateral hydronephrosis. |
 FIGURE 43.3 Tumor pain management algorithm. |
Stenting, Drainage Procedures, and Antibiotics
Common complications of advanced cancer include GI, hepatobiliary, and ureteric obstructions. Stents and laser treatment have a place in both upper GI and rectal obstruction due to advanced malignancy (Fig. 43.2).86,87,88,89 Decompression for obstructive uropathy from advanced disease usually involves placement of nephrostomy tubes or ureteral stents. Malignant obstruction of the bile duct from cholangiocarcinoma, pancreatic adenocarcinoma, or other tumors may cause debilitating symptoms. Treatment of obstruction can be performed endoscopically, percutaneously, or surgically. Stents, nasobiliary drainage, or percutaneous drains may be used for liver hilar strictures. Endoscopic catheter-based therapies such as photodynamic therapy or radiofrequency ablation may prolong patient survival by achieving local tumor control.90
The goals of antibiotic use in terminally ill patients are sometimes to prolong life and always to relieve symptoms.91 Treatment for cystitis, for instance, does not usually prolong life but may relieve the patient from painful dysuria and troublesome polyuria. Antibiotics may also have pain-relieving effects when the source of pain involves infection, as illustrated by the treatment of pyonephrosis or osteitis pubis.
Symptomatic Cancer Pain Management
Successful management strategies usually require a team approach focusing not only on the nociceptive processes but also on other factors that influence the final perception of pain. Figure 43.3 outlines an approach to tumor-related nociceptive and neuropathic pain.
Increasing severe pain and/or increasing and intractable side effects determine the appropriate treatment strategy. Most patients will respond satisfactorily to relatively simple oral pharmacotherapeutic strategies. When the patient requires drug treatment, therapy should comply with two basic principles: use oral analgesics and other noninvasive routes of administrations (e.g., transdermal and transmucosal) whenever possible and administer them in accordance with the principles in the WHO analgesic ladder (see later). Titrate opioid and adjuvant analgesics to maximally effective doses or to the appearance of dose-limiting side effects before considering alternative medications (e.g., opioid rotation) or more specialized (and usually) invasive approaches. As an adjunct—and occasionally as an alternative—to medication management, patients with certain pain syndromes will benefit from relatively simple anesthetic blocks, such as celiac and superior hypogastric plexus blocks, neurolytic subarachnoid and intercostal blocks, and selected peripheral nerve blocks (see Chapter 44).
Severe, uncontrolled pain and/or intractable side effects require interventional pain management to achieve rapid pain control.
Such interventions may include neuraxial (epidural or intrathecal) analgesia and/or parenteral opioid therapy (usually intravenous administration). As many of these patients have large systemic opioid requirements, it is not unusual to combine neuraxial and parenteral therapies. A small percentage of patients may fail these therapies and should then be treated with intrathecal drugs and/or cordotomy or myelotomy (see Chapter 44).
Such interventions may include neuraxial (epidural or intrathecal) analgesia and/or parenteral opioid therapy (usually intravenous administration). As many of these patients have large systemic opioid requirements, it is not unusual to combine neuraxial and parenteral therapies. A small percentage of patients may fail these therapies and should then be treated with intrathecal drugs and/or cordotomy or myelotomy (see Chapter 44).
Occasionally, patients will have pain refractory to all interventional measures outlined, and palliative sedation should be considered (see Chapter 13).
WORLD HEALTH ORGANIZATION ANALGESIC LADDER
In 1986, WHO proposed a method for relief of cancer pain, based on a small number of relatively inexpensive drugs, including morphine.92 Ten years later, a second edition93 took into account many of the advances in understanding and practice that have occurred since the mid-1980s. The groundwork for this revision was started in 1989, in the context of the meeting of a WHO Expert Committee on Cancer Pain Relief and Active Supportive Care.94
The WHO “analgesic ladder” is a simple and effective method for controlling cancer pain (Fig. 43.4). The purpose was to make pain relief readily available to patients with cancer by using effective and inexpensive drugs. Opioid-based pharmacotherapy is the most important of these options. In many countries, access to opioid treatment is limited by governmental regulation intended to prevent misuse.95,96,97,98 Advocacy for improved and affordable access to opioids for legitimate medical reasons must continue. At the same time, clinicians have to acknowledge the serious nature of drug misuse and addiction and the obligation to minimize these outcomes. This obligation is particularly pertinent in the United States because of the troubling increase in prescription drug misuse during recent decades. Codeine and morphine were selected for the original WHO analgesic ladder but have fallen from favor because of the genetically established variation in the effects of codeine and the potential effect of morphine metabolites in patients with renal impairment. The WHO analgesic ladder approach selects different opioids on the basis of pain intensity and any single-entity full µ-agonist opioid is appropriate. According to a Cochrane review, the amount and quality of evidence around the use of opioids for treating cancer pain is low, but 19 out of 20 people with moderate or severe pain who are given opioids and can tolerate them should have that pain reduced to mild or no pain within 14 days.6 Because of opioid-related side effects, 1 to 2 in 10 patients treated with opioids will find adverse events intolerable resulting in a change in treatment. Somnolence, dry mouth, and anorexia were common adverse events in people with cancer pain treated with morphine, fentanyl, oxycodone, or codeine.99 Historically, the proportion of cancer patients who report effective pain relief varies from 75% to 90%.37,100,101
 FIGURE 43.4 World Health Organization analgesic ladder. (With permission from World Health Organization. Cancer Pain Relief with a Guide to Opioid Availability. Geneva, Switzerland: World Health Organization; 1996.) |
TABLE 43.3 A Basic Drug List for Cancer Pain Relief | |||||||||||||||||||||||||||
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Treatment for cancer pain should begin with a straightforward explanation to the patient of the causes of the pain or pains. Many pains respond best to a combination of drug and nondrug measures. Nevertheless, opioids, nonopioid analgesics and adjuvant agents, alone or in combination are the mainstay of cancer pain management (Table 43.3).
Pharmacologic strategies for the control of tumor pain appear in Table 43.4.
