PHYSICAL SYMPTOMS AND THEIR MANAGEMENT
Great emphasis has been placed on addressing dying patients’ pain. Some institutions have made pain assessment a fifth vital sign to emphasize its importance. This also has been advocated by large health care systems such as the Veterans’ Administration and accrediting bodies such as the Joint Commission. Although this embrace of pain as the fifth vital sign has been symbolically important, no data document that it has improved pain management practices. Although good palliative care requires good pain management, it also requires more. The frequency of symptoms varies by disease and other factors. The most common physical and psychological symptoms among all terminally ill patients include pain, fatigue, insomnia, anorexia, dyspnea, depression, anxiety, and nausea and vomiting. In the last days of life, terminal delirium is also common. Assessments of patients with advanced cancer have shown that patients experienced an average of 11.5 different physical and psychological symptoms (Table 10-4).
TABLE 10-4Common Physical and Psychological Symptoms of Terminally Ill Patients |Favorite Table|Download (.pdf) TABLE 10-4Common Physical and Psychological Symptoms of Terminally Ill Patients
|Physical Symptoms ||Psychological Symptoms |
|Pain ||Anxiety |
|Fatigue and weakness ||Depression |
|Dyspnea ||Hopelessness |
|Insomnia ||Meaninglessness |
|Dry mouth ||Irritability |
|Anorexia ||Impaired concentration |
|Nausea and vomiting ||Confusion |
|Constipation ||Delirium |
|Cough ||Loss of libido |
|Swelling of arms or legs || |
|Itching || |
|Diarrhea || |
|Dysphagia || |
|Dizziness || |
|Fecal and urinary incontinence || |
|Numbness/tingling in hands/feet || |
Evaluations to determine the etiology of these symptoms usually can be limited to the history and physical examination. In some cases, radiologic or other diagnostic examinations will provide sufficient benefit in directing optimal palliative care to warrant the risks, potential discomfort, and inconvenience, especially to a seriously ill patient. Only a few of the common symptoms that present difficult management issues will be addressed in this chapter. Additional information on the management of other symptoms, such as nausea and vomiting, insomnia, and diarrhea, can be found in Chaps. 54 and 99, Chap. 38, and Chap. 55, respectively.
The frequency of pain among terminally ill patients varies widely. Substantial pain occurs in 36–90% of patients with advanced cancer. In the SUPPORT study of hospitalized patients with diverse conditions and an estimated survival ≤6 months, 22% reported moderate to severe pain, and caregivers of those patients noted that 50% had similar levels of pain during the last few days of life. A meta-analysis found pain prevalence of 58–69% in studies that included patients characterized as having advanced, metastatic, or terminal cancer; 44–73% in studies that included patients characterized as undergoing cancer treatment; and 21–46% in studies that included posttreatment individuals.
Nociceptive pain is the result of direct mechanical or chemical stimulation of nociceptors and normal neural signaling to the brain. It tends to be localized, aching, throbbing, and cramping. The classic example is bone metastases. Visceral pain is caused by nociceptors in gastrointestinal, respiratory, and other organ systems. It is a deep or colicky type of pain classically associated with pancreatitis, myocardial infarction, or tumor invasion of viscera. Neuropathic pain arises from disordered nerve signals. It is described by patients as burning, electrical, or shocklike pain. Classic examples are poststroke pain, tumor invasion of the brachial plexus, and herpetic neuralgia.
Pain is a subjective experience. Depending on the patient’s circumstances, perspective, and physiologic condition, the same physical lesion or disease state can produce different levels of reported pain and need for pain relief. Systematic assessment includes eliciting the following: (1) type: throbbing, cramping, burning, etc.; (2) periodicity: continuous, with or without exacerbations, or incident; (3) location; (4) intensity; (5) modifying factors; (6) effects of treatments; (7) functional impact; and (8) impact on patient. Several validated pain assessment measures may be used, such as the Visual Analogue Scale, the Brief Pain Inventory, and the pain component of one of the more comprehensive symptom assessment instruments. Frequent reassessments are essential to assess the effects of interventions.
Interventions for pain must be tailored to each individual, with the goal of preempting chronic pain and relieving breakthrough pain. At the end of life, there is rarely reason to doubt a patient’s report of pain. Pain medications are the cornerstone of management. If they are failing and nonpharmacologic interventions—including radiotherapy and anesthetic or neurosurgical procedures such as peripheral nerve blocks or epidural medications—are required, a pain consultation is appropriate.
Pharmacologic interventions follow the World Health Organization three-step approach involving nonopioid analgesics, mild opioids, and strong opioids, with or without adjuvants (Chap. 18). Nonopioid analgesics, especially nonsteroidal anti-inflammatory drugs (NSAIDs), are the initial treatments for mild pain. They work primarily by inhibiting peripheral prostaglandins and reducing inflammation but also may have central nervous system (CNS) effects. They have a ceiling effect. Ibuprofen, up to a total dose of 1600 mg/d given in four doses of 400 mg each, has a minimal risk of causing bleeding and renal impairment and is a good initial choice. In patients with a history of severe gastrointestinal (GI) or other bleeding, it should be avoided. In patients with a history of mild gastritis or gastroesophageal reflux disease (GERD), acid-lowering therapy such as a proton pump inhibitor should be used. Acetaminophen is an alternative in patients with a history of GI bleeding and can be used safely at up to 4 g/d given in four doses of 1 g each. In patients with liver dysfunction due to metastases or other causes and in patients with heavy alcohol use, doses should be reduced.
