Chapter 58: Pain Management and Symptom Control

Cancer is frequently associated with a host of distressing physical and psychosocial symptoms that can occur throughout the disease trajectory (¹). Access to a multidisciplinary supportive care service is imperative for patients with cancer experiencing distressing symptoms, including fatigue, pain, anorexia, nausea, dyspnea, anxiety, depression, and weight loss, to improve the quality of life of patients. Without optimal symptom control, administration of anticancer therapies may be delayed or discontinued (Table 58-1).

Uncontrolled pain has been reported by 42% of patients seen in the outpatient cancer center (¹) and 50% of hospitalized patients with cancer (²). Pain was the most common symptom (82%) among patients with cancer referred to a palliative care service (³). In patients with cancer, pain may be the only symptom present prior to diagnosis and can indicate the recurrence or spread of the disease.

As many as 30% to 50% of patients receiving active anticancer therapy experience pain (¹). Pain resulting from the tumor burden occurs in approximately 65% to 85% of patients with advanced cancer (⁴). In addition, treatment-related pain is reported by approximately 15% to 25% of patients, and 3%-10% of patients with cancer develop chronic nonmalignant pain syndromes similar to the general population (eg, low back pain associated with degenerative disk disease).

Pathophysiology

The pathophysiologic classification of pain forms the basis for therapeutic choices. Pain may be broadly divided into those associated with ongoing tissue damage (nociceptive) and those resulting from nervous system dysfunction (neuropathic). Nociceptive pain can be classified as either somatic or visceral and results from the activation of nociceptors in cutaneous or deep tissues. Nociceptive pain is described by patients as localized aching, throbbing, and gnawing discomfort. Visceral pain is the result of activation of nociceptors resulting from distention, stretching, and inflammation of internal organs. It is often poorly localized discomfort, described as a deep aching or cramping or a pressure-like sensation. An example of visceral pain is abdominal pain due to pancreatic cancer. Breakthrough pain is defined as a transitory exacerbation of discomfort that occurs on a background of stable persistent chronic pain. Causes of breakthrough pain include end-of-dose failure of opioids and pain exacerbation by activity or spontaneous occurrence. Breakthrough pain is also characterized by a short duration, often less than 3 minutes in 43% of cases according to previous prospective surveys (⁵).

Classification of pain can help guide selection of appropriate interventions to improve pain control; however, they have not been universally accepted. Pain mechanism, incidental occurrences, psychological distress, addictive behavior, and cognitive dysfunction have been indicated as factors associated with higher ratings of pain intensity (⁶). The revised Edmonton Classification System for Cancer Pain (Fig. 58-1) characterizing these factors has been used at our institution to guide pain management.

Pain Assessment

Pain can be measured by using visual, analogue, verbal, or numerical scales and, in the research setting, complex pain questionnaires (⁷). The Edmonton Symptom Assessment Scale is a useful assessment tool that allows patients to rate pain between 0 and 10 over the past 24 hours, where 0 signifies no pain and 10 is the worst pain imaginable. Effective pain assessments can be converted into graphic displays of pain and incorporated with other symptoms, allowing quick dissemination of information regarding a patient’s symptom burden to all health-care providers (Fig. 58-2). Pain assessment needs to take into account other symptoms experienced by patients with cancer because they are often are interconnected.

In 1984, the World Health Organization (WHO) proposed an analgesic ladder for the pharmacologic management of cancer pain (⁸) and has shown that the simple principle of escalating from nonopioid to strong opioid analgesics is safe and effective (Fig. 58-3). Other guidelines have been published, such as the Analgesic Quantification Algorithm and National Comprehensive Cancer Network guidelines for treating cancer pain (⁹).

Principles of Management

• Assess pain syndromes and other symptoms accurately.

• Respect and accept the complaint of pain as real.

• Treat pain appropriately.

• Treat underlying disorders.

• Address psychosocial concerns.

• Multidisciplinary approach is essential.

Principles of Pharmacotherapy

• Match the drug to the pain syndrome.

• Low threshold to prescribe opioids for cancer pain.

• Use sustained-release formulations for constant, chronic pain and short acting for breakthrough discomfort.

• Use adjunct medications for certain pain syndromes.

• Use an oral route for analgesics if possible.

• Use an intravenous route for acute titration.

• Sequential opioid trials are often beneficial.

• Become familiarized with equianalgesic dosing.

• Become familiarized with the pharmacokinetics of opioids.

• Differentiate between tolerance, physical dependence, and addiction.

• Use caution with opioid and adjuvant drug titration in the setting of renal impairment.

