The model of palliative care was initially conceived of and developed in response to the needs of the cancer patient. Over time, the definition has evolved. It can be applied to any stage of illness from acute to chronic and its terminal phase.1 Therefore, the principles of palliative care can and should be applied early on throughout the continuum of patient care, including life-extending and curative treatments. Dr. Balfour Mount coined the term palliative care from the Latin word pallium, which referred to an outer garment that cloaked a person or object. The Latin derivation suggests that palliative care can effectively “cloak” the symptoms of serious illness.
The National Consensus Project for Quality Palliative Care (NCP) defines palliative care as “patient- and family-centered care that optimizes quality of life by anticipating, preventing, and treating suffering.” Palliative care throughout the continuum of illness involves addressing physical, intellectual, emotional, social, and spiritual needs of a patient. Additionally, the field facilitates patient autonomy, access to information, and medical decision-making. Palliative care encompasses all health care settings to include acute care hospitals, rehabilitation facilities, hospices, long-term care settings, ambulatory clinics, and community programs within home and/or hospice organizations. The services are offered by an interdisciplinary team consisting of physicians, nurses, social workers, chaplains, therapists, and other professionals.2
The Center to Advance Palliative Care (CAPC) defines palliative care (also known as palliative medicine) as specialized medical care for people with serious illness focused on providing patients with relief of symptoms, pain, and stress of a serious illness—whatever the diagnosis. The goal is to improve quality of life for both the patient and the family. Palliative care is provided by a team of doctors, nurses, and other specialists who work together with other members of the health care team to provide an extra layer of support. It is appropriate at any age and at any stage in a serious illness and can be provided along with curative treatment.3
The World Health Organization (WHO) defines palliative care as “an approach that improves quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial, and spiritual.”4
According to the National Hospice and Palliative Care Organization, hospice is considered to be the model for quality, compassionate care for patients facing a life-limiting illness or injury. Hospice care also involves a team-oriented approach to expert medical care, pain management, and emotional/spiritual support expressly tailored to the patient’s needs and wishes. Support is provided to the patient’s loved ones as well. At the center of hospice and palliative care is the belief that each of us has the right to die pain-free with dignity, and that our families will receive the necessary support to allow us to do so.5
The Medicare Hospice Benefit offers hospice as a health care delivery system under which support and services are provided to a patient certified by a physician with a terminal illness and life expectancy of less than 6 months or less; patients elect comfort-directed care and choose hospice instead of other Medicare-covered treatments to manage the terminal illness and related conditions.6
In essence, hospice is considered a program that delivers palliative care to patients at the end of life, while palliative care can be appropriately offered to patients at any time along the trajectory of any type of serious illness, even concurrent with restorative, life-prolonging therapies.7
The primary goal of palliative care is to offer the best possible quality of life for patients living with serious illness in all stages of the disease and is not limited to end-of-life care. Palliative care services such as facilitating good communication, goal-setting, and aggressive symptom control should be offered alongside curative and disease-modifying treatments for this population. Demographic transitions such as aging of the population and a shift in causes of death to chronic diseases have had major consequences for the experience of the seriously ill to include the dying.8,9 A multi-center study of 9,000 seriously ill patients found that symptoms such as pain, dyspnea anxiety, and depression were common and distressing symptoms among seriously ill patients hospitalized in US tertiary care centers.10 When initiated early in the disease course, palliative care improves the clinical and quality of care outcomes and potentially may prolong survival.11,12 A randomized trial demonstrated that comprehensive palliative care in the outpatient setting for patients with advanced disease and pursuing disease-modifying treatments improved symptom management and patient satisfaction.13 Furthermore, palliative care has been shown to lower costs and reduce rates of hospitalizations, diagnostic and treatment interventions, and unnecessary intensive and emergency department care, particularly when patients are close to dying.14 Obstacles to providing early palliative care are multifactorial. Patients with non-cancer diagnoses such as COPD or CHF are very heterogeneous in their disease manifestations and trajectory toward death making prognostication difficult. Misconception about palliative care being synonymous with hospice care still exists. Although hospice care provides expert palliative care at the end of life (i.e., less than 6 months estimated life expectancy), palliative care as a subspecialty must be provided in the continuum of care from the earliest stages to its terminal phase. This perspective is not only shared by patients and families but also among different clinical providers in various settings, thereby affecting early referral and access to expert palliative care.