If nonopioid analgesics are insufficient, opioids should be introduced. They work by interacting with µ opioid receptors in the CNS to activate pain-inhibitory neurons; most are receptor antagonists. The mixed agonist/antagonist opioids useful for postacute pain should not be used for the chronic pain in end-of-life care. Weak opioids such as codeine can be used initially. However, if they are escalated and fail to relieve pain, strong opioids such as morphine, 5–10 mg every 4 h, should be used. Nonopioid analgesics should be combined with opioids because they potentiate the effect of opioids.
For continuous pain, opioids should be administered on a regular, around-the-clock basis consistent with their duration of analgesia. They should not be provided only when the patient experiences pain; the goal is to prevent patients from experiencing pain. Patients also should be provided rescue medication, such as liquid morphine, for breakthrough pain, generally at 20% of the baseline dose. Patients should be informed that using the rescue medication does not obviate the need to take the next standard dose of pain medication. If after 24 h the patient’s pain remains uncontrolled and recurs before the next dose, requiring the patient to use the rescue medication, the daily opioid dose can be increased by the total dose of rescue medications used by the patient, or by 50% for moderate pain and 100% for severe pain of the standing opioid daily dose.
It is inappropriate to start with extended-release preparations. Instead, an initial focus on using short-acting preparations to determine how much is required in the first 24–48 h will allow clinicians to determine opioid needs. Once pain relief is obtained with short-acting preparations, one should switch to extended-release preparations. Even with a stable extended-release preparation regimen, the patient may have incident pain, such as during movement or dressing changes. Short-acting preparations should be taken before such predictable episodes. Although less common, patients may have “end-of-dose failure” with long-acting opioids, meaning that they develop pain after 8 h in the case of an every-12-h medication. In these cases, a trial of giving an every-12-h medication every 8 h is appropriate.
Because of differences in opioid receptors, cross-tolerance among opioids is incomplete, and patients may experience different side effects with different opioids. Therefore, if a patient is not experiencing pain relief or is experiencing too many side effects, a change to another opioid preparation is appropriate. When switching, one should begin with 50–75% of the published equianalgesic dose of the new opioid.
Unlike NSAIDs, opioids have no ceiling effect; therefore, there is no maximum dose no matter how many milligrams the patient is receiving. The appropriate dose is the dose needed to achieve pain relief. This is an important point for clinicians to explain to patients and families. Addiction or excessive respiratory depression is extremely unlikely in the terminally ill; fear of these side effects should neither prevent escalating opioid medications when the patient is experiencing insufficient pain relief nor justify using opioid antagonists.
Opioid side effects should be anticipated and treated preemptively. Nearly all patients experience constipation that can be debilitating (see below). Failure to prevent constipation often results in noncompliance with opioid therapy. Methylnaltrexone is a drug that targets opioid-induced constipation by blocking peripheral opioid receptors but not central receptors for analgesia. In placebo-controlled trials, it has been shown to cause laxation within 24 h of administration. As with the use of opioids, about a third of patients using methylnaltrexone experience nausea and vomiting, but unlike constipation, tolerance develops, usually within a week. Therefore, when one is beginning opioids, an antiemetic such as metoclopramide or a serotonin antagonist often is prescribed prophylactically and stopped after 1 week. Olanzapine also has antinausea properties and can be effective in countering delirium or anxiety, with the advantage of some weight gain.
Drowsiness, a common side effect of opioids, also usually abates within a week. During this period, drowsiness can be treated with psychostimulants such as dextroamphetamine, methylphenidate, and modafinil. Modafinil has the advantage of everyday dosing. Pilot reports suggest that donepezil may also be helpful for opiate-induced drowsiness as well as relieving fatigue and anxiety. Metabolites of morphine and most opioids are cleared renally; doses may have to be adjusted for patients with renal failure.
Seriously ill patients who require chronic pain relief rarely if ever become addicted. Suspicion of addiction should not be a reason to withhold pain medications from terminally ill patients. Patients and families may withhold prescribed opioids for fear of addiction or dependence. Physicians and health care providers should reassure patients and families that the patient will not become addicted to opioids if they are used as prescribed for pain relief; this fear should not prevent the patient from taking the medications around the clock. However, diversion of drugs for use by other family members or illicit sale may occur. It may be necessary to advise the patient and caregiver about secure storage of opioids. Contract writing with the patient and family can help. If that fails, transfer to a safe facility may be necessary.
Tolerance is the need to increase medication dosage for the same pain relief without a change in disease. In the case of patients with advanced disease, the need for increasing opioid dosage for pain relief usually is caused by disease progression rather than tolerance. Physical dependence is indicated by symptoms from the abrupt withdrawal of opioids and should not be confused with addiction.
Adjuvant analgesic medications are nonopioids that potentiate the analgesic effects of opioids. They are especially important in the management of neuropathic pain. Gabapentin and pregabalin, calcium channel alpha 2-delta ligands, are now the first-line treatments for neuropathic pain from a variety of causes. Gabapentin is begun at 100–300 mg bid or tid, with 50–100% dose increments every 3 days. Usually 900–3600 mg/d in two or three doses is effective. The combination of gabapentin and nortriptyline may be more effective than gabapentin alone. One potential side effect of gabapentin to be aware of is confusion and drowsiness, especially in the elderly. Pregabalin has the same mechanism of action as gabapentin but is absorbed more efficiently from the GI tract. It is started at 75 mg bid and increased to 150 mg bid. The maximum dose is 225 mg bid. Carbamazepine, a first-generation agent, has been proved effective in randomized trials for neuropathic pain. Other potentially effective anticonvulsant adjuvants include topiramate (25–50 mg qd or bid, rising to 100–300 mg/d) and oxcarbazepine (75–300 mg bid, rising to 1200 mg bid). Glucocorticoids, preferably dexamethasone given once a day, can be useful in reducing inflammation that causes pain while elevating mood, energy, and appetite. Its main side effects include confusion, sleep difficulties, and fluid retention. Glucocorticoids are especially effective for bone pain and abdominal pain from distention of the GI tract or liver. Other drugs, including clonidine and baclofen, can be effective in pain relief. These drugs are adjuvants and generally should be used in conjunction with—not instead of—opioids. Methadone, carefully dosed because of its unpredictable half-life in many patients, has activity at the N-methyl-d-aspartamate (NMDA) receptor and is useful for complex pain syndromes and neuropathic pain. It generally is reserved for cases in which first-line opioids (morphine, oxycodone, hydromorphone) are either ineffective or unavailable.