Constipation Prevention and Treatment

A bowel regimen should always be prescribed with an opioid prescription because of the constipation opioids induce.

• Always include stimulant laxatives to prevent opioid-induced constipation.

• Preferred choices include sennosides and polyethylene glycol.

• Decreased motility, gastroparesis, is a common side effect of opioids and can be treated with metoclopramide.

• Activity and adequate hydration are important.

• Bulking agents without a prokinetic may worsen constipation.

• Refractory constipation may be managed with lactulose 30 mL by mouth every 6 h until a large bowel movement occurs.

• Intractable cases may require a suppository or enema.

• Proximal impaction may require oral laxatives.

• In rare cases of hard stools present in the vault, manual disimpaction may be necessary.

• Constipation may be evaluated with imaging to assess the degree of severity of constipation (Fig. 58-4).

Opioid Rotation

Opioid rotation is the switching from one type of opioid to another in the setting of opioid neurotoxicity. The following are reasons to rotate opioids:

• Uncontrolled pain despite escalating opioid doses

• Development of tolerance or dose-limiting side effects of opioid neurotoxicity (hallucinations, confusion, myoclonus)

• Hyperalgesia as a result of the production of excitatory amino acids from the opioid itself

• Cost necessitating switching of opioid

Opioid rotation has been shown to not only improve pain control, resolve delirium, and alleviate myoclonus, but also may improve other symptoms, including depression and insomnia (¹⁰).

In a recent study of an outpatient population of 114 patients with cancer at MD Anderson Cancer Center with mean Eastern Cooperative Oncology Group (ECOG) performance status of 1, opioid rotation for side effects or uncontrolled pain achieved improved symptom control successfully in 65% of the patient population (¹⁰).

Individual variability of opioid activation of multiple subtypes of opioid receptors accounts for the benefits of opioid rotation that should be considered when managing uncontrolled pain (^11,12). In difficult cases, this may include rotation on two or three occasions to reduce opioid neurotoxicity and improve pain control.

The following are general guidelines for opioid rotation:

1. Calculate total daily dose.

2. Calculate dose of new opioid using opioid conversion table (Tables 58-2 and 58-3).

3. Reduce dose of new opioid by 30% to 50% to account for incomplete cross tolerance.

Codeine

Codeine is a prodrug used to treat mild-to-moderate pain, diarrhea, and intractable coughing spells. It is the second most common alkaloid in opium and is hypothesized to be 200 times less potent than morphine. Metabolism by the liver converts 90% of the drug to inactive metabolites and 10% as morphine. The cytochrome oxidase 2D6 (CYP2D6) gene is responsible for the conversion to morphine and, in some groups, may not be fully active, while others may express multiple copies of the gene and be considered ultrarapid metabolizers (¹³). These ultrarapid metabolizers have greater risk of opioid neurotoxicity due to codeine rapidly metabolizing into morphine, especially in the pediatric population. On the other hand, patients who have decreased metabolization may experience ineffective analgesia with the drug.

In addition, some medications are CYP2D6 inhibitors and block conversion of codeine to morphine when coadministered. These include the antidepressants paroxetine, fluoxetine, buproprion, and diphenhydramine. Medications known to increase CYP2D6, such as dexamethasone, should also be used with caution with codeine (Fig. 58-5).

Hydrocodone

Hydrocodone has historically been considered a weak opioid on the WHO ladder. It is manufactured commonly in combination with acetaminophen or ibuprofen. It is a semisynthetic opioid derived from codeine and is metabolized by the liver and excreted in the urine. Hydrocodone is metabolized by cytochrome P450 2D6 to hydromorphone. Recent studies have shown that hydrocodone, when taken at doses of less than 40 mg per day, is equivalent to one and half the strength of morphine; however, the ratio of morphine to hydrocodone at doses greater than or equal to 40 mg per day have been shown to be closer to 1:1 (¹⁴) (Fig. 58-6).

Morphine

Morphine is commonly used as a standard prototype drug for opioid pain management. It is a naturally occurring opioid purified from opium poppy seeds and is available in short- and long-acting preparations. In the liver, it is converted to morphine-3-glucoronide and morphine-6-glucoronide (M3G and M6G, respectively) by glucuronyl transferase. Morphine-3-glucoronide is responsible for excitatory neurotoxic side effects, including myoclonus, hallucinations, seizures, and confusion and accumulates with renal insufficiency. Morphine is available as oral, rectal, intramuscular, intravenous, and sublingual preparations (Fig. 58-7).