The World Health Organization (WHO) identified several components in the provision of palliative care.15 These include the following:
Provides relief from pain and other distressing symptoms
Affirms life and regards dying as a normal process
Intends neither to hasten or postpone death
Integrates the psychological and spiritual aspects of patient care
Offers a support system to help patients live as actively as possible until death
Offers a support system to help the family cope during the patient’s illness and in their own bereavement
Uses a team approach to address the needs of patients and their families, including bereavement counseling, if indicated
Will enhance quality of life, and may also positively influence the course of illness
Is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those investigations needed to better understand and manage distressing clinical complications
Based on these elements, the scope of services in palliative care generally include pain and non-pain symptom control, communication and discussion about goals of care, assistance with the coordination and transition in care, and the provision of psychosocial and spiritual support to both patients and families. These will be described separately.
One of the main tenets of palliative care is relief of pain and other physical, emotional, and psychological symptoms. A meta-analysis of 19 studies concluded that hospice and palliative care teams have improved the pain and symptoms of their patients.16
A thorough assessment of the causes of pain and other symptoms is the building block for effective symptom management. The experience of these symptoms may impact the patient’s physical function, emotional well-being, cognition, nutrition, and overall quality of life. Pain as a symptom is often a combination of sensory, emotional, and cognitive processes. Actual structural pathology is not required for patients to experience pain. This leads to the concept of total pain that encompasses these elements. The approach to treatment is therefore a combination of pharmacologic (e.g., opioids) and non-pharmacologic modalities (e.g., counseling). Pain is experienced by a heterogeneous group of patients to include cancer and non-cancer diagnoses such as neurodegenerative diseases. A study by Morrison and Siu showed that hip fracture patients with advanced dementia versus cognitively intact ones similarly had pain but that the former group received a markedly lower analgesic dosing in both preoperative and postoperative instances.17
Non-pain symptoms occur invariably with different types of patients. The most frequent non-pain symptoms are constipation, chronic nausea and vomiting, anorexia, dyspnea, fatigue, and delirium.18 The subjective nature of these symptoms attests to the variability in their expression among different types of patients. Adopting a comprehensive and multidimensional approach allows formulation of a more effective strategy.
Good communication is an essential component in the delivery of high-quality palliative care. Palliative care specialists are trained to facilitate goals of care discussion and navigate complex medical decision-making among patients, their families, and the medical providers. The clarification of the goals of care will then lead to appropriate and beneficial medical care. Quill’s 2000 study highlighted the dissatisfaction of patients regarding how clinicians communicate to them.19 In the SUPPORT study, only 47% of clinicians caring for hospitalized adults with one or more of nine life-threatening diagnoses knew their patient’s preferences for resuscitation.20 There are four essential questions to ask in setting goals: whose goals are being considered; are the goals achievable; are the goals beneficial; and how are the results measured?
Palliative care as a specialty emphasizes the multidimensional and holistic approach to patient and family care. Most programs provide an inter-professional team that may include specialties from social work, nursing, chaplaincy, psychology, psychiatry, bereavement, physical therapy, speech therapy, occupational therapy, and massage therapy, among other disciplines.
Psychological distress such as depression in advanced illness is associated with higher utilization of health care services and increased mortality rates.21 Patients struggling with depression in chronic, advanced, and terminal illnesses will likely benefit from pharmacologic therapy and supporting psychotherapy and counseling.22 Caregivers, on the other hand, also experience their share of stress and struggles. Schulz’s 1999 study showed that caregivers who report emotional strain are at substantially higher risk for death.23
Another important domain in palliative care is spiritual care. Studies have shown that patients and caregivers would like clinical providers to address their spiritual concerns.24,25
Patients and their families who are dealing with serious illness are already going through a challenging time making sense of the new realities they are facing. The existing medical system adds another layer of complication in terms of its complex and fragmented matrix that could make its navigation frustrating. Palliative care helps facilitate and coordinate plans of care within the various stakeholders of the medical system. This coordination starts with clear communication among patients, families, and the medical providers. Based on the overall goals of care, a sensible and appropriate plan of care is formulated. The provision of resources and transition to appropriate care settings are included in the implementation of the care plan.
Pain is one of the most common symptoms experienced by patients at the end of life. It is frequently under-diagnosed and undertreated in this population and leads to functional decline, depression, increased health care utilization, suffering, and increased desire for hastened death.26
Pain is classified as nociceptive and neuropathic. Nociceptive pain results from the stimulation of pain receptors (nociceptors) and includes somatic and visceral pain. Somatic pain originates from skin, subcutaneous tissues, mucous membranes, muscles, tendons, joints, or bones. It is generally well-localized and is described as sharp, throbbing, dull, aching, pricking, or gnawing. Examples of somatic pain include bone metastases, mucositis, soft tissue inflammation or invasion by tumor, and postoperative states. Visceral pain originates from pathologic processes that affect the internal organs and is generally described as deep, colicky, squeezing, dragging, or pressure like. It tends to be poorly localized and often referred to distant sites (referred pain) and can be associated with nausea, vomiting, and sweating. Primary or metastatic tumors tend to distend, infiltrate, compress, or stretch the thoracic and abdominal viscera, causing pain. Neuropathic pain results from a pathologic process that involves the peripheral or the central nervous system. It is usually described as burning, numbness, tingling, pins and needles, and can be associated with sensory or motor function loss. Common examples of neuropathic pain include neuropathies related to tumor infiltration, trauma, radiation therapy, and chemotherapy (e.g., cisplatin, thalidomide, vincristine, etc.)