Table 43.5 lists the principles of pharmacotherapy endorsed by WHO.
These principles are as follows:
By Mouth
When possible, patients should take analgesic medications by mouth. However, alternative routes such as rectal, transdermal, transmucosal (buccal, intranasal, sublingual), and parenteral (subcutaneous and intravenous) administration may better serve patients with dysphagia, uncontrolled vomiting, or GI obstruction.
TABLE 43.4 Pharmacologic Strategies for the Control of Tumor Pain | |||||||
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TABLE 43.5 The Principles of Drug Therapy for Cancer Pain | ||||||
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By the Clock
After titration to optimal effect, patients with continuous pain should take analgesic medications on an ATC schedule. Once baseline pain is controlled, many patients will require breakthrough pain (BTP) therapy with immediate or rapid-onset opioids because BTP is a common occurrence in cancer patients.
By the Ladder
The WHO analgesic ladder93 is based on the premise that most patients throughout the world will gain adequate pain relief if health care professionals learn how to use a few effective and relatively inexpensive drugs well (Fig. 43.4). Step 1 of the ladder involves the use of nonopioids. If this step does not relieve pain, add an opioid for mild to moderate pain (Step 2). When the opioid for mild to moderate pain in combination with a nonopioid fails to relieve the pain, substitute an opioid for moderate to severe pain (Step 3). Use only one drug from each of the groups at the same time. Give adjuvant drugs for specific indications (see later).
For the Individual
There are no standard doses for opioids. The “right” dose is the dose that relieves the patient’s pain with the minimum of side effects. Adequate pain relief may be judged by patient satisfaction with pain management and/or meeting predefined functional goals. Combination opioid formulations (i.e., those with the nonopioid analgesic acetaminophen or a nonsteroidal anti-inflammatory drug [NSAID] are commonly used for mildto moderate-intensity pain. These have a dose limit due to toxic effects of the coanalgesic.
With Attention to Detail
Carefully determine and monitor the patient’s analgesic regimen. Follow-up regularly with the patient by monitoring adherence, drug efficacy, functional outcomes, side effects, and aberrant drug-related behaviors. Anticipate adverse effects, such as opioid-induced bowel dysfunction, and treat them prophylactically or as soon as they become problematic.
The WHO ladder advocates the use of three classes of analgesics—nonopioid, adjuvant, and opioid. Each of these classes will be considered separately.
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs are essential drugs for the management of a wide variety of acute and chronic pain conditions. Clinicians should be familiar with the use, efficacy, and adverse effects of these agents. NSAIDs include a variety of drugs that differ in their clinical effects and pharmacokinetics. In general, they have high bioavailability, with peak concentrations occurring within the first 4 hours when administered orally. Intravenous forms of ibuprofen and ketorolac are available in the United States. NSAIDs may function to control pain independently (e.g., in the management of mild- to moderate-intensity bone or muscle pain) or may help reduce the dose of opioid required for pain control (opioid-sparing effect). A wide range of drugs with varying effects and side effects are available. These medications are discussed extensively in Chapter 78.
Cyclooxygenase (COX) is the pivotal enzyme in prostaglandin biosynthesis. It exists in two isoforms, constitutive COX-1 (responsible for physiologic functions) and inducible COX-2 (involved in inflammation and upregulated by cytokines, growth factors, and shear stress). Pharmacologic inhibition of COX explains both the therapeutic effects (inhibition of COX-2) and side effects (inhibition of COX-1) of NSAIDs. COX-1 and COX-2 both metabolize arachidonic acid to an unstable precursor, prostaglandin (PG) H2. A variety of PG isomerases use PGH2 as the substrate to form PGs, prostacyclin (PGI2), and thromboxane (Tx) A2. The analgesic and anti-inflammatory effects of NSAIDs are dependent on the extent and duration of COX-2 inhibition in the spinal cord and inflammatory sites. Aspirin differs from NSAIDs because aspirin irreversibly acetylates the enzyme. Most NSAIDs inhibit both COX isoenzymes with little selectivity, although some (coxibs, meloxicam) mainly block COX-2.
PGE2 is the most physiologically abundant product of COX-2 as it exists at some level in nearly all cell types. Apart from biologic effects, such as induction of pain and inflammation, PGE2 also participates in the mechanisms of cell proliferation, apoptosis, and metastasis, contributing to the progression of several human cancers, including colon cancer, breast cancer, and lung cancer, suggesting that NSAID use may be beneficial in these cancers.102,103,104,105 COX-2 is markedly overexpressed in colorectal neoplasm and multiple epidemiologic studies clearly demonstrated that NSAID consumption prevents adenoma formation and decreases the incidence of, and mortality from, colorectal cancer.106 COX-2 inhibition can reduce proliferation, induce apoptosis, suppress tumor angiogenesis, prevent immune suppression, and inhibit carcinogen conversion.106,107 The efficacy of aspirin differs significantly according to COX-2 expression. Aspirin reduces the risk of colorectal cancer in COX-2-expressing cancers, but it is not an effective chemopreventive agent for cancers with weak or absent COX-2 expression.108 In animal models, NSAIDs decrease the number and risk of metastasis109 with some data now emerging of a reduced risk of metastasis development in humans.110
EFFICACY IN CANCER PAIN
Although many NSAIDs are available to treat various painful conditions, it is unclear which agent is most clinically efficacious for relieving cancer-related pain, and if there are clinical differences between these agents that justify their cost differences. In a Cochrane review of the use of NSAIDs either alone or in combination with opioids, the quality of evidence supporting the use of NSAIDs was poor and suggested that moderate to severe cancer pain was reduced to no worse than mild pain after 1 to 2 weeks in approximately 1 of 3 patients. One in 4 patients stopped taking NSAIDs because the drug did not work, and 1 of 20 stopped because of side effects.61 In effect, there is no evidence to support or refute the use of NSAIDs alone or in combination with opioids for cancer pain. McNicol et al.111 assessed and compared the efficacy of various NSAID and NSAID plus opioid combinations in the treatment of cancer pain. They concluded that most studies were of insufficient duration to demonstrate that the longterm use of NSAIDs is safe and effective in patients with cancer. They advised that clinicians should be as cautious in using NSAIDs in this population as they would any other population, especially given additional bleeding risks in cancer patients, and the probability that a patient with cancer may be on a broad regimen of medications, some of which may increase NSAID-related toxicity.