Radiation therapy can treat bone pain from single metastatic lesions. Bone pain from multiple metastases can be amenable to radiopharmaceuticals such as strontium-89 and samarium-153. Bisphosphonates (such as pamidronate [90 mg every 4 weeks]) and calcitonin (200 IU intranasally once or twice a day) also provide relief from bone pain but have an onset of action of days.
Constipation is reported in up to 87% of patients requiring palliative care.
Although hypercalcemia and other factors can cause constipation, it is most frequently a predictable consequence of the use of opioids for the relief of pain and dyspnea and of tricyclic antidepressants, from their anticholinergic effects, and of the inactivity and poor diet that are common among seriously ill patients. If untreated, constipation can cause substantial pain and vomiting and also is associated with confusion and delirium. Whenever opioids and other medications known to cause constipation are used, preemptive treatment for constipation should be instituted.
The physician should establish the patient’s previous bowel habits, including the frequency, consistency, and volume. Abdominal and rectal examinations should be performed to exclude impaction or acute abdomen. A number of constipation assessment scales are available, although guidelines issued in the Journal of Palliative Medicine did not recommend them for routine practice. Radiographic assessments beyond a simple flat plate of the abdomen in cases in which obstruction is suspected are rarely necessary.
Intervention to reestablish comfortable bowel habits and relieve pain and discomfort should be the goals of any measures to address constipation during end-of-life care. Although physical activity, adequate hydration, and dietary treatments with fiber can be helpful, each is limited in its effectiveness for most seriously ill patients, and fiber may exacerbate problems in the setting of dehydration and if impaired motility is the etiology. Fiber is contraindicated in the presence of opioid use. Stimulant and osmotic laxatives, stool softeners, fluids, and enemas are the mainstays of therapy (Table 10-5). In preventing constipation from opioids and other medications, a combination of a laxative and a stool softener (such as senna and docusate) should be used. If after several days of treatment, a bowel movement has not occurred, a rectal examination to remove impacted stool and place a suppository is necessary. For patients with impending bowel obstruction or gastric stasis, octreotide to reduce secretions can be helpful. For patients in whom the suspected mechanism is dysmotility, metoclopramide can be helpful.
TABLE 10-5Medications for the Management of Constipation |Favorite Table|Download (.pdf) TABLE 10-5Medications for the Management of Constipation
|Intervention ||Dose ||Comment |
|Stimulant laxatives || ||These agents directly stimulate peristalsis and may reduce colonic absorption of water. |
| Prune juice ||120–240 mL/d ||Work in 6–12 h. |
| Senna (Senokot) ||2–8 tablets PO bid || |
| Bisacodyl ||5–15 mg/d PO, PR || |
|Osmotic laxatives || ||These agents are not absorbed. They attract and retain water in the gastrointestinal tract. |
| Lactulose ||15–30 mL PO q4–8h ||Lactulose may cause flatulence and bloating. |
| Magnesium hydroxide (Milk of Magnesia) ||15–30 mL/d PO ||Lactulose works in 1 day, magnesium products in 6 h. |
| Magnesium citrate ||125–250 mL/d PO || |
|Stool softeners || ||These agents work by increasing water secretion and as detergents, increasing water penetration into the stool. |
| Sodium docusate (Colace) ||300–600 mg/d PO ||Work in 1–3 days. |
| Calcium docusate ||300–600 mg/d PO || |
|Suppositories and enemas || || |
| Bisacodyl ||10–15 PR qd || |
| Sodium phosphate enema ||PR qd ||Fixed dose, 4.5 oz, Fleet’s. |
Up to 70% of patients with advanced cancer have nausea, defined as the subjective sensation of wanting to vomit.
Nausea and vomiting are both caused by stimulation at one of four sites: the GI tract, the vestibular system, the chemoreceptor trigger zone (CTZ), and the cerebral cortex. Medical treatments for nausea are aimed at receptors at each of these sites: the GI tract contains mechanoreceptors, chemoreceptors, and 5-hydroxytryptamine type 3 (5-HT3) receptors; the vestibular system probably contains histamine and acetylcholine receptors; and the CTZ contains chemoreceptors, dopamine type 2 receptors, and 5-HT3 receptors. An example of nausea that most likely is mediated by the cortex is anticipatory nausea before a dose of chemotherapy or other noxious stimuli.
Specific causes of nausea include metabolic changes (liver failure, uremia from renal failure, hypercalcemia), bowel obstruction, constipation, infection, GERD, vestibular disease, brain metastases, medications (including antibiotics, NSAIDs, proton pump inhibitors, opioids, and chemotherapy), and radiation therapy. Anxiety can also contribute to nausea.