Cancer pain can be also classified as pain caused by the primary disease process (e.g., tumor infiltration of organs, bone, soft tissue, nerves, plexus and meninges); pain resulting from treatment (e.g., post-surgical pain syndromes, peripheral neuropathies following chemotherapy and radiation therapy); and pain unrelated to cancer and its therapies (e.g., degenerative joint disease, chronic headaches, myofascial pain syndromes, peripheral vascular disease). It is important to know that palliative care patients, particularly cancer patients, can have different sources of pain.
Pain assessment involves a thorough history, physical exam, and ancillary tests as appropriate. Pain should be assessed for its onset, location, duration, character, severity, aggravating and relieving factors, timing, previous therapies, response to medications, functional activities, mood, and sleep impairment. Pain intensity should be assessed by the use of pain scales. Commonly used pain scales include the numeric pain rating scale from 0 to 10 (0 = no pain; 10 = the worst possible pain); the pain thermometer; facial expression scales; the Visual Analog Scale (VAS); and the descriptor pain scale.27 New pain complaints or poor response to conventional analgesic therapy require a reassessment of the etiology and the treatment plan.
The WHO Analgesic Ladder Approach remains the mainstay of the pharmacological therapy for cancer pain.28 In one study of patients with cancer, almost 90% had complete relief of pain using the WHO guidelines29 (see Fig. 82–1).
Basic concepts of the WHO ladder approach for controlling pain include giving pain medications orally whenever possible; around the clock when the pain is continuous; and matching the initial drug choice to the intensity of pain. For mild pain (Step 1), non-opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and acetaminophen are recommended. For moderate pain (Step 2), less potent opioids (e.g., codeine, hydrocodone) combined with acetaminophen or NSAIDs are indicated. For severe pain (Step 3), potent opioids (morphine, oxycodone, hydromorphone, fentanyl, and methadone) are the drugs of choice. Adjuvant analgesics (e.g., anticonvulsants, antidepressants for neuropathic pain) may be used at any pain level and can be combined with opioids and non-opioids. Other approaches such as surgery, nerve blocks, radiotherapy, and chemotherapy should also be considered in addition to the traditional analgesics.
NSAIDs and acetaminophen are non-opioid analgesics that are frequently used for the management of mild cancer-related pain.
Acetaminophen is generally well tolerated and does not interfere with platelet and renal function. Due to the potential for liver toxicity, the maximum dose should be limited to 4 g/d with maximal single dose not to exceed 650 mg. In older patients, the maximum dose is 3 g/d. The existence of significant liver disease and heavy alcohol abuse are relative contraindications to acetaminophen use.30
NSAIDs may be used to treat mild to moderate pain associated with an inflammatory component, and metastatic bone pain. They have a ceiling effect and multiple adverse side effects including nephrotoxicity, dyspepsia, gastric ulceration, gastrointestinal bleeding, cardiovascular toxicity (myocardial infarction, stroke, and death), fluid retention, hypertension, and hepatotoxicity. These drugs should be used with caution in the elderly, in patients with history of peptic ulcer disease or prior NSAID gastroduodenopathy, with concurrent corticosteroid or anticoagulant use, cardiovascular disease, hypercoagulable states, or renal disease. The selective Cox-2 inhibitor (Celecoxib) has less gastrointestinal effects when used short term but still has the renal effects and prothrombotic effects.
Opioids remain the cornerstone of cancer pain management. They are widely used because of their safety, reliability, ease of titration, and multiple routes of administration. Opioids are used to treat moderate to severe pain and are mainly effective for nociceptive pain; however, they may also be used for the management of cancer-related neuropathic pain along with adjuvant analgesics (e.g., anticonvulsants and antidepressants).31
The most common opioids used to treat moderate to severe cancer pain are morphine, oxycodone, hydromorphone, fentanyl, methadone, and oxymorphone. Hydrocodone, codeine, and tramadol are generally used to treat mild cancer-related pain.