Acetaminophen
Acetaminophen (APAP) is one of the most popular antipyretic and analgesic medications worldwide. It is used either alone or in combination with other drugs. Its low cost and favorable side effect profile is attractive for use in a variety of painful conditions. The mechanism of action of the drug is not fully understood. However, it is known that acetaminophen is a weak inhibitor of the synthesis of PGs. It may have a selective COX-2 inhibitor effect112 or a central effect, possibly due to activation of descending serotonergic pathways.113 On average, APAP is considered a weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. High use of APAP was associated with an almost twofold increased risk of incident hematologic malignancies such as myeloid neoplasms, non-Hodgkin lymphoma, and plasma cell disorders excluding chronic lymphocytic leukemia/small lymphocytic lymphoma114 but not for other nonhematologic malignancies.115 Severe liver injury can occur when acetaminophen use exceeds maximum dosage (currently 4,000 mg within a 24-hour period) or when an individual takes the drug and also consumes alcohol,116 and with additional warnings that the drug may cause severe skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis.117 Of note, the use of concentrated prescription APAP-containing medications (>500 mg) in combination with other sources of APAP can result in severe liver injury and death.118 Acute liver failure secondary to APAP is most often associated with unintentional overdose, the use of a single product, an opioid-APAP combination, duration of use <7 days, and a median dose of 7.5 g per day.119 Daily doses of APAP of 4 g for 10 days resulted in a maximum increase of serum alanine aminotransferase (ALT) more than 3 times normal in over 30% of patients,120 and daily use of acetaminophen at half the maximum recommended daily dose for 12 weeks in a healthy adult population was associated with a small elevation in mean ALT of no probable clinical significance.121 There is no high-quality evidence to support or refute the use of APAP alone or in combination with opioids for cancer-related pain122 or with advanced disease.123
Opioid-Induced Bowel Dysfunction
Constipation is prevalent in oncology patients even among patients not on opioid therapy.124 GI side effects such as nausea, vomiting, diarrhea, and constipation is associated with chemotherapy including alkylating agents, antimetabolites, immunomodulating agents, and mitotic inhibitors.125 The prevalence of constipation after cytotoxic chemotherapy may be as high as 16% with 5% classified as severe.126 Posttreatment constipation and diarrhea among cancer (particularly colorectal) survivors is prevalent with episodes persisting up to 10 years after treatment.127,128 Opioid-induced constipation (OIC) and opioid-induced bowel dysfunction (OBD) are associated with opioid therapy. OBD is a distressing condition that may persist indefinitely in the clinical setting. Hard dry stool, gas distention, incomplete evacuation, and straining are common sequelae. OBD can affect quality of life significantly and result in hospitalization, pain, and frequent changes in opioid and laxative treatment.129
Clinical reviews on OIC indicate the lack of a common definition130 and may be defined as a change when initiating opioid therapy from baseline bowel habits that is characterized by reduced bowel movement frequency, development or worsening of straining to pass bowel movements, a sense of incomplete rectal evacuation, or harder stool consistency.131 OBD reflects the overall impact of opioids on the GI tract and include symptoms such as dry mouth, gastroesophageal reflux-related symptoms (heartburn), nausea, vomiting, chronic abdominal pain, bloating, constipation-related symptoms: straining, hard stools, painful, infrequent and incomplete bowel movements (BMs), and diarrhea-related symptoms: urgency, loose and frequent BMs.132,133 OIC is the most common form of OBD.
Endogenous opioids and opioid receptors are widely distributed throughout the body, with strong expression in the CNS, peripheral nervous system, and enteric nervous system (ENS) and also within the endocrine and immune systems. The ENS has a network of small ganglia that can regulate GI motility and secretion independently of the CNS. Neurons in the ENS form plexuses between the circular and longitudinal muscle layers (the myenteric plexus) and between the mucosal and circular muscle layers (the submucosal plexus). The myenteric plexus innervates both the longitudinal and the circular muscle layers, and its primary role is to coordinate motility patterns. Submucosal plexuses are found in the small and large intestine and are primarily involved in the regulation of secretion and local blood flow. Opioids inhibit enteric neuronal activity in both the small intestine and the colon. The expression of µ-opioid receptors on myenteric and submucosal ganglia suggests that receptor agonists cause constipation by inhibiting peristaltic smooth muscle contractions by effects on the myenteric ganglia and also by inhibiting water and electrolyte movement across the lumen via effects on the submucosal ganglia. Opioid receptors and endogenous opioid agonists are altered in GI disease.134 The mechanisms for OBD are associated with delays in gastric emptying, oral-cecal transit and colonic transit time, and inhibition of defecation, all of which are predominately mediated through peripheral µ receptors.135,136,137 The effects of opioids on the gut also are partly a result of their ability to accumulate in the intestinal tissue and have a direct local effect on the bowel.135 Centrally mediated antitransit effects are implicated in the pathophysiology of OBD. Opioids act centrally through alterations in autonomic outflow to the gut; however, their overall impact on GI motility appears to be correlated to their ability to penetrate the CNS.138 Opioids mainly exert their action on the ENS where they bind to opioid receptors in the myenteric and submucosal plexuses and on immune cells in the lamina propria.139 The coordination of the contractile and propulsive gut motility is determined by a balance between acetylcholine and nitric oxide/vasoactive intestinal peptide release.140,141 Because opioids inhibit neurotransmitter release, administration will directly disrupt this balance, resulting in abnormal coordination of motility.142
The Bowel Function Index (BFI numerical analogue scale 0 to 100), calculated as the mean of three variables (ease of defecation, feeling of incomplete bowel evacuation, and personal judgment of constipation), was developed to evaluate bowel function in opioid-treated patients with pain.143 This clinician-administered tool allows easy measurement of OIC from the patient’s perspective.
