Palliative Care. e CHAPTER 9 DEFINITIONS INTRODUCTION KEY CONCEPTS. Jill Astolfi

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1 Palliative Care Jill Astolfi e CHAPTER 9 KEY CONCEPTS The goal of palliative care is to improve overall quality of life for patients, caregivers, and families while managing both general and disease-specific symptoms each patient may experience. Both palliative care and hospice use a team approach to address the total care of the patient and manage his or her symptoms. Palliative care should be instituted at the time of diagnosis and carried through to a patient s death; it can and should be administered simultaneously while a patient is receiving curative or life-prolonging therapies. It is important to address and manage each end-of-life symptom to improve the quality of life for the patient. Patients may experience different pain syndromes at the end of life. Knowledge of pain classification is important and necessary to determine the appropriate medication treatment for each patient. An interdisciplinary team approach is beneficial throughout the care of the patient. This is evident when addressing more psychologically based symptoms, such as delirium. Various symptoms will develop as death approaches. Anticipation, preparation, and access to appropriate treatment measures are necessary for a peaceful death. INTRODUCTION Approximately 2.4 million people die each year in the United States, most as a result of chronic illnesses. For patients with advanced disease or life-limiting illness, access to appropriate symptom management is of great concern, as is access to social, psychological, and spiritual support. A field of medicine known as palliative care focuses on reducing suffering and improving the quality of life for patients, their families, and caregivers. The purpose of palliative care is symptom assessment, prevention, and management. In addition, palliative care establishes goals of care with each patient and caregiver and extends support to the patient, family, and caregivers while addressing the individual patient s needs across all models of patient care settings (i.e., hospital, home, nursing home, and hospice). 2 Palliative care teams depend on the expertise of healthcare professionals from various disciplines; this helps to address the complex needs of seriously ill patients and their families. Typical members of a palliative care team are physicians, nurses, and social workers, with additional support from pharmacy, chaplaincy, nutrition, and other disciplines as needed. Pharmacists serve an integral role in palliative care and hospice teams. They often participate in interdisciplinary team meetings; others are employed by home health and hospital agencies and provide consultative services to interdisciplinary teams. Other pharmacists may work for an in-house hospice pharmacy or be employed by specialized hospice pharmacies throughout the country. Pharmacists typically provide appropriate medication recommendations and education for both staff and patients on appropriate use of medications. Some pharmacists are allowed to alter or initiate medications and dosages within a confined algorithm. Others provide recommendations to nurses and physicians regarding medication therapy. Overall, pharmacists can improve patient outcomes and symptom management by providing cost-effective medication recommendations; reviewing medication profiles; decreasing or eliminating duplicative medications; recommending alternative medication dosage forms (i.e., compounded medications) when appropriate; monitoring medications for both effectiveness and side effects; and educating staff, patients, and family on appropriate use of medication. DEFINITIONS 2 Although used interchangeably, the terms palliative care and hospice have distinct and separate definitions. The World Health Organization (WHO) defines palliative care as a team-centered approach to improving the quality of life for patients, families, and caregivers dealing with advanced disease. The focus of palliative care is to prevent and treat symptoms while addressing the social, physiologic, and spiritual concerns of the patient. 3 A key aspect of the WHO definition is extending services to patients earlier in their disease states. Palliative care can be given simultaneously with curative or life-prolonging treatment, or it can be administered as the main goal of care. 3 Hospice is a specific type of palliative care whose healthcare team is dedicated to managing patients with advanced illness with a life expectancy of less than 6 months. The National Hospice and Palliative Care Organization (NHPCO) defines hospice as [a] model for quality, compassionate care for people facing a lifelimiting illness or injury. Hospice and palliative care involve a teamoriented approach to expert medical care, pain management, and emotional and 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 and with dignity, and that our families will receive the necessary support to allow us to do so. 4 9

2 20 SECTION Foundation Issues Typical hospice care is administered in a patient s home; however, care can be administered to patients throughout the entire healthcare system. Although palliative care and hospice are similar, ideally, palliative care treatment would lead to hospice care as a patient s disease progresses. Often admissions to hospice and palliative care programs are instituted too late for optimal benefits for the patient. The median length of service for a hospice patient is 9. days. In 20, approximately.65 million patients were served by more than 4,800 hospices in the United States. More than million (,059,000) patients died while on hospice care; other patients either remained on hospice (33,000) or were discharged alive (278,000). 