Morphine is the most commonly used opioid to treat cancer pain. It is available in short- and long-acting preparations and can be administered orally, rectally, and parenterally. Morphine is metabolized in the liver by the Cytochrome P450-2D6 enzyme to morphine 6-glucoronide and morphine 3-glucoronide, both of which are pharmacologically active and excreted by the kidneys. These metabolites accumulate in renal impairment leading to opioid toxicity which is manifested by change in mental status, sedation, myoclonus, seizures, and hyperalgesia. Morphine has a short half-life of approximately 4 hours, but is also available in released-controlled preparations that provide continuous analgesia with once or twice a day dosing.
Oxycodone is a synthetic opioid that can be used for management of moderate to severe cancer pain. It has short half-life (3.5–6 hours) and it is metabolized in the liver. Oxycodone is available in a single immediate release agent and in fixed combination with aspirin and acetaminophen. It is also available as a sustained release preparation which provides analgesia for 8 to 12 hours.32
Hydromorphone is a synthetic short-acting opioid that can be used orally or parenterally. It is more potent than morphine and tends to be preferred in renal failure because it has less active metabolites as compared to morphine.
Oxymorphone is a semisynthetic opioid available in oral immediate-release and extended-release formulations with demonstrated efficacy and tolerability comparable to morphine and oxycodone.33
Fentanyl is a potent short-acting opioid used for management of severe cancer pain. It is available in transdermal, transmucosal, and parenteral formulations. The transdermal preparation is especially useful in patients with difficulty swallowing and can provide continuous pain relief for 40 to 72 hours. Fentanyl transdermal patch should be used only when a steady state of pain relief has been achieved using another opioid. Fentanyl is also available in an oral transmucosal form (lozenge on a stick) and as a buccal tablet, both of which can be used for management of breakthrough pain in cancer patients already receiving maintenance opioid therapy.34
Methadone is a synthetic opioid particularly useful for severe cancer pain not responsive to conventional doses of other opioids. It also has an effect on neuropathic pain because it inhibits the N-methyl-d-aspartate (NMDA) receptors, which are implicated in the development of neuropathic pain. Methadone is metabolized in the liver by the Cytochrome P-450 3A4 and can be safely used in patients with renal impairment. It interacts with several drugs metabolized by the Cytochrome P-450 system, which requires careful attention by the prescriber. It has been shown to prolong the QT interval and must be used with caution in patients with cardiac disease. Methadone has a long elimination half-life (range 15–190 hours) and can accumulate after repetitive dosing leading to drug toxicity.35
Tramadol and codeine are used for the management of mild pain. Tramadol is a synthetic analog of codeine which binds to the µ opioid receptors and inhibits neuronal reuptake of serotonin and norepinephrine.36 Codeine is considered a weak opioid and is available in several dosage forms and in combination with acetaminophen. It is a good medication for cough but otherwise restricted due to its potential for renal toxicity and delirium.
Common side effects of opioids include constipation, nausea and vomiting, sedation, confusion, respiratory depression, urinary retention, pruritus, and myoclonus.37
Constipation occurs with all opioids and requires the use of laxatives. Nausea and vomiting is usually transitory and occurs with initiation of opioid therapy. Antiemetics such as prochlorperazine, ondansetron, and metoclopramide may be used as needed to control opioid-induced nausea and vomiting.38 Sedation and somnolence may occur at the initiation of opioid therapy or increase in opioid dose. Opioid dose reduction or use of psychostimulant drugs such as methylphenidate or modafinil may be used to counteract sedation induced by opioids.39 Respiratory depression may occur with the initiation of opioid therapy and upward titration. Clinically significant respiratory depression is associated with somnolence and mental status changes and naloxone may be given as needed if this occurs.37 Pruritus is associated with histamine release and can be managed by antihistamines. Myoclonus can occur with any opioid and is usually dose related. Switching to a different opioid or adding a benzodiazepine can be used to treat this symptom.37
Adjuvant analgesics (co-analgesics) are drugs that have a primary indication other than pain but have analgesic properties in some situations. In palliative care pain management, anticonvulsants and antidepressants are generally used to treat neuropathic pain.
The two most commonly utilized anticonvulsants to treat neuropathic pain are gabapentin and pregabalin. Both drugs have been shown to be effective for the management of diabetic neuropathy and postherpetic neuralgia.31 Gabapentin has also been shown to be effective to treat neuropathic cancer pain already treated with opiods.40 Gabapentin and pregabalin are generally well tolerated and lack significant drug–drug interactions. Both drugs are excreted by the kidneys, which necessitates dose reduction in the setting of renal impairment. Their main side effects include sedation, dizziness, somnolence, edema, and weight gain.
Most tricyclic antidepressants (amitriptyline, imipramine, doxepin, clomipramine, desipramine, and nortriptyline) are effective for the management of neuropathic pain.40 The utilization of these drugs is limited by numerous side effects which include sedation, urinary retention, constipation, dry mouth, increased intraocular pressure, dizziness, and prolongation of the QT interval and cardiac arrhythmias. These agents may also lead to delirium, falls, and cognitive impairment in geriatric patients.