Hydromorphone

Hydromorphone is a semisynthetic opioid derived from morphine and is five to seven times more potent. It is available for administration via all routes, including neuroaxial. It may be an alternative to morphine when dose-limiting side effects require rotation to a more potent opioid. Long-acting formulations are available, known by the trade name Exalgo, but are expensive.

Oxycodone

Oxycodone is another semisynthetic opioid derived from thebaine, a minor natural component of opium similar to morphine and codeine. Oxycodone has been known to be 1.5 times more potent than morphine. Previously, its dosage was limited by its combination with acetaminophen or aspirin, but now it is commonly available as oxycodone by itself as a pill in the United States. It has a higher bioavailability than morphine and exists both as extended-release and short-acting formulations.

Oxymorphone

Oxymorphone is produced after the CYP2D6 metabolism of oxycodone. It is a semisynthetic opioid and, like oxycodone, is also derived from thebaine. It has a low bioavailability orally and is three times more potent than morphine. Its maximum serum concentration is reached in 30 minutes, and the effects of immediate-release tablets may last up to 6 to 8 hours. Extended-release oxymorphone effects last 12 hours, and it should be dosed as such due to its long half-life of 14 hours. Oxymorphone should be given on an empty stomach because coadministration with food can result in increased absorption and result in opioid toxicities.

Meperidine

Meperidine (Demerol) is a weaker opioid with a potency 1/10 that of morphine. Dose escalation is limited by the risk of accumulation of the metabolite nor-meperidine, metabolized by the liver. Both meperidine and nor-meperidine cause central nervous system toxicity, including convulsions, especially in renal impairment and in the geriatric population. Due these risks, it is becoming less commonly used.

Fentanyl

Fentanyl is a synthetic opioid that is 80 to 100 times more potent than morphine and has a rapid onset and short duration of analgesia. It is used often in the setting of acute or incidental breakthrough pain. Transdermal sustained-release formulations, fentanyl patches, are a good choice for stable pain and are changed every 72 hours. Fentanyl patches are convenient in patients with oral routes that are limited or unavailable. Oral transmucosal fentanyl has been used for breakthrough pain; however, fentanyl has a very rapid onset of action, which makes it difficult to calculate total dose delivered, and erratic equianalgesic dosing often raises safety concerns.

Methadone

Methadone is a synthetic opioid. Recent research (¹⁵) has characterized appropriate equianalgesic dosing (^16,17), and advantages include low cost, less-active metabolites, good bioavailability, and N-methyl-D-aspartate antagonism, which may account for the absence of the development of tolerance associated with chronic use. Methadone potency can be 10 to 15 times that of morphine; thus, caution should be exercised when rotating to methadone. Close monitoring when initiated is necessary due to its tendency to accumulate as time advances before reaching a steady state. The half-life varies with the individuals; it can be between 15 and 190 hours. Clinicians prescribing methadone should be aware of potential drug interactions due to metabolism via the cytochrome P450 system, with these drugs including antifungals, antiretrovirals, and selective serotonin inhibitors (¹⁸). Methadone also has been associated with QTc interval prolongation (^19,20), so proper cardiac monitoring is indicated. Prospective studies at MD Anderson Cancer Center found it to be safe in advanced cancer (²¹). It is being researched as a viable first-line treatment option for pain management (²²) and is especially useful in refractory cancer pain (²³).

Adjuvant Medications

Although opioids are often first-line analgesics, adjuvant medications are useful for pain control in some settings, such as neuropathic pain. Due to the delay in onset as well as side effects with some drug groups, adjuvant drugs may be best reserved after optimal trials of opioids. Of the tricyclic antidepressants drug class, nortriptyline is felt to be the most efficacious and has less cardiovascular side effects. Tricyclic antidepressants are limited by anticholinergic and sedative side effects. Anticonvulsants are helpful in treating brachial and lumbosacral plexopathies. Side effects and safety limit their wide use. For the adjuvant treatment of neuropathic pain, gabapentin has been shown to be effective but does require dose adjustment in renal failure. Pregabalin has been used as an alternative to gabapentin but is costly and has not shown greater efficacy (Table 58-4).

Nonpharmacologic Treatment

Adjuvant nonpharmacological treatments include nerve blocks, neurosurgical procedures, and radiation therapy. Physical and psychological interventions to treat pain include counseling, psychotherapy, relaxation techniques, massage therapy, music therapy, and acupuncture. Addressing psychosocial and spiritual distress for both patients and family may be needed for patients with cancer experiencing complex, total pain at the end of life (Table 58-5).