5 In 983, the Medicare Hospice Benefit (MHB) was introduced. The intent of the MHB was to care for terminally ill patients at home. A variety of diagnoses are appropriate for hospice services, including cancer, acquired immunodeficiency syndrome (AIDS), Parkinson s disease, and cardiac and pulmonary diseases. Because a patient s care might be provided in a nursing home, an assisted living facility, an inpatient unit, or a boarding home, the MHB covers four levels of hospice care: routine home care (home hospice care, care within a nursing home, or care in an assisted living facility), respite care (limited to 5 days; provided to relieve the caregiver; often provided in a nursing home), general inpatient hospice care (provided in a hospital or facility or a hospice free-standing unit; used to manage severe uncontrolled symptoms), and continuous home care (provided for patients eligible for general inpatient care but who prefer to stay at home). Most hospice care in the United States is provided at home. The MHB is responsible for 80% of all hospice care payments and includes coverage of physician, nursing, and social services (counseling and bereavement for both patient and caregiver) for terminally ill patients. To be eligible for MHB, a patient must be referred to a hospice program, and care planning must focus on comfort rather than disease modification. At the time of hospice admission, patients elect MHB (election is reversible), thereby changing coverage from Medicare Part B to Medicare Part A. The interdisciplinary hospice team then develops a plan of care (POC) with the patient and caregiver. A physician, usually a hospice medical director or the primary care physician, certifies that the disease state is terminal and that the expected life span is less than 6 months. Patients are often eligible for hospice care beyond 6 months if they live longer than initially expected. There is no copayment for hospice services. MHB uses a per diem method of payment. Payment is made to the hospice, which in turn provides payment to the hospital, pharmacy, durable medical equipment providers, and others for services rendered for each patient. The per diem is set annually but varies per level of care and geographic area. Included are case management with nursing staff, social work, counseling and chaplains (bereavement counseling continued after death for caregivers), physician oversight, durable medical equipment (e.g., beds, walkers, and commodes), home health aide services, speech and nutritional services, physical and occupational therapy when appropriate, general inpatient level of care if symptoms are uncontrolled, respite care to provide relief for caregivers, and continuous care. Medication not related to the terminal diagnosis, treatments intended to cure the terminal disease, and nursing home room and board are not included in the MHB. Medicare does continue to pay for other disease states, but these payments are not included under the MHB. Medicaid and private pay insurance often mirror the MHB, but there may be capped rates of reimbursement for several services, including levels of care. Most hospices receive charitable donations to cover the cost of care for patients who cannot afford to pay for their own care and are not eligible for other payment programs. 6 SYMPTOM MANAGEMENT 4 Patients with chronic or life-limiting illnesses experience an array of symptoms requiring palliative management. Some symptoms are disease or treatment specific, whereas other, more common symptoms are experienced by patients despite diagnosis. Pain Pain, a common symptom, is feared by most patients. 7 Its management can be complex and challenging, yet with careful assessment and a comprehensive POC, pain can be managed and in some cases completely resolved. Despite advances in the understanding of pain management, pain is often untreated or undertreated. In these cases, other symptoms can worsen, leading to even more suffering for the patient. As defined by the American Pain Society (APS), pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. 8 It is a complex, subjective phenomenon that can affect a patient s psychosocial and physical functioning. Pain assessment and understanding basic pain management principles are a necessary skill set for any clinician involved in palliative care. All members of palliative care and hospice teams play a role in the assessment of pain and the establishment and implementation of the POC. Pain assessment should include a thorough history and comprehensive physical examination that provides information about the location, quality, intensity, onset, duration, and frequency of pain, as well as factors that relieve or exacerbate the pain. Use of various pain scales can help in assessing a patient s pain intensity. 9 A simple way of assessing pain is to ask the patient to rate the pain using a numeric scale in which 0 is no pain at all and 0 is the worst pain the person can imagine. Visual analog pain scales provide a line, often 00 mm in length and labeled no pain on one end and very severe pain on the other, on which the patient marks the intensity of pain. Scores on visual analog scales are expressed as the number of millimeters from the 0 point where the patient marks the line, such as 20 mm or 80 mm. Various pictorial pain scales are available, usually with faces showing an increasing level of discomfort. Pictures are particularly useful in certain patients, such as young children and those with dementia, as well as those who are unable to read, speak, or understand the language being used by healthcare providers. At times, patients may express pain through other forms of suffering, such as depression, anxiety, and social or spiritual suffering. Assessing, addressing, and treating each is important in managing a patient s pain. 0 5 Pain can be classified as either nociceptive (somatic or visceral pain) or neuropathic. Patients, particularly at end of life, may present with either type of pain, and these types may occur alone or concurrently. Identifying the correct pain syndrome helps to control pain using appropriate therapies, both nonpharmacologic and pharmacologic. Nociceptive pain arises from actual or potential tissue damage to the musculoskeletal or visceral tissue. It includes somatic and visceral pain. Somatic pain, the most common pain type, results from bone, joint, muscle, skin, or connective tissue damage. It presents as a well-localized aching, throbbing, stabbing, or pressure sensation, and its source is skin, muscle, or bone. Examples include arthritis and bone fracture. This type of pain responds to nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and opioids to some extent. Bisphosphonates or calcitonin may be used as adjuvant treatment in patients whose pain does not respond to NSAIDs or corticosteroids. 2 Palliative radiotherapy directed at the pain site may be beneficial in relieving pain in patients who do not respond to other adjuvant treatments.