There is evidence that some of the selective serotonin and norepinephrine reuptake inhibitors (SNRIs) such as duloxetine, venlafaxine, and milnacipran are effective for the management of neuropathic pain. Overall, the side effect profile of the SNRIs is more favorable than the tricyclic antidepressants.40 The most common side effects of the SNRIs include nausea, sexual dysfunction, and somnolence.
Corticosteroids are commonly used as adjuvant analgesics for several cancer pain syndromes including bone metastases, superior vena cava syndrome, neuropathic pain due to infiltration or compression by tumor, spinal cord compression, symptomatic lymphedema, and increased intracranial pressure. They also have an effect on appetite, energy level, nausea, and sense of well-being. Commonly used corticosteroids are dexamethasone, prednisone, and methylprednisolone.41
With advanced disease, patients experience a constellation of symptoms that contribute to suffering near the end of life. In addition to pain, the most common symptoms experienced by terminally ill patients include fatigue, anorexia/cachexia, constipation, nausea and vomiting, dyspnea, and delirium.
A comprehensive symptom assessment is essential when providing palliative care. Symptom assessment should include a complete history, physical examination, and laboratory tests and/or diagnostic imaging when appropriate to identify underlying and possibly treatable causes. Proper symptom management frequently involves the use of pharmacological and non-pharmacological interventions. Patient, family, and members of the interdisciplinary team should work in collaboration when determining the goals of care and the treatment plan. Patient and family education on the nature and progression of the symptoms and potential side effects of interventions is also important.
Constipation is a very common problem in palliative care patients and almost universal in patients on chronic use of opioids. It can be associated with multiple factors including medications (opioids, anticholinergics, antidepressants, calcium channel blockers, serotonin antagonists, vinca alkaloids, thalidomide, diuretics, iron, antacids, anticonvulsants), reduced physical activity, low fiber diet, dehydration, metabolic abnormalities (hypercalcemia, hypokalemia, uremia, hypothyroidism), spinal cord lesion, autonomic neuropathy, and pathology of the gastrointestinal tract (hemorrhoids, bowel obstruction, anal fissure, colon strictures, diverticulosis, and previous bowel surgery).42
The assessment of constipation includes a history and a physical examination focused on the abdominal and rectal areas. A medication review is necessary since many drugs used in palliative care cause constipation. Imaging studies should be obtained when bowel obstruction or fecal impaction are suspected.42
The management of constipation should be directed to the underlying and potentially reversible causes and the use of laxatives is usually necessary. When appropriate, patients should be encouraged to ambulate and to have an adequate fluid and fiber intake. Privacy and comfort for toileting should also be provided.
The goal of laxative therapy is to achieve comfortable defecation rather than a defined frequency of evacuation. Regular use of laxatives is always indicated in patients on opioid therapy.
The use of peristaltic agents such as sennosides (senna) is usually recommended for opioid-induced constipation. Stools softeners (docusate) are frequently used for the management of opioid-induced constipation despite the lack of evidence for its effectiveness.43 Other stimulant laxatives (bisacodyl, castor oil) may be helpful short-term agents. Osmotic agents (lactulose, sorbitol, polyethylene glycol) and saline laxatives (magnesium hydroxide, magnesium citrate) may be used as needed. Enemas and/or suppositories (bisacodyl) should be used for fecal impaction. Tap water enemas and oil retention enemas are preferable to salt-containing enemas because they are less irritating to the rectal mucosa. Manual disimpaction may be necessary for fecal impaction. The use of bulk forming agents (psyllium and methylcellulose) should be avoided in frail and debilitated patients who cannot drink enough fluids because of the potential for fecal impaction and bowel obstruction with poor liquid intake.42
Patients with opioid-induced constipation refractory to regular laxative therapy may benefit from the use of methylnaltrexone, which is a peripherally acting µ-opioid receptor antagonist, and from lubiprostone, a locally acting type-2 chloride channel (CIC-2) activator.43
Nausea and vomiting are common symptoms in palliative care patients and can be extremely debilitating. The pathophysiology of nausea and vomiting involves the stimulation of the vomiting center located in the medullary lateral reticular formation of the brain by the following mechanisms: (a) chemoreceptor trigger zone located on the floor of the fourth ventricle; (b) cerebral cortex; (c) limbic system; (d) pharynx and gastrointestinal tract; and (e) vestibular apparatus. The neurotransmitters that mediate nausea and vomiting include dopamine, serotonin, acetylcholine, and histamine.