Fatigue is among the most common and distressing symptoms encountered in approximately 60% to 90% of patients with cancer (²⁴). The National Comprehensive Cancer Network defines cancer-related fatigue as a persistent subjective sense of physical, emotional, as well as cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and is both distressing and interferes with usual function (²⁵). Fatigue may include a lack of interest and difficulty maintaining attention, concentration, or motivation in objects or activities (Table 58-6). Patients may present with depressed mood, have a flat affect, and appear lethargic or somnolent. Rest or sleep does not eliminate or alleviate symptoms of cancer-related fatigue.

Fatigue may be experienced at any point in the cancer trajectory and often worsens at the end of life. Cancer-related fatigue may render patients unable to tolerate physical or mental activity, resulting in an inability to complete activities of daily living, impairment in social and occupational function, and diminished overall quality of life. Fatigue may also heighten other symptoms associated with cancer.

The etiology of cancer-related fatigue is often multifactorial (Fig. 58-8), including not only the underlying cancer itself but also treatments such as chemotherapy or radiation therapy. Fatigue may be exacerbated by other underlying metabolic abnormalities, such as hypothyroidism or hypogonadism, and can be amplified by psychosocial distress (see Fig. 58-8).

Fatigue Assessment

Assessment of fatigue requires a multidimensional approach. Fatigue severity is included on the Edmonton Symptom Assessment Scale, where 0 equals no fatigue and 10 equals the worst fatigue imaginable (see Fig. 58-2). Other numeric and verbal rating scales have been validated for fatigue, including the Functional Assessment of Cancer Therapy–Fatigue, Piper Fatigue Scale, Schwartz Cancer Fatigue Scale, Fatigue Symptom Inventory, and Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F).

Significant fatigue, diminished energy, or increased need to rest disproportionate to any recent change in activity level must be present in addition to five or more of the other symptoms present daily or nearly every day during the same 2-week period in the past month (²⁶).

Cancer-related fatigue should not primarily be a consequence of comorbid psychiatric disorders, which must be excluded, including major depression, somatization disorder, somatoform disorder, or delirium.

Fatigue Management

The initial assessment of fatigue should focus on contributing factors that can be corrected, such as hypothyroidism, anemia, B₁₂ deficiency, and renal insufficiency. Treatment of cancer-related fatigue should be considered only after correction of underlying etiologies (^27,28). Treatment of pain, depression, anxiety, sleep disturbances, dehydration, and cancer anorexia-cachexia syndrome are critical to improve symptoms of fatigue. Medications that exacerbate fatigue should be reviewed and, if indicated, discontinued; underlying infections should be aggressively treated; and patients with symptomatic anemia should receive blood transfusions when appropriate (²⁸).

Corticosteroids

Low-dose steroids may alleviate some symptoms of fatigue. Recent studies have confirmed their short-term benefit; however, more studies are required to determine the optimal dose (²⁹).

Methylphendiate

Psychostimulants such as methylphenidate may be useful if the patient is experiencing concomitant problems, such as depression or drowsiness related to opioids (^30,31,32). However, a recent randomized trial examining methylphenidate reported no significant difference in median FACIT-F scores in regard to cancer-related fatigue when compared with a placebo (³³).

Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) may improve fatigue; however, their benefit has not been proven and may be indirectly related to the treatment of underlying mood disorder. A Cochrane review that included two double-blind, placebo-controlled studies (n = 645) using paroxetine in a meta-analysis did not show any significant improvement in fatigue in patients with cancer (³⁴).

Testosterone Replacement

Recently, there has been evidence that patients with cancer with hypogonadism on chronic opioid therapy may benefit from testosterone replacement (³⁵). A pilot study of testosterone replacement at 4 weeks in hypogonadal males with advanced cancer did not have significant improvement of fatigue as measured with FACIT-F, although there was a trend for improvement with longer duration of treatment (³⁶).

Homeopathic Dietary Supplements

Studies have evaluated dietary supplements for treatment of fatigue. Ginseng has been used medicinally in the Far East for several millennia and is a widely used supplement to treat fatigue in the United States. The composition of the active ingredients of ginseng root (ginsenosides and saponins) varies, and standardization can be problematic. A recent double-blind, randomized controlled trial of 132 patients with either a mixed solid tumor or cancer survivors has shown significant improvement in fatigue scores when patients were prescribed American ginseng, 2,000 mg daily, for at least 4 weeks (³⁷). Other potentially promising homeopathic supplements include guarana extract and L-carnitine.