3 Visceral pain originates in the internal organs (stomach, intestines, liver, and pancreas) and presents as a poorly localized gnawing, cramping, aching, squeezing, or pressurelike sensation. Common examples of this pain syndrome are bowel obstruction and liver metastasis. Opioids are used to treat this type of pain, as are adjuvant medications, including medications to reduce the amount of gastrointestinal (GI) stimulation, such as antiemetics and anticholinergics (for peristalsis and secretions). 2 Neuropathic pain arises from dysfunction of the peripheral and central nervous system (CNS). It is characterized by numbness, tingling, burning, lancinating or radiating, electrical sensations, or other abnormal sensations. Although opioid therapy will address some of this pain, more often adjuvant medications are needed to palliate neuropathic pain syndromes, including tricyclic antidepressants, anesthetics, muscle relaxants, and topical capsaicin. 2 An important aspect to symptom management is the use of nonpharmacologic therapies. Interventions such as therapeutic and physical exercise, massage, hot and cold treatment, music therapy, relaxation and imagery techniques, and complementary or alternative medications are very helpful and often potentiate medication therapy. 3 Nonopioid and Opioid Therapy There are several methods of approaching pain management therapy. Often patients require different medications to address the variety of pain syndromes. Adopting a stepwise approach to the use of pain medication can be beneficial to effective pain management. The WHO has developed a simple three-step model for managing cancer pain that can be applied to other chronic or life-limiting illnesses. 4 This approach uses nonopioid medications such as acetaminophen, NSAIDs, and adjuvants for mild pain. More severe pain should be treated with opioids, along with nonopioids and adjuvants, as represented in efigure 9-. This approach relieves pain in 80% to 90% of patients with cancer. 4 Nonopioid Analgesics Acetaminophen is a medication with minimal side effects and drug interactions that is used for management of mild musculoskeletal pain or is used in conjunction with other medications for more efigure 9- World Health Organization s pain ladder. Available at Freedom from cancer pain Opioid for moderate-tosevere pain +/ Nonopioid +/ Adjuvant Pain persisting or increasing Opioid for mild-to-moderate pain +/ Nonopioid +/ Adjuvant Pain persisting or increasing Nonopioid +/ Adjuvant 3 2 severe pain syndromes. Although lacking in antiinflammatory properties, it is frequently used to treat fever and pain. The ceiling dose of acetaminophen limits its daily dosage to less than 4 g. Beyond the recommended maximum daily dosage, there is an increased risk of side effects, most notably liver dysfunction. Because of liver toxicity, acetaminophen should be used in reduced doses or avoided in patients with liver insufficiency. 5 NSAIDs such as ibuprofen, naproxen, and celecoxib are used for treating mild, moderate, and severe pain alone or in conjunction with other medications. They are useful analgesics, antipyretics, and antiinflammatory medications. For this reason, they are particularly helpful for nociceptive, inflammatory pain syndromes. NSAIDs potentiate the effectiveness of opioids, thereby reducing the needed opioid dose and lessening adverse effects (e.g., confusion, sedation, and dizziness). 6 Similar to acetaminophen, the NSAIDs exhibit a ceiling effect and have relatively few adverse effects and drug interactions. However, renal and liver insufficiency or failure is considered a relative contraindication. Opioids Opioid analgesics are very useful for treating pain in palliative and end-of-life care. Pain relief from opioids is mediated through binding to opioid receptors (mu, kappa, and delta) located within the brain and spinal cord; this binding prevents the release of neurotransmitters involved in the transmission of pain. Opioids are classified as agonist, mixed agonist antagonist, and antagonist. 7 A full agonist is a substance that produces the same or similar effect as the body s normal chemical messenger at the receptor site. It is the preferred agent to treat moderate-to-severe pain. Examples of opioids that are full agonists are morphine, oxycodone, hydromorphone, fentanyl, and methadone. For a complete listing of opioids, refer to Table A mixed agonist antagonist acts as an agonist at some opioid receptors and an antagonist at others. Such an agent has limited use in pain and palliative care. An antagonist demonstrates the opposite action to that of an agonist at the receptor site. It is used for acute overdose and, in some cases, to treat opioid-induced constipation. Morphine is considered the gold standard agonist because there is an abundance of data and experience with this opioid medication. It is used as a measure of equianalgesic dosing. 