The etiology of nausea and vomiting tend to be multifactorial and may include drugs (opioids, antibiotics, anticonvulsants, digoxin, iron, SSRIs, chemotherapy), electrolyte/metabolic imbalance (hypercalcemia, hypokalemia, hyponatremia, liver failure, uremia), gastrointestinal pathology (constipation, fecal impaction, peritoneal carcinomatosis bowel obstruction, gastroparesis, radiation therapy to the abdominal area, mucosal irritation), vestibular pathology (motion sickness, tumors of the base of the skull), increased intracranial pressure (intracranial tumor, infection, bleed, cerebral infarct), and emotional factors (anxiety, fear).
The assessment involves a thorough history and physical exam, and appropriate laboratory tests (e.g., electrolytes, BUN, Creatinine, liver enzymes, etc.). Imaging studies can be performed when there is suspicion of gastrointestinal pathology (fecal impaction, bowel obstruction, adynamic ileus) or CNS pathology (brain tumors).
The management should be target to the underlying cause(s) and involves non-pharmacological and pharmacological approaches. Non-pharmacological approaches include offering small and frequent meals with foods chosen by the patient, avoiding fatty meals, providing a quiet atmosphere during meals, maintaining good oral hygiene, and providing medications after meals except for anti-emetics.
The use of anti-emetics is usually required. There are several classes of anti-emetics that can be utilized in managing nausea and vomiting in palliative care patients: dopamine antagonists, serotonin antagonists, anticholinergics, antihistamines, benzodiazepines, and corticosteroids.
Dopamine antagonists (prochlorperazine, chlorpromazine, promethazine, droperidol, haldol, metoclopramide), and serotonin antagonists (ondansetron, granisetron, dolansetron, palonosetron) are commonly used to treat nausea and vomiting related to drugs, gastrointestinal pathology, and electrolyte/metabolic imbalance. All the dopamine antagonists have the potential for sedation, hypotension, extrapyramidal side effects, and prolongation of the QTc interval. Metoclopramide is usually indicated for gastroparesis. Serotonin antagonists are used for refractory nausea and chemotherapy and radiation-induced nausea and vomiting. These drugs do not have the sedative properties of the dopamine antagonists, but they can cause constipation and prolongation of the QTc interval.44
Anticholinergics (scopolamine, glycopyrrolate, hyoscyamine) and octreotide, a somatostatin analog, can be used to decrease gastrointestinal secretion production and alleviate nausea and vomiting and cramping associated with terminal bowel obstruction.45
Antihistamines (diphenhydramine, meclizine, hydroxyzine, promethazine) can be used for nausea and vomiting associated with vestibular pathology. Benzodiazepines (lorazepam) are used when there is a strong component of anxiety and for nausea induced by chemotherapy.45,46
Corticosteroids (dexamethasone) are used for chemotherapy-associated nausea and for increased intracranial pressure. Antacids, H2-blockers (ranitidine, famotidine), and proton-pump inhibitors (omeprazole, lansoprazole, pantoprazole) can alleviate nausea and vomiting related to gastric mucosal irritation, peptic ulcer disease, gastritis, and esophagitis.45,46
A new class of anti-emetics, neurokinin-1 (NK1) receptor antagonists (aprepitant), is used in combination with dexamethasone and a serotonin antagonist for chemotherapy-related nausea and vomiting.45,46 Olanzapine can also be used for chemotherapy-induced nausea and vomiting.47
Cannabinoids have been studied to determine its benefit in the treatment of chemotherapy-induced nausea and vomiting as well as nausea and vomiting related to HIV/AIDS and advanced cancer. To date, cannabinoids and derivatives are not recommended in the management of nausea and vomiting as there is paucity in the evidence to support its safety and therapeutic efficacy.47–49
Dyspnea is a common symptom at the end of life and can be very distressing to patients, families, and caregivers. It can be related to multiple factors including cardiopulmonary disease (congestive heart failure, COPD, pulmonary fibrosis, pulmonary embolism), acute superimposed illness (pneumonia, atelectasis, pleural effusion, pneumothorax), cancer treatment (radiation pneumonitis), cancer-related complications (lung cancer, pleural effusion, pericardial effusion, superior vena cava syndrome, lymphangitic carcinomatosis), psychogenic factors (anxiety, fear), neuromuscular diseases (amyotrophic lateral sclerosis), and miscellaneous causes (anemia, uremia).
The assessment of dyspnea includes a complete medical history and a physical examination to identify the underlying cause(s). Diagnostic evaluation should be guided by the goals of care. An initial assessment may include a complete blood cell count, chest radiography, electrocardiogram, and pulse oximetry. Other tests such as chest CT, arterial blood gases, pulmonary function tests, echocardiogram, and ventilation-perfusion scan may not be appropriate for the patient whose life expectancy is of days or a few weeks.