Integrative Nonpharmacological Interventions

Exercise therapy, such as brisk walking, may help with fatigue. In a recent meta-analysis of randomized trials examining supervised exercise therapy supported exercise improving cancer-related fatigue. These findings suggest that combined aerobic and resistance exercise regimens, with or without stretching, should be included as part of rehabilitation programs for patients with cancer (³⁸). Yoga has also been studied for the treatment of cancer-related fatigue with some positive results, although level of bias and inconsistent methods in previous randomized studies may have influenced results (³⁹). Indirect natural light (⁴⁰) and massage therapy may also help to reduce fatigue.

In addition, treatment of fatigue should address underlying psychosocial factors such as depression, anxiety, as well as other symptoms, including pain, cachexia, or dyspnea, to be effective. Cognitive-behavioral therapy, in treating psychosocial distress or insomnia, may indirectly improve symptoms of fatigue. In the future, multimodality treatment of cancer-related fatigue should be personalized for each individual cancer patient, and more research is needed to develop successful interventions.

The anorexia-cachexia syndrome (Figs. 58-9 and 58-10) is characterized by a loss of appetite coinciding with significant weight loss; loss in lean body mass, including muscle wasting; loss of fat; fatigue; immune dysfunction; and metabolic derangements. Cancer cachexia has been defined as a multifactorial syndrome of ongoing skeletal muscle mass atrophy with or without the loss of fat mass that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Diagnosis of cachexia has been agreed on by a panel of experts as a weight loss greater than 5% or weight loss greater than 2% in individuals already with a body mass index (BMI) less than 20 (⁴¹). Studies have shown that even a loss of 5% or more of premorbid weight prior to chemotherapy is associated with shorter survival (⁴²).

Cachexia is found in the majority of patients with advanced cancer and is a major contributing factor to death in about 50% of these patients (⁴²). Complex interactions between tumor and host lead to an aberrant immune response, neurohormonal dysfunction, and endocrine dysregulation. Both cachexia and fatigue are associated with increased proinflammatory cytokines (interleukin [IL] 1, IL-6, tumor necrosis factor alpha), low testosterone levels, abnormal cortisol secretion, and resistance to insulin and ghrelin (⁴³). These cellular derangements are associated with increased production of acute-phase proteins in the liver and loss of muscle protein due to proteolysis and lipolysis and results in elevated triglycerides and decreased high-density lipoproteins.

Unfortunately, neither nutritional supplementation nor artificial feeding reverses the cancer anorexia-cachexia syndrome (⁴³). Multiple studies have examined the role of total parenteral and enteral nutrition in patients with cancer and have reported limited benefits. Artificial feeding of patients with cancer with cachexia was found to increase acute-phase protein production without influencing the rate of albumin synthesis (⁴⁴). Other contributory factors resulting in weight loss (ie, depression, nausea, dysphagia, bowel obstruction, or constipation) should be treated aggressively.

Treating patients in the early stages of weight loss may be important to maintain or increase lean body mass because it is difficult to reverse cachexia in late stages (⁴³). A comprehensive history, including recent changes in weight and diet patterns, is important. Simple and inexpensive tests are available to assess body composition, such as anthropometric measurements, skinfold thickness, arm muscle circumference and area, and weight and BMI. Laboratory markers such as electrolytes, serum albumin, transferrin, and prealbumin may also be useful.

Management

For management, identify etiology and treat the underlying cause:

• Treat nausea/early satiety: metoclopramide 5 to 10 mg every 4 to 6 hours (renal adjustment required) (see Table 58-7 for nausea agents)

• Progestational agents

  • – Megestrol acetate: 40 to 120 mg by mouth four times a day (risk of thromboembolism, hypogonadism, and adrenal suppression)

• Corticosteroids

  • – Dexamethasone: 4 mg by mouth twice a day (lower mineralocorticoid effect than other steroids (⁴³)

• For patients with cancer with depression: use antidepressants such as tricyclic antidepressants and SSRIs (ie, mirtazapine 15 mg by mouth at bedtime)

Nutritionist Consultation

Counseling and psychosocial support for cachectic patients and their family caregivers are critical at the end of life and will decrease patient-family conflict. Counseling should emphasize the pleasure of eating as well as promote the social participation of patients in family meals as opposed to increasing caloric intake. Counseling should highlight the normal loss of appetite as patients, who are often not hungry, approach the end of life, and family caregivers should not pressure patients to eat, which can result in nausea and psychological distress.