7 Adverse effects of morphine, such as nausea and vomiting, pruritus, and sedation, occur soon after drug absorption but typically subside after a few days of use. Morphine is metabolized via the hepatic system to morphine 3-glucuronide and morphine 6-glucuronide, both of which can be toxic to patients if accumulation occurs. Metabolite effects are seen within several days after initiating the medication. If side effects or metabolite accumulation outweigh the beneficial use of morphine, switching to an alternative opioid may be warranted. Oxycodone is a synthetic opioid that serves as an alternative to morphine. It is available in long-acting and immediate-release formulations. Adverse effects are similar to those of morphine. Fentanyl is a highly potent opioid. Its lipophilic properties allow this medication to be absorbed parenterally, transdermally, and transmucosally. 7 Transdermal fentanyl is particularly useful for patients who are unable to swallow and those who are noncompliant with their medications. However, patients with lean body mass and body temperature changes may have absorption issues with transdermal fentanyl. Methadone is a synthetic opioid useful in the management of severe pain. It is the only available liquid long-acting opioid agent. Its long half-life allows for prolonged dosing intervals of 8 to 2 hours. Methadone acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, which may explain its usefulness for neuropathic pain syndromes. Despite benefits, there is no set established method of 2 e CHAPTER Palliative Care 9

4 22 SECTION Foundation Issues dosing or equianalgesic dosing of methadone. Close monitoring is thus necessary when initiating a patient on this medication. 8 Other opioids may be used in palliative care, including hydromorphone, codeine, oxymorphone, and tramadol. Nausea, vomiting, sedation, pruritus, and most other adverse effects of opioids will subside within a few days. 9 One common adverse effect that does not subside is constipation. As a result, opioid-induced constipation requires treatment. It is best managed by starting a prophylactic laxative regimen and continuing it for the duration of opioid use. 20 Respiratory depression is a potentially lifethreatening complication of opioid use and is often considered the most serious side effect because opioids can depress both the rate and the depth of respiration. However, with careful dosing and slow titration of the opioid, especially in opioid-naive patients, this side effect can be managed, monitored, and controlled, and opioids can be safely administered. Often healthcare providers are leery of prescribing opioids because of legal scrutiny. Prescribers may be concerned that patients will become addicted to opioid medication. As a terminal disease progresses, tolerance will develop to the current opioid regimen, and increased doses may be needed to adequately manage the pain. Tolerance, the need for increased medication dosing to achieve the same effect, is typical in patients with pain. Most patients taking opioids, whether for pain or illicit use, become physically dependent, such that abrupt discontinuation of the medication results in a withdrawal syndrome. Addiction or psychologic dependence is characterized by compulsive medication use and medication-seeking behavior despite potential or actual harm to the patient. The use of opioids to treat pain experienced by a terminally ill patient at appropriate and monitored doses and titrations, however, rarely results in addiction. Pain management concepts are thoroughly reviewed in Chapter 44, although medication and doses discussed in this chapter pertain more specifically to palliative care pain management needs. Clinical Controversy... Opioid Use Many ethical issues arise from the use of opioid medications in palliative and hospice care. Questions about the appropriate pain management and fears of addiction often play a role in decisions made regarding opioid use and dosing for terminally ill patients. Prescribers are often concerned about legal ramifications regarding excess prescribing of opioids or complications of death surrounding opioid use. At times, prescribers may fear that opioid use will hasten death, particularly as a result of respiratory depression. They therefore tend to underprescribe opioid medications that terminally ill patients may need. Overdosing or hastening of death in terminally ill patients may be unfounded, but it continues to be a source of discussion, debate, and concern for those in the healthcare community. Adjuvants and Coanalgesics Adjuvant analgesics are medications with primary indications other than pain but with analgesic properties in patients with certain pain syndromes. A wide variety of medication classes are used for neuropathic, bone, and visceral pain. They can be used alone or in combination with other pain management therapies (e.g., opioid therapy) and are usually considered after opioid therapy has been optimized or the patient has demonstrated intolerance to an opioid. Clinicians should be familiar with the indications, common adverse effects, adverse reactions, pharmacokinetics, and dosing guidelines of these medications for pain. Typical adjuvants are antidepressants, anticonvulsants, corticosteroids, and disease-modifying medications and therapies (etable 9-).