The management of dyspnea involves the treatment of possible reversible causes (e.g., antibiotics for pneumonia, diuretics for CHF exacerbation, bronchodilators, and corticosteroids for COPD exacerbation) while taking into consideration the patient’s life expectancy, the degree of invasiveness of the therapeutic interventions, and the patient/family’s goals of care.
Non-pharmacological approaches for the symptomatic control of dyspnea include the use of a fan, positioning in bed in a more upright position, pursed-lip breathing or deep breathing, and relaxation therapy. When hypoxemia is the underlying cause of dyspnea, supplemental oxygen may be helpful. Oxygen has not been shown to relieve dyspnea in non-hypoxemic patients. The use of non-invasive positive pressure ventilation (NPPV) in dyspneic patients at the end of life may be considered to alleviate the work of breathing, easing dyspnea, and helping maintain wakefulness by reducing the amount of opioids needed to maintain comfort.50
The pharmacological management of dyspnea involves opioids, corticosteroids, benzodiazepines, and phenothiazines. The use of opioids has become an established treatment strategy for the symptomatic management of dyspnea in advanced lung disease. Opioids decrease the sensation of breathlessness, decrease the ventilator response to hypoxia and hypercapnia, and decrease oxygen consumption at rest and during exercise.51 Morphine is the most commonly used because of its availability and ease of administration; however, other opioids (e.g., oxycodone, codeine) can be used. Respiratory depression is generally not seen with careful titration of morphine. Moreover, no studies have found excess mortality associated with the use of opioids for dyspnea.52
The use of nebulized morphine is not indicated because of the lack of high level significant scientific evidence for this approach.
Corticosteroids (dexamethasone, prednisone, methylprednisolone) can be effective for dyspnea associated with tumor-related airway obstruction, lymphangitic carcinomatosis, superior vena cava syndrome, COPD, asthma, interstitial lung disease, and radiation pneumonitis, and chemotherapy-induced pneumonitis. Benzodiazepines (lorazepam, midazolam) are helpful in relieving anxiety associated with breathlessness.53 Phenothiazines (promethazine, chlorpromazine) may be used for the management of dyspnea not responsive to opioids or benzodiazepines.51
Fatigue is the most common symptom associated with advanced cancer and it can be associated with multiple factors including cancer treatment (radiation, chemotherapy, surgery), paraneoplastic syndrome, sleep disorders, anemia, uncontrolled pain and non-pain symptoms, medications (opioids, anticholinergics, benzodiazepines, antiemetics, antihistamines), cachexia and muscle wasting, deconditioning, emotional factors (depression, anxiety), and comorbid illnesses (endocrine dysfunction, cardiac disease, pulmonary disease, liver disease, uremia, infection).
The assessment of fatigue involves a thorough history and physical exam. The onset, pattern, duration, exacerbation and relieving factors, and the effect of the quality of life and function need to be assessed. The assessment also includes a medication review and the identification of possible reversible factors.
Treatment involves addressing underlying causes (pain, depression, anemia, sleep disturbance) as indicated. Non-pharmacological measures include patient and family education about fatigue, sleep hygiene, stress management, exercise, and energy conservation strategies.
The pharmacological approaches for fatigue include the use of psychostimulants (methylphenidate, dextroamphetamine, modafinil), and corticosteroids (dexamethasone) for patients with advanced disease.54
The anorexia/cachexia syndrome is a hypermetabolic state characterized by progressive weight loss, lipolysis, loss of visceral and skeletal protein, and profound loss of appetite.55 Anorexia/cachexia syndrome is a marker of disease progression and poor prognosis which may have a negative impact on the patient’s functional status and quality of life.56
The pathophysiology of anorexia/cachexia involves an ongoing inflammatory state caused by cancer and mediated by various cytokines, particularly tumor necrosis factor. Secondary causes include: (1) impaired oral intake related to factors such as stomatitis, changes in taste, dysphagia, nausea and vomiting, autonomic dysfunction, gastroparesis, gastrointestinal pathology, pain, chemotherapy, radiotherapy, drugs, and metabolic changes (hypercalcemia, uremia); (2) catabolic states unrelated to cancer, such as infections, heart failure, poorly controlled diabetes, renal or liver failure; (3) loss of muscle mass related to aging, prolonged bed rest, growth hormone deficiency, and testosterone deficiency.55,57
The assessment should include an evaluation of the appetite and oral intake and associated symptoms such as early satiety, nausea and vomiting, or mucositis, pain, depression, delirium. A medication review is also important since anorexia can be a side effect of drugs (antidepressants, antibiotics, iron supplements, digoxin). A physical exam should be directed at identifying the underlying possible cause (s), wasting of skeletal muscle, strength, and mobility.