Dyspnea is a subjective symptom defined as an “uncomfortable awareness of breathing” (⁴⁵). It is often described as a sensation of air hunger, suffocation, choking, or heavy breathing. Dyspnea may be related to underlying tumor progression, altered by psychosocial factors, including anxiety, and exacerbated by preexisting pulmonary comorbidities. Shortness of breath can develop in response to pain or a mismatch between perceived ventilation rate and respiratory drive. Dyspnea is considered refractory when it persists at rest or with minimal activity and is distressful despite optimal medical therapy (⁴⁶).

Dyspnea in patients with advanced cancer is an indicator of poor prognosis (^47,48). The etiology of dyspnea is often multifactorial. It is postulated that in the brain, the cortical-limbic network is responsible for dyspnea perception. Recent research reported that the anterior cingulate cortex and the dorsolateral prefrontal cortex are involved in sensing dyspnea (⁴⁹). In addition, the insular cortex is modulated by sensations of dyspnea, and studies of patients with asthma have shown that it is downregulated in patients experiencing dyspnea as well as pain (⁵⁰).

Treatment of Dyspnea

The aim of treatment of dyspnea is to improve the patient’s perception of shortness of breath and involves not only treating the underlying cause but also palliating symptoms of air hunger. Treating the underlying etiologies can vary from thoracentesis for a pleural effusion, blood transfusions for anemic patients, corticosteroids for systemic inflammation or lymphangitic carcinomatosis, or antibiotics for pneumonia.

Symptomatic relief may include oxygen therapy, bilevel positive airway pressure, or high-flow oxygen therapy (⁵¹). In patients with chronic obstructive pulmonary disease (COPD), long-term oxygen therapy has shown mortality reduction but does not necessarily improve dyspnea. Palliative oxygenation is often prescribed irrespective of oxygen saturations. Oxygen delivery by nasal cannula does not always equate to relief of dyspnea in nonhypoxemic patients with advanced illness when compared with room air.

Pharmacological interventions for dyspnea include opioids, benzodiazepines, and corticosteroids and are often utilized when medical therapy fails to improve the perception of dyspnea. Opioids, when titrated carefully, will often improve dyspnea without reducing oxygenation or causing respiratory depression (⁴⁹). Immediate-release, short-acting, and sustained-release morphine have been used in clinical trials of dyspnea management. The American Thoracic Society and the Canadian Thoracic Society advocate opioid dose titration to achieve the lowest effective dose based on patient ratings of shortness of breath (⁴⁹).

Corticosteroids are most useful in situations of lymphangitic spread or inflammation causing obstruction of airways (⁵²). Bronchodilators may also play a role when dyspnea is related to bronchospasm and reduce airway smooth muscle tone, thereby improving airflow and deflating an overinflated lung (⁴⁹). Tachycardia is a common side effect of bronchodilators.

Integrative approaches may also be effective, such as relaxation techniques or guided imagery, for patients with anticipatory or anxiety-driven dyspnea. Low-dose benzodiazepines in conjunction with opioids may have a role in the treatment of dyspnea complicated by severe anxiety, but they have the potential to cause delirium and decrease respiratory drive (⁵³). Acupuncture has also been researched for the treatment of dyspnea. In a study by Jones and colleagues (⁵⁴), one 45-minute session of transcutaneous electrical nerve stimulation at acupuncture sites resulted in improvement of dyspnea, increased FEV₁ (forced expiratory volume in first second of expiration) and blood levels of β-endorphin compared with placebo. Suzuki and colleagues reported exertional dyspnea was reduced in patients with COPD after receiving acupuncture once a week for 12 weeks compared to placebo (⁵⁵). Assist devices can be used to minimize muscular effort: postural drainage, a fan with airflow directed to the face (⁵⁶). Incentive spirometry can also help in certain settings.

Delirium, an acute state of encephalopathy, results from diffuse organic brain dysfunction. The prevalence of delirium is approximately 10% in hospitalized medical and surgical patients and is noted in 26% to 44% of patients with advanced cancer at the time of hospital admission. Roughly half of these cases may be reversible. In patients with advanced cancer, over 80% of patients will develop delirium at the end of life (⁵⁷). Delirium is often misdiagnosed and associated with increased morbidity and mortality (⁵⁸). It complicates assessment of pain and other symptoms and results in distress for patients, family caregivers, and health-care providers.

Clinical Presentation of Delirium

Delirium is characterized by waxing-and-waning mentation. The main diagnostic criteria, according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) (DSM-IV-TR), include a disturbance of consciousness with reduced ability to focus, sustain, or shift attention; a change in cognition (disorientation/language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting dementia; and a disturbance that develops over a short period of time (hours to days) and fluctuates during the course of the day. Three clinical variants of delirium have been designated based on type of arousal disorder: hypoactive, hyperactive, and mixed.