Medical treatment of nausea is directed at the anatomic and receptor-mediated cause that a careful history and physical examination reveals. When a single specific cause is not found, many advocate beginning treatment with a dopamine antagonist such as haloperidol or prochlorperazine. Prochlorperazine is usually more sedating than haloperidol. When decreased motility is suspected, metoclopramide can be an effective treatment. When inflammation of the GI tract is suspected, glucocorticoids such as dexamethasone are an appropriate treatment. For nausea that follows chemotherapy and radiation therapy, one of the 5-HT3 receptor antagonists (ondansetron, granisetron, dolasetron, palonosetron) is recommended. Studies suggest palonosetron has higher receptor binding affinity and clinical superiority to the other 5-HT3 receptor antagonists. Clinicians should attempt prevention of postchemotherapy nausea rather than provide treatment after the fact. Current clinical guidelines recommend tailoring the strength of treatments to the specific emetic risk posed by a specific chemotherapy drug. When a vestibular cause (such as “motion sickness” or labyrinthitis) is suspected, antihistamines such as meclizine (whose primary side effect is drowsiness) or anticholinergics such as scopolamine can be effective. In anticipatory nausea, a benzodiazepine such as lorazepam is indicated. As with antihistamines, drowsiness and confusion are the main side effects.
Dyspnea is a subjective experience of being short of breath. Frequencies vary among causes of death, but it can affect 80–90% of dying patients with lung cancer, COPD, and heart disease. Dyspnea is among the most distressing physical symptoms and can be even more distressing than pain.
As with pain, dyspnea is a subjective experience that may not correlate with objective measures of Po2, Pco2, or respiratory rate. Consequently, measurements of oxygen saturation through pulse oximetry or blood gases are rarely helpful in guiding therapy. Despite the limitations of existing assessment methods, physicians should regularly assess and document patients’ experience of dyspnea and its intensity. Guidelines recommend visual or analogue dyspnea scales to assess the severity of symptoms and the effects of treatment. Potentially reversible or treatable causes of dyspnea include infection, pleural effusions, pulmonary emboli, pulmonary edema, asthma, and tumor encroachment on the airway. However, the risk-versus-benefit ratio of the diagnostic and therapeutic interventions for patients with little time left to live must be considered carefully before one undertakes diagnostic steps. Frequently, the specific etiology cannot be identified, and dyspnea is the consequence of progression of the underlying disease that cannot be treated. The anxiety caused by dyspnea and the choking sensation can significantly exacerbate the underlying dyspnea in a negatively reinforcing cycle.
When reversible or treatable etiologies are diagnosed, they should be treated as long as the side effects of treatment, such as repeated drainage of effusions or anticoagulants, are less burdensome than the dyspnea itself. More aggressive treatments such as stenting a bronchial lesion may be warranted if it is clear that the dyspnea is due to tumor invasion at that site and if the patient and family understand the risks of such a procedure. Usually, treatment will be symptomatic (Table 10-6). A dyspnea scale and careful monitoring should guide dose adjustment. Low-dose opioids reduce the sensitivity of the central respiratory center and the sensation of dyspnea. If patients are not receiving opioids, weak opioids can be initiated; if patients are already receiving opioids, morphine or other strong opioids should be used. Controlled trials do not support the use of nebulized opioids for dyspnea at the end of life. Phenothiazines and chlorpromazine may be helpful when combined with opioids. Benzodiazepines can be helpful if anxiety is present but should be neither used as first-line therapy nor used alone in the treatment of dyspnea. If the patient has a history of COPD or asthma, inhaled bronchodilators and glucocorticoids may be helpful. If the patient has pulmonary edema due to heart failure, diuresis with a medication such as furosemide is indicated. Excess secretions can be dried with scopolamine, transdermally or intravenously. Use of oxygen is controversial. There are conflicting data on its effectiveness for patients with proven hypoxemia. But there is no clear benefit of oxygen compared to room air for nonhypoxemic patients. Noninvasive positive-pressure ventilation using a facemask or nasal plugs may be used for some patients for symptom relief. For some families and patients, oxygen is distressing; for others, it is reassuring. More general interventions that medical staff can do include sitting the patient upright, removing smoke or other irritants such as perfume, ensuring a supply of fresh air with sufficient humidity, and minimizing other factors that can increase anxiety.
TABLE 10-6Medications for the Management of Dyspnea |Favorite Table|Download (.pdf) TABLE 10-6Medications for the Management of Dyspnea
|Intervention ||Dose ||Comments |
|Weak opioids || ||For patients with mild dyspnea |
| Codeine (or codeine with 325 mg acetaminophen) ||30 mg PO q4h ||For opioid-naïve patients |
| Hydrocodone ||5 mg PO q4h || |
|Strong opioids || ||For opioid-naïve patients with moderate to severe dyspnea |
| Morphine || |
5–10 mg PO q4h
30–50% of baseline opioid dose q4h
|For patients already taking opioids for pain or other symptoms |
| Oxycodone ||5–10 mg PO q4h || |
| Hydromorphone ||1–2 mg PO q4h || |
|Anxiolytics || ||Give a dose every hour until the patient is relaxed, then provide a dose for maintenance |
| Lorazepam ||0.5–2.0 mg PO/SL/IV qh then q4–6h || |
| Clonazepam ||0.25–2.0 mg PO q12h || |
| Midazolam ||0.5 mg IV q15min || |
More than 90% of terminally ill patients experience fatigue and/or weakness. Fatigue is one of the most commonly reported symptoms of cancer treatment as well as in the palliative care of multiple sclerosis, COPD, heart failure, and HIV. Fatigue frequently is cited as among the most distressing symptoms.