5 etable 9- Adjuvant Analgesics Used in Palliative Care Medication Class Dosing Indication Antidepressants Amitriptyline TCA 0 50 mg/day Neuropathic pain syndromes Nortriptyline TCA 0 50 mg/day Neuropathic pain syndromes Paroxetine SSRI antidepressant 0 40 mg/day Neuropathic pain syndromes Citalopram SSRI antidepressant 0 40 mg/day Neuropathic pain syndromes Duloxetine SNRI 60 mg/day Neuropathic pain syndromes Anticonvulsants Carbamazepine First-generation anticonvulsant mg/day Neuropathic pain syndromes Gabapentin Second-generation anticonvulsant mg/day Neuropathic pain syndromes Pregabalin Second-generation anticonvulsant mg/day Neuropathic pain syndromes Corticosteroids Prednisone Corticosteroids mg/day Bone pain Dexamethasone Corticosteroids 4 20 mg/day Bone pain Other Lidocaine Anesthetics Various; dependent on Neuropathic pain syndromes dosage form Baclofen Muscle relaxant mg/day Neuropathic pain syndromes Calcitonin Polypeptide hormone IU/day IV or SC Bone pain Pamidronate Bisphosphonates mg IV Bone pain 23 e CHAPTER Palliative Care 9 IU, international unit; SNRI, selective norepinephrine reuptake inhibitor; SC, subcutaneous; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. Dypsnea Dyspnea, or breathlessness, is a common, distressing symptom experienced by those with debilitating or chronic diseases and those who are terminally ill. Although difficult to clearly define and assess, dyspnea is described as a subjective perception or an uncomfortable awareness of breathing. 2 It may evoke panic, anxiety, worry, frustration, anger, or depression in patients. Just as multiple factors can contribute to dyspnea, varied mechanisms can produce respiratory changes that are manifest as dyspnea. Therefore, it is best to determine the underlying specific cause of dyspnea and develop a treatment plan accordingly. 22 However, unnecessary interventions to determine underlying causes should be avoided and may be inappropriate in terminal dyspnea. 23 Primary causes of dyspnea include chronic diseases (e.g., chronic obstructive pulmonary disease [COPD], congestive heart failure, and neuromuscular disease), other illnesses (e.g., pneumonia and pulmonary embolism), and cancer-induced complications (e.g., bronchial obstruction). Dyspnea can also be caused or worsened by factors such as anemia, pleural effusion, pneumonia, anxiety, and tumor growth. General treatment strategies should be introduced to reduce dyspnea. These may include repositioning the patient to an upward sitting or leaning position, rearranging furniture to allow for easier mobility, or providing support to reduce the need for exertion. Fans and open windows increase air flow over the face, thus stimulating the trigeminal nerve and thereby reducing the sensation of air hunger. 24 In addition, anxiety must be addressed with medications or behavioral treatments, such as relaxation exercises, education, and distraction. Although oxygen will not reverse the cause of breathlessness, it may provide relief in some patients through improvement of ventilatory muscle function in hypoxemic COPD patients. 25 However, the majority of patients who report breathlessness are not hypoxemic; therefore, oxygen may not be beneficial in patients with terminal diagnoses other than respiratory disease. The effect of oxygen on quality of life has not been systematically studied, and clinical appropriateness is uncertain. Medication Therapy Opioids remain the medication of choice in the treatment of terminal dyspnea. The exact mechanism of action of opioids for treatment of dyspnea is unclear; however, it is known to reduce the sensation of breathlessness 26 as a result of the body s ventilatory response to decreased oxygen and rising carbon dioxide levels. Opioids can be used alone or in combination with other medications to control breathlessness. Opioid-naive patients should begin with 5 to 5 mg of oral morphine. Opioid-tolerant patient dosages may be increased by 25% to 50% and titrated appropriately. For severe intractable dyspnea, opioids should be administered parenterally. Parenteral morphine can be administered 2 to 5 mg every 0 minutes until breathlessness is relieved. etable 9-2 outlines opioid treatment options and dosing in palliative care. Essentially, all routes of administration of opioids have been useful for dyspnea relief. However, evidence supporting use of nebulized opioids is limited, and further clinical trials are needed to determine the role of nebulized opioids. 