Metoclopramide is commonly prescribed for patients with symptoms of gastroparesis.144,145,146 It is a dopamine receptor antagonist, serotonin 5-hydroxytryptamine type 4 (5-HT4) receptor agonist, and weak inhibitor of 5-hydroxytryptamine type 3 (5-HT3) receptors. Activity appears to be by both peripheral (in the upper GI tract) and central mechanisms by inducing antidopaminergic effects. Recommended use of metoclopramide at the lowest effective dose for each patient beginning with 5 mg three times daily up to a maximum recommended dose of 40 mg per day.147 Adverse events include restlessness, drowsiness, fatigue, and extrapyramidal effects, especially in younger patients and in children. Patients may experience extrapyramidal side effects at doses greater than 20 mg daily.148 Metoclopramide is an inhibitor of CYP2D6 enzyme. Concurrent use of antidepressants such as tricyclics, selective serotonin reuptake inhibitors (SSRIs), and antidepressants acting as serotonin-norepinephrine reuptake inhibitors (SNRIs) (venlafaxine or duloxetine) may enhance adverse effects associated with metoclopramide.
The goals of therapy typically are threefold: keep stool volume maximized to trigger enterochromaffin cell serotonin release via mucosal stretch, keep stool softer and mechanically make it easier to move, and enhance peristalsis. Most treatment for constipation begins with encouraging exercise, activity, fluid intake, and dietary fiber and the use of stool softeners and laxatives. Fiber-bulking agents are organic polymers that retain water in stool. It is important that adequate water be taken concomitantly with fiber. Without sufficient fluid, fiber may worsen constipation. Many practitioners recommend a combination of a stool softener with a stimulant laxative for patients on chronic opioid therapy. Stool softeners, such as docusate sodium, are detergents that allow better water penetration into stool, making it softer and more voluminous. Stimulant laxatives, such as senna and bisacodyl, induce peristalsis via mechanisms that are not well understood. In vitro, applying senna to intestinal mucosa leads to immediate contraction. After optimal titration of these agents with persistent constipation, oral osmotics are commonly added to enhance laxation by pulling along water due to osmotic forces. Osmotics include sugars, such as lactulose or sorbitol; magnesium salts, such as magnesium citrate; or inert substances, such as polyethylene glycol. When unsuccessful, rescue oral and rectal interventions are also often needed. Rectal interventions include such agents as bisacodyl suppositories and phosphosoda enemas to soften, lubricate, and mobilize hard, dry distal stool. Often, synergism of multiple categories of agents is required for successful laxation. Another strategy has been the development of peripherally acting µ-opioid receptor antagonists (PAMORAs) that selectively target µ receptors in the GI tract. PAMORAs agents currently available include oral naloxegol and alvimopan and subcutaneously administered methylnaltrexone.
Naloxegol is a polymer conjugate of naloxone. The polyethylene glycol (PEG) moiety limits the ability to cross the blood-brain barrier. PEGs are also used as osmotic laxatives (e.g., macrogol 3,350/4,000), where they act as nonmetabolized, nonabsorbable, osmotic agents, forming hydrogen bonds with water in the intestinal lumen. PEGylation makes naloxegol a substrate for the P-glycoprotein (P-gp) transporter. Due to the reduced permeability and increased efflux of naloxegol across the blood-brain barrier, related to P-gp transporter, the CNS penetration of naloxegol is negligible and it reduces OIC in the GI tract without reversing the central analgesic effect.149 administration of naloxegol with food is associated with increased bioavailability. The concentration and activity of naloxegol are increased by the concurrent use of CYP3A4 inhibitors and reduced by CYP3A4 inducers. Naloxegol is administered at a dose of 25 mg once daily on an empty stomach at least 1 hour before the first meal of the day or 2 hours after the first meal of the day. Cancer patients with symptoms of bowel obstruction and those with increased risk of GI perforation including GI or peritoneal tumors, recurrent or advanced ovarian cancer, and patients treated with vascular endothelial growth factor (VEGF) inhibitors should avoid the use of naloxegol.
Methylnaltrexone-bromide is a PAMORA and a quaternary methyl derivative of naltrexone. The addition of a methyl group to the nitrogen ring increases polarity and reduces lipophilicity such that the drug does not pass the blood-brain barrier. It is administered subcutaneously and is rapidly absorbed, with the peak plasma concentration attained within 30 minutes, and plasma elimination half-life (t1/2) is approximately 8 hours.150 It induces bowel movement in approximately 50% to 60% treated patients within 4 hours of its administration.151,152 It is indicated for OIC patients with advanced disease who are receiving palliative care with inadequate response to laxative therapy.153 Recommended dosing is 8 mg for patients weighing 38 to less than 62 kg and 12 mg for patients between 62 to 114 kg. Usual dosing is one dose every other day and not more than one dose per day. Common side effects include abdominal pain, flatulence, and nausea. Contraindications include administration to patients with known or suspected mechanical bowel obstruction. Rare cases of GI perforation involving various regions of the GI tract have been reported in advanced illness patients.154 Alvimopan is another orally administered PAMORA that does not cross the blood-brain barrier at clinically relevant doses and does not reverse analgesia or cause opioid withdrawal symptoms. The FDA approved alvimopan for postoperative ileus following partial small or large bowel resection with primary anastomosis in hospitalized patients.