The multiple causes of fatigue in the terminally ill can be categorized as resulting from the underlying disease; from disease-induced factors such as tumor necrosis factor and other cytokines; and from secondary factors such as dehydration, anemia, infection, hypothyroidism, and drug side effects. Apart from low caloric intake, loss of muscle mass and changes in muscle enzymes may play an important role in fatigue of terminal illness. The importance of changes in the CNS, especially the reticular activating system, have been hypothesized based on reports of fatigue in patients receiving cranial radiation, experiencing depression, or having chronic pain in the absence of cachexia or other physiologic changes. Finally, depression and other causes of psychological distress can contribute to fatigue.
Like pain and dyspnea, fatigue is subjective. Objective changes, even in body mass, may be absent. Consequently, assessment must rely on patient self-reporting. Scales used to measure fatigue, such as the Edmonton Functional Assessment Tool, the Fatigue Self-Report Scales, and the Rhoten Fatigue Scale, are usually appropriate for research rather than clinical purposes. In clinical practice, a simple performance assessment such as the Karnofsky Performance Status or the ECOG’s question “How much of the day does the patient spend in bed?” may be the best measure. In this 0–4 performance status assessment, 0 = normal activity; 1 = symptomatic without being bedridden; 2 = requiring some, but <50%, bed time; 3 = bedbound more than half the day; and 4 = bedbound all the time. Such a scale allows for assessment over time and correlates with overall disease severity and prognosis. A 2008 review by the European Association of Palliative Care also described several longer assessment tools with 9–20 items, including the Piper Fatigue Inventory, the Multidimensional Fatigue Inventory, and the Brief Fatigue Inventory (BFI).
For some patients, there are reversible causes such as anemia, but for most patients at the end of life, fatigue will not be “cured.” The goal is to ameliorate it and help patients and families adjust expectations. Behavioral interventions should be used to avoid blaming the patient for inactivity and to educate both the family and the patient that the underlying disease causes physiologic changes that produce low energy levels. Understanding that the problem is physiologic and not psychological can help alter expectations regarding the patient’s level of physical activity. Practically, this may mean reducing routine activities such as housework and cooking or social events outside the house and making it acceptable to receive guests lying on a couch. At the same time, institution of exercise regimens and physical therapy can raise endorphins, reduce muscle wasting, and reduce the risk of depression. In addition, ensuring good hydration without worsening edema may help reduce fatigue. Discontinuing medications that worsen fatigue may help, including cardiac medications, benzodiazepines, certain antidepressants, or opioids if pain is well-controlled. As end-of-life care proceeds into its final stages, fatigue may protect patients from further suffering, and continued treatment could be detrimental.
There are woefully few pharmacologic interventions that target fatigue and weakness. Glucocorticoids can increase energy and enhance mood. Dexamethasone is preferred for its once-a-day dosing and minimal mineralocorticoid activity. Benefit, if any, usually is seen within the first month. Psychostimulants such as dextroamphetamine (5–10 mg PO) and methylphenidate (2.5–5 mg PO) may also enhance energy levels, although a randomized trial did not show methylphenidate beneficial compared with placebo in cancer fatigue. Doses should be given in the morning and at noon to minimize the risk of counterproductive insomnia. Modafinil, developed for narcolepsy, has shown some promise in the treatment of severe fatigue and has the advantage of once-daily dosing. Its precise role in fatigue at the end of life has not been determined. Anecdotal evidence suggests that L-carnitine may improve fatigue, depression, and sleep disruption. Similarly, some studies suggest ginseng can reduce fatigue.
PSYCHOLOGICAL SYMPTOMS AND THEIR MANAGEMENT
Depression at the end of life presents an apparently paradoxical situation. Many people believe that depression is normal among seriously ill patients because they are dying. People frequently say, “Wouldn’t you be depressed?” However, depression is not a necessary part of terminal illness and can contribute to needless suffering. Although sadness, anxiety, anger, and irritability are normal responses to a serious condition, they are typically of modest intensity and transient. Persistent sadness and anxiety and the physically disabling symptoms that they can lead to are abnormal and suggestive of major depression. Although as many as 75% of terminally ill patients experience emotional distress and depressive symptoms, <30% of terminally ill patients have major depression. Depression is not limited to cancer patients but found in patients with end-stage renal disease, Parkinson’s disease, multiple sclerosis, and other terminal conditions.
Previous history of depression, family history of depression or bipolar disorder, and prior suicide attempts are associated with increased risk for depression among terminally ill patients. Other symptoms, such as pain and fatigue, are associated with higher rates of depression; uncontrolled pain can exacerbate depression, and depression can cause patients to be more distressed by pain. Many medications used in the terminal stages, including glucocorticoids, and some anticancer agents, such as tamoxifen, interleukin 2, interferon α, and vincristine, also are associated with depression. Some terminal conditions, such as pancreatic cancer, certain strokes, and heart failure, have been reported to be associated with higher rates of depression, although this is controversial. Finally, depression may be attributable to grief over the loss of a role or function, social isolation, or loneliness.
Diagnosing depression among seriously ill patients is complicated because many of the vegetative symptoms in the DSM-V (Diagnostic and Statistical Manual of Mental Disorders) criteria for clinical depression—insomnia, anorexia and weight loss, fatigue, decreased libido, and difficulty concentrating—are associated with the dying process itself. The assessment of depression in seriously ill patients therefore should focus on the dysphoric mood, helplessness, hopelessness, and lack of interest and enjoyment and concentration in normal activities. The single questions “How often do you feel downhearted and blue?” (more than a good bit of the time or similar responses) and “Do you feel depressed most of the time?” are appropriate for screening. Visual Analog Scales can also be useful in screening.