27,28 Opioids, despite the route of administration, should be titrated to respiratory relief rather than to a specific respiratory rate. Anxiolytics, such as benzodiazepines, work similarly to opioids in treating dyspnea by reducing the ventilatory drive that is initiated from low oxygen and rising carbon dioxide levels. 29 They can be administered in conjunction with opioids in patients experiencing anxiety-related dyspnea but should not be considered first-line management for dyspnea. Benzodiazepines can cause hypotension, and when combined with other CNS depressants, they can cause increased sedation and respiratory depression. Additionally, benzodiazepines can worsen delirium by causing further confusion, particularly in the elderly patient population. Lorazepam and alprazolam are commonly used benzodiazepines because of their relatively short half-lives. Some patients have a reversible airway component to their dyspnea (i.e., COPD or asthma) and may benefit from corticosteroids. Corticosteroids such as prednisone, dexamethasone, and methylprednisolone treat bronchospasms, reduce edema from inflammation or tumor growth, promote a positive effect on a patient s well-being,

6 24 SECTION Foundation Issues etable 9-2 Opioid Therapy Options for Patients Receiving Palliative Care Opioid-Naive Patients with Mild Dyspnea Treatment options: Hydrocodone 5 mg PO every 4 h Codeine 30 mg PO every 4 h For breakthrough symptom management, give an equivalent dose every 2 h as needed. Opioid-Naive Patients with Severe Dyspnea Treatment options: Morphine sulfate 5 mg PO every 4 h Oxycodone 5 mg PO every 4 h Hydromorphone mg PO every 4 h For breakthrough symptom management, give an equivalent dose every 2 h as needed. Titrate in increments of 50% 00% every 24 h as needed. For patients with severe pulmonary disease, such as COPD, start at 50% of the above doses and titrate more conservatively with increments of 25% every 24 h as needed. Opioid-Tolerant Patients Increase baseline opioid dose by 25% 50% and titrate as above. COPD, chronic obstructive pulmonary disease; PO, by mouth. Reprinted from the Lancet Oncology, Vol. 3, Thomas J, VonGuten C, Clinical management of dyspnea, , Copyright 2002, with permission from Elsevier. and stimulate appetite. Therefore, corticosteroids are useful in lung conditions that involve inflammation or obstruction; however, it may take up to a few weeks to see a complete response. Adverse effects of corticosteroid use include insomnia, nervousness, indigestion, hyperglycemia, arthralgia, and hirsutism. Because these agents can cause insomnia, corticosteroids should be administered no later than 2:00 or 3:00 pm. Inhaled corticosteroids used to prophylactically suppress inflammation in the airways are not effective for acute bronchospasms. They are recommended for patients with COPD or asthma who have frequent breathing exacerbations that require antibiotics or systemic corticosteroid therapy. Bronchodilators such as salbutamol, albuterol, and ipratropium are useful for treating reversible bronchospasm. Methylxanthines such as theophylline may have a role in bronchodilation as well. The narrow therapeutic window of this drug class and the drugs adverse effects limit their clinical value in palliative care treatment. Further research is needed to assess the role of bronchodilators in terminal dyspnea. Detailed information on treatment measures for COPD and patients with asthma is contained in Chapters 5 and 6. Recommendations within this chapter refer specifically to medications and doses used in hospice patient population for the relief of dyspnea. Nausea and Vomiting Nausea and vomiting are very common at the end of life, occurring in 20% to 60% of all patients with advanced cancer. 30 These symptoms can occur in all patients regardless of diagnosis; patients at most risk are females, younger than 65 years of age, have stomach or pancreatic cancer, have recently received chemotherapy, or have recently started on opioid therapy (within the last 3 4 days). Nausea and vomiting can affect the total well-being of the patient and his or her quality of life, appetite, weight loss, and pain management. Nausea is an unpleasant sensation that the patient may vomit. It occurs at the back of the throat or in the upper gastric region or abdomen. It is often associated with cold sweats, pallor, diarrhea, and tachycardia. Retching is a forceful spasmodic contraction of the abdominal muscles and the diaphragm, which may or may not be associated with nausea. Vomiting is the forceful expulsion of abdominal contents through the oral or nasal cavity. Similar to retching, it may or may not be associated with nausea. 