The management of anorexia/cachexia involves treating reversible causes (pain, depression, discontinuation of certain drugs, mucositis), pharmacological interventions and dietary planning. The most common pharmacological agents used for the palliative treatment of anorexia/cachexia include corticosteroids, progestational drugs, and cannabinoids. Metoclopramide may be considered to relieve early satiety through stimulation of gastric emptying.
Corticosteroids (dexamethasone, prednisone) promote appetite and a sense of well-being in patients with advanced disease. However, they are not associated with significant weight gain and their appetite stimulation effect tends to be transient. They may be beneficial for patients who also have nausea, asthenia, and pain.54
Megestrol acetate (progestational agent) promotes weight gain, appetite increase, and a sense of well-being in cancer patients. The increase in body weight is primarily an increase in fat mass. It is well tolerated but it can lead to adrenal insufficiency, hypogonadism, glucose intolerance and thromboembolic events (deep vein thrombosis).54
Cannabinoids such as dronabinol promotes weight gain in AIDS patients with anorexia/cachexia but they have not shown activity against cancer-related anorexia/cachexia.54,58
Dietary planning is also important and it involves offering foods that are preferred by patients; offering small portions more frequently; providing soft, pureed, and easy to swallow foods; and avoiding foods with strong odors and tastes.
Delirium is the most frequent occurring mental disorder in the final weeks of life and it is extremely common in the last 24 to 48 hours.59 Delirium is characterized by a disturbance in attention (inability to direct, focus, sustain, and shift attention), and awareness and cognition (memory deficit, disorientation, language, visuospatial ability, or perception) that develops over a short period of time (hours to days). Additional features of delirium include psychomotor disturbances (hypoactivity, hyperactivity with increased sympathetic activity); impairment of sleep; and variable emotional disturbances (fear, depression, euphoria, perplexity). In addition, there is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by a medical condition, substance intoxication or withdrawal, or medication side effect.60
Several factors contribute to delirium in patients with advanced illness, including drugs (opioids, antidepressants, benzodiazepines, glucocorticoids, drugs with anticholinergic activity); withdrawal from medications/alcohol; infection; brain tumor/metastases; metabolic factors (hypercalcemia, hypo or hypernatremia, dehydration, uremia, liver failure, hypo- or hyperglycemia); pain; hypoxia; paraneoplastic syndromes; and cancer treatments (chemotherapy, radiation therapy).
Assessment of delirium involves an evaluation of potentially reversible causes through a medical history, medication review, physical examination, and laboratory parameters when appropriate.
The management of delirium imposes a unique challenge because of the frequent combination of reversible and irreversible factors in patients with advanced disease. The management will depend on the goals of the patient and family and the estimated life expectancy. In patients with very limited life expectancy where delirium is part of the natural progression of the disease process, symptomatic and supportive treatment only would be appropriate. In patients with longer life expectancy and still receiving therapy, an approach involving treating correctable causes combined with symptomatic and supportive treatment would be appropriate.
The pharmacological management of delirium is indicated for patients who are agitated, fearful, combative, delusional, and hallucinatory. Antipsychotics are the drugs of choice to treat delirium at the end of life and haloperidol is the most often recommended one. It can be administered via oral, intravenous, intramuscular, or subcutaneous routes. Antipsychotics should be used with caution in patients with Lewy-body dementia, Parkinson dementia, and Parkinson disease because of the risk of extrapyramidal side effects. Olanzapine, risperidone, quetiapine, and aripiprazole have also been used to control delirium at the end of life.61
Benzodiazepines may have a limited role in combination with an antipsychotic to treat delirium in patients with uncontrolled agitation, but are not recommended as a sole agent unless the delirium is caused by benzodiazepine or alcohol withdrawal.61
Measures to help reduce anxiety and disorientation should also be instituted and include a quiet, well-lit room with familiar objects, pictures of familiar people at the bedside, visible clock, a calendar, the presence of a few family members and friends, and avoidance of over stimulation.
The rise of palliative care as a medical field of specialized care for patients with incurable illnesses has set the scene of prognostication as a core skill. Unlike prognostication in acute illness, in palliative care, prognosis relates to the chronicity and progression of diseases that are, oftentimes, disabling and life-limiting. There are a number of reasons attesting to the necessity of prognostication in chronic and serious illness. These include but not limited to:62
To provide patients and families with important information about what the future holds
To help patients develop insight into their illness
To assist patients to understand what is most important to them
To help patients and families clarify goals
To assist clinicians in medical decision-making
To establish the eligibility of patients in other appropriate services such as hospice or home care
To determine if patients might be eligible for clinical trials
To assist the medical team to formulate plans of care consistent with patient’s and families’ goals
To assist the health system in general for policy making and appropriate resource allocation
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