Physicians must treat any physical symptom, such as pain, that may be causing or exacerbating depression. Fostering adaptation to the many losses that the patient is experiencing can also be helpful. Nonpharmacologic interventions, including group or individual psychological counseling, and behavioral therapies such as relaxation and imagery can be helpful, especially in combination with drug therapy.
Pharmacologic interventions remain the core of therapy. The same medications are used to treat depression in terminally ill as in non–terminally ill patients. Psychostimulants may be preferred for patients with a poor prognosis or for those with fatigue or opioid-induced somnolence. Psychostimulants are comparatively fast acting, working within a few days instead of the weeks required for selective serotonin reuptake inhibitors (SSRIs). Dextroamphetamine or methylphenidate should be started at 2.5–5.0 mg in the morning and at noon, the same starting doses used for treating fatigue. The dose can be escalated up to 15 mg bid. Modafinil is started at 100 mg qd and can be increased to 200 mg if there is no effect at the lower dose. Pemoline is a nonamphetamine psychostimulant with minimal abuse potential. It is also effective as an antidepressant beginning at 18.75 mg in the morning and at noon. Because it can be absorbed through the buccal mucosa, it is preferred for patients with intestinal obstruction or dysphagia. If it is used for prolonged periods, liver function must be monitored. The psychostimulants can also be combined with more traditional antidepressants while waiting for the antidepressants to become effective and then tapered after a few weeks if necessary. Psychostimulants have side effects, particularly initial anxiety, insomnia, and rarely paranoia, which may necessitate lowering the dose or discontinuing treatment.
Mirtazapine, an antagonist at the postsynaptic serotonin receptors, is a promising psychostimulant. It should be started at 7.5 mg before bed. It has sedating, antiemetic, and anxiolytic properties with few drug interactions. Its side effect of weight gain may be beneficial for seriously ill patients; it is available in orally disintegrating tablets.
For patients with a prognosis of several months or longer, SSRIs, including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine, and serotonin-noradrenaline reuptake inhibitors such as venlafaxine, are the preferred treatment because of their efficacy and comparatively few side effects. Because low doses of these medications may be effective for seriously ill patients, one should use half the usual starting dose for healthy adults. The starting dose for fluoxetine is 10 mg once a day. In most cases, once-a-day dosing is possible. The choice of which SSRI to use should be driven by (1) the patient’s past success or failure with the specific medication, (2) the most favorable side effect profile for that specific agent, and (3) the time it takes to reach steady-state drug levels. For instance, for a patient in whom fatigue is a major symptom, a more activating SSRI (fluoxetine) would be appropriate. For a patient in whom anxiety and sleeplessness are major symptoms, a more sedating SSRI (paroxetine) would be appropriate.
Atypical antidepressants are recommended only in selected circumstances, usually with the assistance of a specialty consultation. Trazodone can be an effective antidepressant but is sedating and can cause orthostatic hypotension and, rarely, priapism. Therefore, it should be used only when a sedating effect is desired and is often used for patients with insomnia, at a dose starting at 25 mg. In addition to its antidepressant effects, bupropion is energizing, making it useful for depressed patients who experience fatigue. However, it can cause seizures, preventing its use for patients with a risk of CNS neoplasms or terminal delirium. Finally, alprazolam, a benzodiazepine, starting at 0.25–1.0 mg tid, can be effective in seriously ill patients who have a combination of anxiety and depression. Although it is potent and works quickly, it has many drug interactions and may cause delirium, especially among very ill patients, because of its strong binding to the benzodiazepine–γ-aminobutyric acid (GABA) receptor complex.
Unless used as adjuvants for the treatment of pain, tricyclic antidepressants are not recommended. Similarly, monoamine oxidase (MAO) inhibitors are not recommended because of their side effects and dangerous drug interactions.
In the weeks or months before death, delirium is uncommon, although it may be significantly underdiagnosed. However, delirium becomes relatively common in the hours and days immediately before death. Up to 85% of patients dying from cancer may experience terminal delirium.
Delirium is a global cerebral dysfunction characterized by alterations in cognition and consciousness. It frequently is preceded by anxiety, changes in sleep patterns (especially reversal of day and night), and decreased attention. In contrast to dementia, delirium has an acute onset, is characterized by fluctuating consciousness and inattention, and is reversible, although reversibility may be more theoretical than real for patients near death. Delirium may occur in a patient with dementia; indeed, patients with dementia are more vulnerable to delirium.
Causes of delirium include metabolic encephalopathy arising from liver or renal failure, hypoxemia, or infection; electrolyte imbalances such as hypercalcemia; paraneoplastic syndromes; dehydration; and primary brain tumors, brain metastases, or leptomeningeal spread of tumor. Commonly, among dying patients, delirium can be caused by side effects of treatments, including radiation for brain metastases, and medications, including opioids, glucocorticoids, anticholinergic drugs, antihistamines, antiemetics, benzodiazepines, and chemotherapeutic agents. The etiology may be multifactorial; e.g., dehydration may exacerbate opioid-induced delirium.
Delirium should be recognized in any terminally ill patient with new onset of disorientation, impaired cognition, somnolence, fluctuating levels of consciousness, or delusions with or without agitation. Delirium must be distinguished from acute anxiety and depression as well as dementia. The central distinguishing feature is altered consciousness, which usually is not noted in anxiety, depression, and dementia. Although “hyperactive” delirium characterized by overt confusion and agitation is probably more common, patients also should be assessed for “hypoactive” delirium characterized by sleep-wake reversal and decreased alertness.