3 The etiology of nausea and vomiting is complex and requires careful assessment and treatment selection of medication according to the underlying cause. There are a number of different areas in the body that participate in the development of nausea and vomiting, including two main organ systems: the GI tract and the area postrema (the chemoreceptor trigger zone, the vestibular apparatus, and the cerebral cortex of the brain). Each area responds to emetic stimuli modulated by specific neurotransmitters (dopamine, acetylcholine, serotonin, and histamine) binding to receptors. All four neurotransmitters are located in the area postrema and the GI tract; whereas serotonin is most prevalent in the GI tract, acetylcholine and histamine regulate the vestibular apparatus. The cortex is not associated with specific neurotransmitters and has a more complex mechanism. 32 The etiology and pathophysiology of nausea and vomiting are reviewed thoroughly in Chapter 22. As with any symptom, general treatment measures and nonpharmacologic interventions are often helpful. Making dietary changes to avoid sweet, salty, fatty, or spicy foods can help reduce nausea and vomiting, as can eating smaller meals and avoiding noxious smells. Acupuncture and acupressure have been demonstrated to greatly improve outcomes of nausea and vomiting. 33 Medication Therapy Routine antiemetic medication administration helps to prevent recurrent nausea and vomiting. If a patient experiences refractory nausea and cannot tolerate oral medications, alternative routes of administration, such as rectal, IV, or subcutaneous, may be necessary. The main drug classes used to palliate nausea and vomiting are dopamine antagonists, antihistamines, anticholinergics, serotonin antagonists, and prokinetic agents. Dopamine antagonists are the treatment of choice for nausea and vomiting. Antagonism occurs at the dopamine receptors in the chemoreceptor trigger zone. Dopamine antagonists can be divided into two classes, phenothiazines and butyrophenones. Phenothiazines include prochlorperazine, promethazine, and chlorpromazine. These agents antagonize other receptor types, which results in multiple adverse effects, such as sedation and anticholinergic side effects of blurred vision, dry mouth, constipation, and urinary retention. Butyrophenones are more specific for dopamine receptors, the most commonly used agent being haloperidol. Haloperidol is one of the most useful medications for nausea and vomiting in palliative care. As a result of its affinity for dopamine receptors, haloperidol is associated with extrapyramidal symptoms, including dystonia, akathisia, and Parkinson-like symptoms. 34 Common antihistamines with anticholinergic effects are effective in the management of vestibular- or movement-induced nausea and vomiting. These agents include meclizine and hydroxyzine. Anticholinergic medications such as hyoscyamine, glycopyrrolate, and scopolamine are also used for movement-induced nausea and vomiting. Adverse effects of these agents include dry mouth, urinary retention, blurred vision, and drowsiness. Anxiety- or anticipatory-induced nausea and vomiting may benefit from benzodiazepine therapy, although there is limited evidence to support their use. Medications such as lorazepam can be useful for nausea and vomiting that appear to be caused by anxiety. Corticosteroids have a nonspecific antiemetic effect. The mechanism of action is not well understood, but they are especially useful in nausea caused by increased intracranial pressure,

7 which often results from brain tumors. Dexamethasone has synergistic antiemetic effects when combined with serotonin agents or phenothiazines. Serotonin receptor antagonists such as ondansetron are effective for chemotherapy- and radiation-induced nausea and vomiting. Because the majority of hospice patients have discontinued aggressive treatment, including chemotherapy, and the role of these agents is often limited in that setting. Prokinetic agents are useful for dysmotility issues in the GI tract. They act by mediating activity via the cholinergic system. Metoclopramide administration for this purpose often helps alleviate nausea and vomiting. Another concern for patients with advanced disease is complete or partial bowel obstruction. Bowel obstruction is the blockage of forward flow of gastric and intestinal contents through the GI tract. It can be caused by ineffective motility of the bowel or by an occlusion of the bowel lumen (e.g., by a malignant tumor). The gut becomes dilated and inflamed near the obstruction, causing an increase in peristalsis and oversecretion of intraluminal fluid. 