Antiemetics
Nausea and vomiting is a common problem in oncology. Although opioids,155 chemotherapy,156 and radiation therapy157 are commonly associated with nausea and vomiting, advanced disease is also frequently associated with nausea particularly in the last week of life.158 Depending on the anatomic area irradiated, an estimated 50% to 80% of patients undergoing radiation therapy develop radiation therapy-induced nausea and vomiting (RINV).159 Total body irradiation, half body irradiation, or abdominal radiotherapy are at a major risk of nausea and vomiting. The pathophysiology of nausea and vomiting is a complex process. The act of vomiting is coordinated by the vomiting center of the brain located in the lateral reticular formation of the medulla with efferent pathways through the vagus, phrenic, and spinal nerves. The vomiting center receives afferent input from various sources including the chemoreceptor trigger zone (CTZ) in the area postrema in the floor of the fourth ventricle, the vagus and sympathetic nerves, as well as impulses directly from the GI tract and other sources. The CTZ is also activated by mediators in the circulation, which may include hormones, peptides, medications, or toxins. The act of vomiting involves neurotransmitters (including serotonin, substance P, and dopamine found in the CTZ), the vomiting center, and enterochromaffin cells in the GI tract release efferent impulses that are transmitted to the abdominal musculature, salivation center, and respiratory center. CTZ effects are largely mediated through central dopamine type 2 (D2) receptors.
Opioids have emetogenic effects by central stimulation, vestibular effects and by inhibiting gut motility. The primary mechanism of opioid-induced nausea and emesis is central with direct stimulation of the CTZ.160 Although opioid stimulation of the CTZ involve opioid receptors, signaling from the CTZ involves D2 and 5-HT3 receptors and opioid stimulation of the vestibular apparatus and sensory input to the vomiting center may involve H1 and muscarinic acetylcholine pathways (Fig. 43.5).161 The peripheral inhibitory effect of opioids on GI transit and stimulation of the pyloric sphincter delays gastric emptying or causes gastroparesis. Chemotherapy likely causes nausea and vomiting through stimulation of the CTZ mediated by 5-HT3 and neurokinin type 1 (NK1) receptors. Because of these effects, 5-HT3 and NK1 receptor antagonists are the most effective agents currently available. In most cases of chemotherapy-induced nausea and vomiting (CINV), these agents are used in conjunction with glucocorticoids.162,163,164,165 Glucocorticoids are effective only for preventing nausea and vomiting and not for treating established nausea and vomiting.166
Typical strategies for management and minimization of opioid-induced nausea and vomiting include dose reduction, dose titration, opioid rotation, and the use of antiemetics. Commonly used antiemetics are listed in Table 43.6. It is not uncommon for patients to experience nausea and/or vomiting when starting opioid therapy, but these side effects tend to subside within days or weeks167 unless opioid-induced bowel dysfunction develops. Until the late 1970s, dopamine-receptor antagonists,
such as metoclopramide, prochlorperazine, and haloperidol, formed the basis of antiemetic therapy. In 1991, the first 5-HT3-receptor antagonist, ondansetron, was approved by the FDA for the treatment of chemotherapy-induced emesis followed by two additional 5-HT3-receptor antagonists, granisetron and dolasetron, in 1997. Droperidol and ondansetron have an FDA black box warning after reports of prolonged rate-corrected QT (QTc) interval. Palonosetron is a second-generation 5-HT3-receptor antagonist that has a prolonged t1/2 with higher receptor binding affinity than other antiemetic agents. Aprepitant, the first NK1 receptor antagonist, was approved for chemotherapy-induced emesis in 2003. In 2008, fosaprepitant, a prodrug and intravenous form of aprepitant, was approved by the FDA. Dronabinol (Schedule III) and nabilone (Schedule II) are cannabis-derived pharmaceuticals indicated for the treatment of nausea and vomiting associated with cancer chemotherapy and of anorexia associated with weight loss in patients with acquired immune deficiency syndrome.168
such as metoclopramide, prochlorperazine, and haloperidol, formed the basis of antiemetic therapy. In 1991, the first 5-HT3-receptor antagonist, ondansetron, was approved by the FDA for the treatment of chemotherapy-induced emesis followed by two additional 5-HT3-receptor antagonists, granisetron and dolasetron, in 1997. Droperidol and ondansetron have an FDA black box warning after reports of prolonged rate-corrected QT (QTc) interval. Palonosetron is a second-generation 5-HT3-receptor antagonist that has a prolonged t1/2 with higher receptor binding affinity than other antiemetic agents. Aprepitant, the first NK1 receptor antagonist, was approved for chemotherapy-induced emesis in 2003. In 2008, fosaprepitant, a prodrug and intravenous form of aprepitant, was approved by the FDA. Dronabinol (Schedule III) and nabilone (Schedule II) are cannabis-derived pharmaceuticals indicated for the treatment of nausea and vomiting associated with cancer chemotherapy and of anorexia associated with weight loss in patients with acquired immune deficiency syndrome.168
 FIGURE 43.5 Opioid-induced nausea and vomiting pathophysiology and antiemetic therapy. 5-HT3, 5-hydroxytryptamine type 3; CTZ, chemoreceptor trigger zone; D2, dopamine type 2; DRA, dopamine receptor antagonist; GI, gastrointestinal; H1, histamine H1; M1, O-desmethyl tramadol; NK1, neurokinin type 1; NK1R, neurokinin type 1 receptor. (Modified from Smith HS, Laufer A. Opioid induced nausea and vomiting. Eur J Pharmacol 2014;722:67-78. Copyright © 2014 Elsevier. With permission.) |
Postoperatively, ondansetron is more effective than metoclopramide for the treatment of opioid-induced emesis.169 Nausea and vomiting after acute administration of opioids may be partly related to serotonin receptor signaling.170 Many consider dopamine receptor antagonists, including prochlorperazine and haloperidol as the preferred drugs for managing opioid-induced nausea and vomiting.171,172 Olanzapine, an atypical thienobenzodiazepine antipsychotic agent that is indicated for the treatment of schizophrenia and bipolar disorder, is also useful for the treatment of intractable nausea particularly at reducing during the delayed and overall phase of the CINV prevention.173 It is also useful for the treatment of morphine-induced emesis and as an adjunct for the treatment of neuropathic pain associated with sleep disturbance.161 It blocks multiple neurotransmitter receptors, including dopaminergic (D2), serotonergic (5-HT3), adrenergic, histaminergic, and muscarinic receptors. Dose titration of olanzapine is over a period of 7 to 10 days (in the range of 2.5 to 7.5 mg) given at bedtime.