Delirium Assessment

Delirium is often misdiagnosed as anxiety, insomnia, worsening pain, or mood disturbance, resulting in inappropriate treatment with anxiolytics or hypnotics, inappropriate increase in opioids, or use of antidepressants, which can worsen symptoms. Maintaining a high index of suspicion can help to avoid misdiagnosis of delirium, and routine use of screening tools such as the Memorial Delirium Assessment Scale or Mini-Mental State Examination is recommended. Clinicians should pay attention to metabolic derangements that may precipitate delirium, such as liver or renal failure. Medications may be the cause as well and include opioids (responsible for almost 60% of cases in patients with cancer [⁵⁹]), benzodiazepines, some antiemetics, and corticosteroids (Fig. 58-11).

Delirium Management

1. Provide patients a safe environment, including fall precautions; minimize noise and excessive light; place patients in a familiar setting with visible clock and calendar; and have family at bedside to help reorient patients.

2. Treat underlying causes, such as hypercalcemia or pneumonia.

3. Treat agitation (Table 58-8).

4. To treat severe agitation secondary to delirium, it may be necessary to give haloperidol more frequently initially. In patients refractory to haloperidol, a combination of haloperidol and a benzodiazepine may be necessary. However, in a study by Brietbart (⁶⁰), lorazepam alone was ineffective in the treatment of delirium and actually contributed to its worsening and increased cognitive impairment in terminal patients with HIV. Newer atypical antipsychotics may be just as effective as typical antipsychotics but are more expensive. Olanzapine may be more sedating. Sometimes, acute dystonia and extrapyramidal side effects are seen with haloperidol, in which case benztropine can be administered. Once symptoms are under control, reducing haloperidol to the minimal effective dose is recommended (^61,62).

5. Counseling a patient’s family caregivers and health-care providers regarding the patient’s expression of previously well-controlled physical symptoms by grimacing or moaning may be inhibition of emotions due to delirium. In such cases, treatment should be directed at controlling delirium and not inappropriately increasing opioids (Fig. 58-12).

Palliative Sedation

Instances of refractory delirium, as well as other uncontrolled symptoms at the end of life, may require palliative sedation. Palliative sedation is defined as the monitored use of sedative medication to reduce patients’ awareness of intractable and refractory symptoms near the end of life when other interventions have failed to control them (⁶³). It is important to ensure all available symptomatic measures, including consulting palliative medicine specialists, have been tried before deeming symptoms refractory. The goal of palliative sedation is to control symptoms, not hasten death, which is differentiated from physician-assisted euthanasia. Therefore, it is imperative to discuss this with the patient and family caregivers to avoid misunderstanding. Midazolam, titrated to control symptoms, is often used for palliative sedation. Patients need regular assessments, including use of the Richmond Agitation Sedation Scale, to monitor for excessive sedation. If underlying symptoms have improved or been controlled, sedatives may be decreased and even discontinued.

Clinical depression is a common mood disorder encountered in patients with cancer and can affect from 25% to 35% of the patient population (⁶⁴). Clinical depression increases in frequency in advanced disease (⁶⁵), and diagnosis can be challenging in these patients. For instance, symptoms often strongly associated with clinical depression in healthy individuals (including fatigue, impaired decision-making ability, insomnia, and poor appetite) are frequently commonly encountered in patients with advanced disease. Per DSM-IV criteria (⁶⁶), the cardinal features of clinical depression include anhedonia; feelings of guilt, hopelessness, or worthlessness; and suicidal ideation, and a thorough patient history directed at assessment for these symptoms is needed.

In addition, the diagnosis of clinical depression can be difficult to differentiate from adjustment disorder, anticipatory grief, or delirium. Validated measures of assessing depression in the primary care setting include the WHO-5 well-being index (⁶⁷), PHQ-9 screening test (⁶⁸), Hamilton Rating Scale for Depression (HAM-D) (⁶⁹), and Montgomery-Asberg Depression Rating Scale (⁷⁰) (MADRS). Other factors that increase the risk of depression include a history of substance abuse, family history of depression and suicide, concurrent life stressors, and poor social support.