In some cases, use of formal assessment tools such as the Mini-Mental Status Examination (which does not distinguish delirium from dementia) and the Delirium Rating Scale (which does distinguish delirium from dementia) may be helpful in distinguishing delirium from other processes. The patient’s list of medications must be evaluated carefully. Nonetheless, a reversible etiologic factor for delirium is found in fewer than half of terminally ill patients. Because most terminally ill patients experiencing delirium will be very close to death and may be at home, extensive diagnostic evaluations such as lumbar punctures and neuroradiologic examinations are usually inappropriate.
One of the most important objectives of terminal care is to provide terminally ill patients the lucidity to say goodbye to the people they love. Delirium, especially with agitation during the final days, is distressing to family and caregivers. A strong determinant of bereavement difficulties is witnessing a difficult death. Thus, terminal delirium should be treated aggressively.
At the first sign of delirium, such as day-night reversal with slight changes in mentation, the physician should let the family members know that it is time to be sure that everything they want to say has been said. The family should be informed that delirium is common just before death.
If medications are suspected of being a cause of the delirium, unnecessary agents should be discontinued. Other potentially reversible causes, such as constipation, urinary retention, and metabolic abnormalities, should be treated. Supportive measures aimed at providing a familiar environment should be instituted, including restricting visits only to individuals with whom the patient is familiar and eliminating new experiences; orienting the patient, if possible, by providing a clock and calendar; and gently correcting the patient’s hallucinations or cognitive mistakes.
Pharmacologic management focuses on the use of neuroleptics and, in the extreme, anesthetics (Table 10-7). Haloperidol remains first-line therapy. Usually, patients can be controlled with a low dose (1–3 mg/d), usually given every 6 h, although some may require as much as 20 mg/d. It can be administered PO, SC, or IV. IM injections should not be used, except when this is the only way to get a patient under control. Newer atypical neuroleptics, such as olanzapine, risperidone, and quetiapine, have shown significant effectiveness in completely resolving delirium in cancer patients. These drugs also have fewer side effects than haloperidol, along with other beneficial effects for terminally ill patients, including antinausea, antianxiety, and weight gain. They are useful for patients with longer anticipated life expectancy because they are less likely to cause dysphoria and have a lower risk of dystonic reactions. Also, because they are metabolized through multiple pathways, they can be used in patients with hepatic and renal dysfunction. Olanzapine has the disadvantage that it is available only orally and that it takes a week to reach steady state. The usual dose is 2.5–5 mg PO bid. Chlorpromazine (10–25 mg every 4–6 h) can be useful if sedation is desired and can be administered IV or PR in addition to PO. Dystonic reactions resulting from dopamine blockade are a side effect of neuroleptics, although they are reported to be rare when these drugs are used to treat terminal delirium. If patients develop dystonic reactions, benztropine should be administered. Neuroleptics may be combined with lorazepam to reduce agitation when the delirium is the result of alcohol or sedative withdrawal.
TABLE 10-7Medications for the Management of Delirium
If no response to first-line therapy is seen, a specialty consultation should be obtained with a change to a different medication. If patients fail to improve after a second neuroleptic, sedation with an anesthetic such as propofol or continuous-infusion midazolam may be necessary. By some estimates, at the very end of life, as many as 25% of patients experiencing delirium, especially restless delirium with myoclonus or convulsions, may require sedation.
Physical restraints should be used with great reluctance and only when the patient’s violence is threatening to self or others. If they are used, their appropriateness should be reevaluated frequently.
Sleep disorders, defined as difficulty initiating sleep or maintaining sleep, sleep difficulty at least 3 nights a week, or sleep difficulty that causes impairment of daytime functioning, occur in 19–63% of patients with advanced cancer. Some 30–74% of patients with other end-stage conditions, including AIDS, heart disease, COPD, and renal disease, experience insomnia.
Patients with cancer may have changes in sleep efficiency such as an increase in stage I sleep. Other etiologies of insomnia are coexisting physical illness such as thyroid disease and coexisting psychological illnesses such as depression and anxiety. Medications, including antidepressants, psychostimulants, steroids, and β agonists, are significant contributors to sleep disorders, as are caffeine and alcohol. Multiple over-the-counter medications contain caffeine and antihistamines, which can contribute to sleep disorders.
Assessment should include specific questions concerning sleep onset, sleep maintenance, and early-morning wakening as these will provide clues to the causative agents and to management. Patients should be asked about previous sleep problems, screened for depression and anxiety, and asked about symptoms of thyroid disease. Caffeine and alcohol are prominent causes of sleep problems, and a careful history of the use of these substances should be obtained. Both excessive use and withdrawal from alcohol can be causes of sleep problems.
The mainstays of intervention include improvement of sleep hygiene (encouragement of regular time for sleep, decreased nighttime distractions, elimination of caffeine and other stimulants and alcohol), intervention to treat anxiety and depression, and treatment for the insomnia itself. For patients with depression who have insomnia and anxiety, a sedating antidepressant such as mirtazapine can be helpful. In the elderly, trazodone, beginning at 25 mg at nighttime, is an effective sleep aid at doses lower than those which cause its antidepressant effect. Zolpidem may have a decreased incidence of delirium in patients compared with traditional benzodiazepines, but this has not been clearly established. When benzodiazepines are prescribed, short-acting ones (such as lorazepam) are favored over longer-acting ones (such as diazepam). Patients who receive these medications should be observed for signs of increased confusion and delirium.