TABLE 43.6 Antiemetics | ||||||||||||||||||||||||||||||||||||||||||||||||
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Many of the commonly prescribed antiemetic agents (e.g., phenothiazines, antihistamines, anticholinergic drugs, and metoclopramide) are generally effective but are often associated with undesirable side effects such as sedation, blurred vision, dysphoria, and extrapyramidal reactions. 5-HT3 receptors are located centrally in the CTZ as well as peripherally on vagal nerve terminals. Ondansetron is effective for the control of opioid-induced nausea and vomiting.174 The antiemetic actions noted from cannabinoids and endocannabinoids have been linked to CB1 effects, where antagonists can provoke acute emesis and agonists reduce acute nausea and vomiting.
Adjuvant Analgesics
An adjuvant analgesic is a medication with a primary indication other than pain relief, but it may provide or enhance analgesia in certain circumstances. In the area of cancer pain, the common adjunctive analgesics are corticosteroids, anticonvulsants, and antidepressants. These drugs play an important role for some patients who cannot otherwise attain an acceptable balance between relief and opioid side effects. Adjuvant analgesics divide broadly into general purpose analgesics, adjuvants used for musculoskeletal pain, and those with specific use for neuropathic, bone, or visceral pain. Although ketamine has been used in the treatment of cancer pain refractory to opioid therapy, it is not licensed for this purpose and the evidence supporting its use is very low quality with potentially serious adverse events at higher doses175 and will not be considered further.
GENERAL PURPOSE ADJUVANTS
Corticosteroids are the most widely used general purpose adjuvant analgesics and are available in a wide variety of formulations.176 Various guidelines recommend the use of steroids as adjuvants for cancer pain but these guidelines are based on expert opinion.177,178,179,180,181 Steroids are used to treat pain associated with increased intracranial pressure, acute spinal cord compression, superior vena cava syndrome, metastatic bone pain, neuropathic pain due to infiltration or compression, symptomatic lymphedema, and hepatic capsular distension. The mechanism for pain relief is unknown but the anti-inflammatory effect of steroids is often proposed as the putative mechanism.182 The available data suggest that moderate doses of corticosteroids equivalent to methylprednisolone 32 mg or dexamethasone 8 mg daily are well tolerated for up to 7 days but that high doses equivalent to methylprednisolone 125 mg daily administered over 8 weeks have a significantly adverse impact and may even increase mortality.183 Overall, data supporting the role of steroids for cancer pain control is weak and likely with only short-term benefit.182
Topical agents (see Chapter 80) may also be useful as an adjunctive form of pharmacotherapy, without increasing systemic toxicity. These agents are used for a variety of painful conditions such as strains or sprains, muscle aches, osteoarthritis of hand or knee, or neuropathic pain. Typical topical analgesic drugs include NSAIDs, salicylate rubefacients, capsaicin, and lidocaine. Agents such as diclofenac Emulgel, ketoprofen gel, piroxicam gel, and diclofenac plaster work reasonably well for strains and sprains. For hand and knee osteoarthritis, topical diclofenac and topical ketoprofen rubbed on the skin for at least 6 to 12 weeks help reduce pain by at least half in a modest number of people. For postherpetic neuralgia, topical high-concentration capsaicin can reduce pain by at least half in a small number of people.184 There are a number of drugs in the area of pain management that have been formulated and compounded to treat conditions such as diabetic neuropathy, fibromyalgia, postherpetic neuralgia, joint pain, arthritis, and others. Significant portions of these compounded analgesic preparations are topical/transdermal dosage forms such as gels and creams. Although the efficacy and doses of these drugs in systemic dosage forms have been widely established, little is known about the permeation and efficacy of these compounds from these gels. A multicenter, phase III, randomized, double-blind, placebo-controlled trial was to investigate the efficacy of 2% ketamine plus 4% amitriptyline cream for reducing chemotherapy-induced peripheral neuropathy (CIPN) in 462 cancer survivors was ineffective for this problem.185 A study examining topical 5% amitriptyline and 5% lidocaine in the treatment of mixed sources (noncancer) neuropathic pain showed that topical lidocaine reduced pain intensity but the clinical improvement was minimal and that topical 5% amitriptyline was not effective.186 Although anecdotally, topical lidocaine may benefit some patient, there is no evidence from good quality randomized controlled studies to support the use of topical lidocaine to treat neuropathic pain.187
MUSCULOSKELETAL PAIN ADJUVANTS
The term muscle relaxants or muscle relaxers is broad and includes a wide range of drugs with different indications and mechanisms of action. Muscle relaxers are either antispasmodic or antispasticity medications. The antispasmodic agents are further subclassified into the benzodiazepines and the nonbenzodiazepines. Nonbenzodiazepines include a variety of drugs that can act at the brain stem or spinal cord level and include carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, meprobamate, methocarbamol, tizanidine, zopiclone, and orphenadrine. Only three muscle relaxants—baclofen, dantrolene, and tizanidine—are FDA approved to treat spasticity. Tizanidine is an agonist at α2-adrenergic receptor sites and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. It has linear pharmacokinetics over a dose of 1 to 20 mg.188 In multiple dose, controlled clinical studies, 48% of patients receiving any dose of tizanidine reported sedation as an adverse event and sedation appears to be dose related.189 A single dose of 8 mg of tizanidine reduces muscle tone in patients with spasticity for a period of several hours. The effect peaks at approximately 1 to 2 hours and dissipates between 3 and 6 hours.
The FDA-approved muscle relaxers for spasms (including carisoprodol, cyclobenzaprine, orphenadrine, metaxalone, chlorzoxazone, and methocarbamol) have only been approved for short-term use (up to 21 days), and their long-term efficacy is unknown. Evidence supporting the effectiveness of these drugs for muscle spasm is sparse; most trials are old and not of good quality. Much of the evidence from clinical trials regarding the use of these agents is limited because of poor methodologic design, insensitive assessment methods, and small numbers of patients.190 These drugs are often used for treatment of musculoskeletal conditions, whether muscle spasm is present or not. Pharmacologic and nonpharmacologic approaches do not differ significantly from patients with musculoskeletal pain who do not have cancer (see Chapters 80 and 89), other than disease- or treatment-specific issues relevant to the cancer patient. Drug-drug and drug-disease interactions must always be considered and be an ongoing component of reassessment.