Common antidepressants and their common initial doses are as follows (⁷⁸):

• Nortriptyline 25 mg/d (at bedtime)

• Amitriptyline 25 mg/d (at bedtime)

• Fluoxetine 10 to 20 mg/d

• Paroxetine 10 mg/d

• Sertraline 20 mg/d

• Citalopram 20 mg/d

• Venlafaxine 37.5 mg/d

• Mirtazapine 15 mg/d (at bedtime)

• Methylphenidate 5 to 10 mg in the morning and 5 mg at noon

Escitalopram has a lower side-effects profile and works slightly faster than other first-generation SSRIs. Side effects include reduced appetite, nausea, and anxiety. Antidepressants should be given for a trial of 6 weeks for beneficial effects, and if there is no significant improvement, they may need adjustment of dose or a change to an alternate medication. In patients with cancer with unclear criteria for clinical depression or suicidal ideation, consultation with a psychiatrist is indicated.

The majority of chronically ill patients in the United States want to be informed about their prognosis (⁷⁴) and appreciate being told the truth (⁷²). Health-care providers’ ability to accurately prognosticate life expectancy of patients with cancer is still limited. In addition, a patient’s acceptance of information regarding prognosis and end-of-life issues is heavily influenced by the manner in which this information is conveyed. It is common that health-care professionals feel uncomfortable with discussing prognosis and other end-of-life issues. Reasons include lack of training, stress, feeling rushed and not having enough time to address emotional needs of patients, fear of upsetting the patient or family, or reluctance to diminish hope with regard to the unavailability of further curative treatment. Avoidance of end-of-life discussions can lead to patient dissatisfaction and further psychological distress.

There are few trials testing the effectiveness of different strategies in delivering bad news (⁷⁴). Most recommendations on discussing bad news agree on the following key features: preparing for the discussion, addressing the message content, dealing with the patient’s responses, and ending the encounter (⁷⁴) (Table 58-9).

Important guidelines regarding end-of-life discussions have emphasized the following: identify the reason for discussion and patients’ expectations, elicit their knowledge of the situation, consider cultural awareness and preferences in regard to information, validate feelings and take an empathetic approach, explain information using language without medical jargon, use easy-to-understand terms, explain the limitations of prognostication and end-of-life information, and avoid exact timelines (⁷⁵).

Family meetings are championed by health-care professionals as a tool to improve communication and can be helpful to inform, deliberate, clarify goals, and mediate difficult end-of-life discussions that family members might have in regard to the care of the patient. They can help to formulate acceptable care plans between patient, family caregivers, and health-care providers (⁷⁵) and clarify goals of care so everyone is on the “same page” (⁷⁶) (see Table 58-9).

Spirituality has generally been defined as a way an individual seeks and expresses meaning and purpose in life and how one experiences connectedness to the moment, self, others, nature, and the significant or sacred. While religiosity has been defined as the active participation in an organized religion (⁷⁷), recent studies conducted at MD Anderson have indicated that a majority of our patients identify themselves as being spiritual or religious. Almost all patients report that their spirituality or religious faith is a source of strength and assists with coping with a life-threatening illness. Caregivers have also shown similar patterns of identification with spirituality and religiosity. Caregivers expressed that their spirituality had helped them cope with their loved one’s illness and had a positive impact on their loved one’s physical and emotional well-being (⁷⁷). Patients with increased spiritual distress tend to have an association with a higher physical symptom burden. Acknowledging and addressing spiritual needs can be of value for improved quality of life in patients with advanced cancer.

Health care has traditionally been delivered in a dichotomous model with a focus on curative or life-prolonging treatment followed by an abrupt transition to palliative or hospice care in anticipation of death. In recent years, there has been a renewed emphasis on improving quality of life and integration of supportive care and palliative medicine earlier in the disease trajectory and concurrent with life-prolonging treatments. Integrating palliative care into the current best practice of cancer treatment allows for the prevention and relief of suffering while ensuring dignity during significant illness for both cancer survivors and patients at the end of life.

Patients with cancer will encounter distressing symptoms that can diminish a their quality of life and interfere with the ability to receive cancer therapy. Physical and emotional symptoms are encountered at any point during the illness trajectory from diagnosis, treatment, survivorship, or end of life. An oncologist may be overwhelmed with the challenges of cancer treatment when patients have uncontrolled symptoms. In collaboration with an interdisciplinary palliative care team, health-care providers may simultaneously treat cancer aggressively while maintaining the integrity of human life and diminishing unnecessary suffering.

There is an urgent need to incorporate assessment and treatment of physical and emotional symptoms facing patients with cancer and integrating a palliative medicine team into the delivery of cancer care. For patients with complex symptoms, early adoption of interdisciplinary palliative care can aggressively treat symptoms to prevent the sequelae of physical and emotional pain. In addition, an open dialogue with patients and family caregivers regarding issues of treatment options, prognosis, and end-of-life care, including a transition from focus on curing cancer to care directed at controlling symptoms, is needed along the continuum of cancer treatment.