SOCIAL NEEDS AND THEIR MANAGEMENT
Dying can impose substantial economic strains on patients and families, causing distress. In the United States, with one of the least comprehensive health insurance systems among the developed countries, ~20% of terminally ill patients and their families spend >10% of family income on health care costs over and above health insurance premiums. Between 10 and 30% of families sell assets, use savings, or take out a mortgage to pay for the patient’s health care costs. Nearly 40% of terminally ill patients in the United States report that the cost of their illness is a moderate or great economic hardship for their family.
The patient is likely to reduce and eventually stop working. In 20% of cases, a family member of the terminally ill patient also stops working to provide care. The major underlying causes of economic burden are related to poor physical functioning and care needs, such as the need for housekeeping, nursing, and personal care. More debilitated patients and poor patients experience greater economic burdens.
This economic burden should not be ignored as a private matter. It has been associated with a number of adverse health outcomes, including preferring comfort care over life-prolonging care as well as consideration of euthanasia or physician-assisted suicide. Economic burdens increase the psychological distress of families and caregivers of terminally ill patients, and poverty is associated with many adverse health outcomes. Importantly, recent studies found that “patients with advanced cancer who reported having end-of-life conversations with physicians had significantly lower health care costs in their final week of life. Higher costs were associated with worse quality of death.” Assistance from a social worker, early on if possible, to ensure access to all available benefits may be helpful. Many patients, families, and health care providers are unaware of options for long-term care insurance, respite care, the Family Medical Leave Act (FMLA), and other sources of assistance. Some of these options (such as respite care) may be part of a formal hospice program, but others (such as the FMLA) do not require enrollment in a hospice program.
Settling personal issues and closing the narrative of lived relationships are universal needs. When asked if sudden death or death after an illness is preferable, respondents often initially select the former but soon change to the latter as they reflect on the importance of saying goodbye. Bereaved family members who have not had the chance to say goodbye often have a more difficult grief process.
Care of seriously ill patients requires efforts to facilitate the types of encounters and time spent with family and friends that are necessary to meet those needs. Family and close friends may need to be accommodated with unrestricted visiting hours, which may include sleeping near the patient even in otherwise regimented institutional settings. Physicians and other health care providers may be able to facilitate and resolve strained interactions between the patient and other family members. Assistance for patients and family members who are unsure about how to create or help preserve memories, whether by providing materials such as a scrapbook or memory box or by offering them suggestions and informational resources, can be deeply appreciated. Taking photographs and creating videos can be especially helpful to terminally ill patients who have younger children or grandchildren.
Caring for seriously ill patients places a heavy burden on families. Families frequently are required to provide transportation and homemaking as well as other services. Typically, paid professionals such as home health nurses and hospice workers supplement family care; only about a quarter of all caregiving consists of exclusively paid professional assistance. The trend toward more out-of-hospital deaths will increase reliance on families for end-of-life care. Increasingly, family members are being called upon to provide physical care (such as moving and bathing patients) and medical care (such as assessing symptoms and giving medications) in addition to emotional care and support.
Three-quarters of family caregivers of terminally ill patients are women—wives, daughters, sisters, and even daughters-in-law. Because many are widowed, women tend to be able to rely less on family for caregiving assistance and may need more paid assistance. About 20% of terminally ill patients report substantial unmet needs for nursing and personal care. The impact of caregiving on family caregivers is substantial: both bereaved and current caregivers have a higher mortality rate than that of non-caregiving controls.
It is imperative to inquire about unmet needs and to try to ensure that those needs are met either through the family or by paid professional services when possible. Community assistance through houses of worship or other community groups often can be mobilized by telephone calls from the medical team to someone the patient or family identifies. Sources of support specifically for family caregivers should be identified through local sources or nationally through groups such as the National Family Caregivers Association (www.nfcacares.org), the American Cancer Society (www.cancer.org), and the Alzheimer’s Association (www.alz.org).
EXISTENTIAL NEEDS AND THEIR MANAGEMENT
Religion and spirituality are often important to dying patients. Nearly 70% of patients report becoming more religious or spiritual when they became terminally ill, and many find comfort in religious or spiritual practices such as prayer. However, ~20% of terminally ill patients become less religious, frequently feeling cheated or betrayed by becoming terminally ill. For other patients, the need is for existential meaning and purpose that is distinct from and may even be antithetical to religion or spirituality. When asked, patients and family caregivers frequently report wanting their professional caregivers to be more attentive to religion and spirituality.
Health care providers are often hesitant about involving themselves in the religious, spiritual, and existential experiences of their patients because it may seem private or not relevant to the current illness. But physicians and other members of the care team should be able at least to detect spiritual and existential needs. Screening questions have been developed for a physician’s spiritual history taking. Spiritual distress can amplify other types of suffering and even masquerade as intractable physical pain, anxiety, or depression. The screening questions in the comprehensive assessment are usually sufficient. Deeper evaluation and intervention are rarely appropriate for the physician unless no other member of a care team is available or suitable. Pastoral care providers may be helpful, whether from the medical institution or from the patient’s own community.
Precisely how religious practices, spirituality, and existential explorations can be facilitated and improve end-of-life care is not well established. What is clear is that for physicians, one main intervention is to inquire about the role and importance of spirituality and religion in a patient’s life. This will help a patient feel heard and help physicians identify specific needs. In one study, only 36% of respondents indicated that a clergy member would be comforting. Nevertheless, the increase in religious and spiritual interest among a substantial fraction of dying patients suggests inquiring of individual patients how this need can be addressed. Some evidence supports specific methods of addressing existential needs in patients, ranging from establishing a supportive group environment for terminal patients to individual treatments emphasizing a patient’s dignity and sources of meaning.