NEUROPATHIC PAIN ADJUVANTS
Neuropathic pain, caused by a lesion or disease affecting the somatosensory nervous system, is a common and oftentimes very debilitating source of distress in patients with cancer (see Chapters 24, 25, 26, 27, 28 and 42). In cancer and chronic noncancer pain, there is a large variety of causes. Most treatment strategies for cancer-related neuropathic pain are extrapolated from noncancer-related neuropathic pain (see Chapters 24, 25, 26, 27, 28).191,192,193,194 Table 43.7 summarizes those agents that are used to treat neuropathic pain in noncancer patients. Of note, opioids are recommended as third line contrasting with previous recommendations.195 This is largely because of the potential risk of abuse, particularly with high doses, and concerns about prescription opioid-associated overdose mortality, diversion, misuse, and other opioid-related morbidity. In addition, high-concentration capsaicin patches and cannabinoids are considered for the first time in therapeutic recommendations for neuropathic pain.
The causes of neuropathic pain in noncancer patients are diverse and generally can be considered as central or peripheral. Neuropathic pain has been extensively discussed in Chapters 24, 25, 26, 27, 28. Although chronic noncancer neuropathic pain occurs in oncology patients, unique sources of pain including disease infiltration of central and peripheral nervous tissue, paraneoplastic peripheral neuropathy, pain resulting
from leptomeningeal metastases and neuropathic pain secondary to therapeutic interventions (postsurgical, radiation therapy, and CIPN) occur in cancer patients. Furthermore, combinations of different sources of pain may also occur. For example, a patient with persistent CIPN-associated pain may develop both central and peripheral sources of pain (brachial plexus tumor infiltration extending to the spinal canal causing cord compression). Management of such pain complaints may require multiple approaches including disease control (chemotherapy, radiation therapy) and symptomatic pharmacologic approaches. Extrapolation of treatment guidelines from noncancer pain patients are not appropriate for the management of oncology-associated neuropathic pain. Data relating to the use of neuropathic pain adjuvant medications for the management or prevention of CIPN-associated pain is inconsistent. Chemotherapeutic agents causing nerve dysfunction mainly target axons, dorsal root ganglia, and terminal trees of intraepidermal nerve fibers.196 Purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, retinoic acid, or vitamin E) for platin drug toxicity were not beneficial.197 Typical medications used for management of CIPN are antidepressants (tricyclics, SNRIs) or antiepileptic drugs (AEDs) (gabapentin, pregabalin). Venlafaxine is a reasonably well-tolerated antidepressant and is a serotonin reuptake inhibitor and weak norepinephrine reuptake inhibitor. Although some studies suggest benefit for use in acute oxaliplatin-induced198 or acute taxane-oxaliplatin-related199 neuropathy, others have found little compelling evidence to support the use of venlafaxine in neuropathic pain.200 Because of the lack of effective management for CIPN, the National Cancer Institute sponsored a series of trials aimed at prevention and management.201 A total of 15 studies were approved, evaluating use of various neuromodulatory agents (including nortriptyline, gabapentin, and lamotrigine) which have shown benefit in other neuropathic pain states. Gabapentin doses were targeted to 2,700 mg per day for a total of 6 weeks. Aside from duloxetine, none demonstrated therapeutic benefit for patients with CIPN. Smith et al.202 studied the effect of duloxetine at initial doses of 30 mg for 1 week then 60 mg for 4 additional weeks for painful CIPN induced by paclitaxel, other taxane, or oxaliplatin. Fifty-nine percent of patients experienced some decrease in pain after 5 weeks of taking duloxetine, and more duloxetine-treated patients decreased their opioid analgesic intake. In a retrospective review on the use of duloxetine for paclitaxel-induced CIPN, some benefit was observed in younger patients, but elderly patients (>60 years) tended to be less responsive and experienced more drug-related adverse events.203 It should also be noted, especially in breast cancer patients, that if duloxetine and tamoxifen are taken together, duloxetine-induced CYP P450 2D6 enzyme inhibition could inhibit tamoxifen conversion to its active metabolite, endoxifen.204
from leptomeningeal metastases and neuropathic pain secondary to therapeutic interventions (postsurgical, radiation therapy, and CIPN) occur in cancer patients. Furthermore, combinations of different sources of pain may also occur. For example, a patient with persistent CIPN-associated pain may develop both central and peripheral sources of pain (brachial plexus tumor infiltration extending to the spinal canal causing cord compression). Management of such pain complaints may require multiple approaches including disease control (chemotherapy, radiation therapy) and symptomatic pharmacologic approaches. Extrapolation of treatment guidelines from noncancer pain patients are not appropriate for the management of oncology-associated neuropathic pain. Data relating to the use of neuropathic pain adjuvant medications for the management or prevention of CIPN-associated pain is inconsistent. Chemotherapeutic agents causing nerve dysfunction mainly target axons, dorsal root ganglia, and terminal trees of intraepidermal nerve fibers.196 Purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, retinoic acid, or vitamin E) for platin drug toxicity were not beneficial.197 Typical medications used for management of CIPN are antidepressants (tricyclics, SNRIs) or antiepileptic drugs (AEDs) (gabapentin, pregabalin). Venlafaxine is a reasonably well-tolerated antidepressant and is a serotonin reuptake inhibitor and weak norepinephrine reuptake inhibitor. Although some studies suggest benefit for use in acute oxaliplatin-induced198 or acute taxane-oxaliplatin-related199 neuropathy, others have found little compelling evidence to support the use of venlafaxine in neuropathic pain.200 Because of the lack of effective management for CIPN, the National Cancer Institute sponsored a series of trials aimed at prevention and management.201 A total of 15 studies were approved, evaluating use of various neuromodulatory agents (including nortriptyline, gabapentin, and lamotrigine) which have shown benefit in other neuropathic pain states. Gabapentin doses were targeted to 2,700 mg per day for a total of 6 weeks. Aside from duloxetine, none demonstrated therapeutic benefit for patients with CIPN. Smith et al.202 studied the effect of duloxetine at initial doses of 30 mg for 1 week then 60 mg for 4 additional weeks for painful CIPN induced by paclitaxel, other taxane, or oxaliplatin. Fifty-nine percent of patients experienced some decrease in pain after 5 weeks of taking duloxetine, and more duloxetine-treated patients decreased their opioid analgesic intake. In a retrospective review on the use of duloxetine for paclitaxel-induced CIPN, some benefit was observed in younger patients, but elderly patients (>60 years) tended to be less responsive and experienced more drug-related adverse events.203 It should also be noted, especially in breast cancer patients, that if duloxetine and tamoxifen are taken together, duloxetine-induced CYP P450 2D6 enzyme inhibition could inhibit tamoxifen conversion to its active metabolite, endoxifen.204
TABLE 43.7 Drugs or Drug Classes with Strong or Weak Recommendations for Management of Neuropathic Pain | |||||||||||||||||||||||||||||||||||||||||||
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BONE PAIN ADJUVANTS
NSAIDs, corticosteroids, calcitonin, radiopharmaceuticals, and bisphosphonates all have a potential place in the treatment of cancer-related bone pain. The use of calcitonin has been disappointing in the management of painful bone metastases.205,206 Dexamethasone is useful for the management of radiationinduced bone pain flares,207 but there is no evidence of benefit for management of painful bone metastases. The risk of bone loss and fractures is increased with systemic glucocorticoid use with the highest rate of bone loss that occurs within the first 3 to 6 months of therapy.208 More than 10% of patients who receive long-term steroid therapy are diagnosed with a fracture, and 30% to 40% have radiographic evidence of vertebral fractures.209 Exposure to steroids is also a leading cause of osteonecrosis (avascular necrosis).210,211
VISCERAL PAIN ADJUVANTS
The literature offers little support for the potential efficacy of adjuvant agents for the management of bladder spasm, tenesmoid pain, and colicky intestinal pain. Although there is no well-established pharmacotherapy for painful rectal spasms, diltiazem can help in the management of proctalgia fugax.212 Inhaled salbutamol also shortened the attack of severe pain in a randomized double-blind trial in 18 patients with proctalgia fugax.213
Most treatments for proctalgia fugax (e.g., oral diltiazem, topical glyceryl nitrate, nerve blocks) act by relaxing the anal sphincter spasm. The effectiveness of these treatments is supported only by case reports or case series.214 For chronic proctitis associated with radiation therapy, anti-inflammatory agents such as sulfasalazine or 5-aminosalicylic acid (mesalamine) are usually first-line treatments, but they have low efficacy even in combination with other agents such as steroids and antibiotics.215 Belladonna and opium suppositories have been used in the management of moderate to severe pain associated with ureteral spasm. The recommended adult dose of belladonna and opium rectal suppositories for the treatment of moderate to severe pain associated with ureteral spasm is 1 suppository (each suppository: belladonna 16.2 mg/opium 30 mg OR belladonna 16.2 mg/opium 60 mg) rectally once or twice a day; maximum of 4 doses per day. Belladonna and opium rectal suppositories have not been found by the FDA to be safe and effective and are not recommended for use.
Most treatments for proctalgia fugax (e.g., oral diltiazem, topical glyceryl nitrate, nerve blocks) act by relaxing the anal sphincter spasm. The effectiveness of these treatments is supported only by case reports or case series.214 For chronic proctitis associated with radiation therapy, anti-inflammatory agents such as sulfasalazine or 5-aminosalicylic acid (mesalamine) are usually first-line treatments, but they have low efficacy even in combination with other agents such as steroids and antibiotics.215 Belladonna and opium suppositories have been used in the management of moderate to severe pain associated with ureteral spasm. The recommended adult dose of belladonna and opium rectal suppositories for the treatment of moderate to severe pain associated with ureteral spasm is 1 suppository (each suppository: belladonna 16.2 mg/opium 30 mg OR belladonna 16.2 mg/opium 60 mg) rectally once or twice a day; maximum of 4 doses per day. Belladonna and opium rectal suppositories have not been found by the FDA to be safe and effective and are not recommended for use.
Psychotropic Drugs
Psychoactive substances are substances that affect mental processes, for example, cognition or affect. This and its equivalent, psychotropic drug, are the most neutral and descriptive term for the whole class of substances, licit and illicit, of interest to drug policy. In a large population study in The Netherlands, cancer patients were often prescribed psychotropic drugs including benzodiazepines, antidepressants, and antipsychotics.216 The pattern of use was more common soon after diagnosis with increases in the terminal stage of the disease. The presence of pain and (to a greater extent) poor pain control were associated with increased use of certain psychotropic drugs, such as anxiolytics and hypnotics.217 Use of hypnotics or anxiolytics drugs is associated with increased mortality and should be used cautiously.218,219,220,221 Among drugs most frequently involved in drug overdose deaths in the United States, alprazolam and diazepam are featured.222 Concurrent benzodiazepine use was also associated with an increased risk of death from overdose in patients receiving opioids.33 Cancer patients often require the use of a psychoactive drug. Some need it for pain relief (e.g., tricyclic antidepressants for nerve injury pain), whereas others need an antiemetic (e.g., lorazepam for CINV). Still, others require an anxiolytic, such as clonazepam or alprazolam. Some require a night sedative and others an antidepressant for identifiable depression. The concurrent use of two centrally acting drugs (e.g., opioid with psychotropic drug or two psychotropic drugs together) is more likely to produce sedation in ill and malnourished cancer patients than in others. A comprehensive review of psychotropic drugs in pain management appears in Chapters 31 and 81.
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