35 This cycle leads to nausea and vomiting, abdominal distension, change in bowel sounds or habits, stomach cramping, and colic. Bowel obstruction is most common in abdominal and pelvic cancers. Surgery is generally not recommended for patients with a life expectancy of less than 2 months 36 because high rates of infection and complications result without much if any improvement in survival, quality of life, or palliation of symptoms. 37 With bowel obstructions, the goals of any treatment must be made clear to the patient and caregivers. These are to reverse the underlying cause, if possible (e.g., postradiation bowel damage, inflammatory bowel syndrome, hernia, or lumen adhesions); minimize or eliminate obstruction; and enhance quality of life for the patient. Although nasogastric (NG) tube placement can relieve symptoms, placement should be for a limited amount of time while other treatment options are explored. NG tubes are intrusive and distressing and can cause complications. 38 Thus, they should be placed only as a last resort. If there is no reversible cause of the obstruction, a combination of medication therapy is usually indicated and effective for symptom control. Medications include opioids (for pain), anticholinergics (to control gastric secretions), and antiemetics (if needed). Scopolamine and octreotide help control gastric secretions and nausea and vomiting. Octreotide is a synthetic somatostatin that inhibits the release of several GI hormones and therefore regulates GI functioning by decreasing secretion production, blood flow, and bowel flow. Patients with a complete bowel obstruction should not be administered metoclopramide. Rather, the focus should be on controlling the secretions. This can be accomplished with anticholinergic medications. Constipation Constipation is a prevalent condition in patients receiving palliative care. Up to 20% of Americans have chronic constipation, and it affects 50% to 90% of terminally ill patients. 39 Preventing constipation is of key importance; however, early recognition and treatment are paramount if prevention is not possible. Constipation can cause great discomfort; can negatively affect the activities of daily living; and can decrease nutritional intake, socialization, and quality of life. If it is left untreated, it can lead to fecal impaction and bowel obstruction. Two aspects should be considered when assessing constipation, measurable symptoms (frequency and characteristics of stool) and patient perception. 40 Constipation is a subjective symptom, and as such, assessment and measurement rely on patient definition. However, if a patient has fewer than three bowel movements per week, a thorough assessment is warranted. 4 Constipation is also defined as the discomfort associated with reduced bowel movement frequency. 42 Constipation can be broadly categorized as functional or anatomical. Functional constipation can be caused by abnormalities in the neural regulation or motor function of the colon. Dysfunction in the colon leads to decreased colonic transit time, resulting in 25 e CHAPTER Palliative Care 9

8 26 SECTION Foundation Issues constipation. Anatomical constipation is caused by physical obstacles such as tumor and stricture. The etiology of constipation varies in palliative care. For most patients at the end of life, correcting the underlying pathophysiologic cause of constipation is often not possible or appropriate; therefore, the goals of constipation management in palliative care are to reestablish bowel habits, relieve pain and discomfort, and improve the quality of life. Patients at risk of constipation are those with low intake of food, fiber, and fluids; with impaired mobility; with complicating medical condition, such as bowel obstruction; or taking prescribed medications that impair GI motility. Several medications can cause constipation. Patients prescribed opioids require a preventive maintenance bowel regimen because opioids are one of the most constipating medication classes used in palliative and hospice care. Tolerance develops to many adverse effects of opioids but not to the drugs constipating effects. Prophylactic constipation management is warranted for patients initiated on opioid therapy. Many diseases and conditions common at the end of life can cause constipation; these include bowel cancer, anal fissure, bowel obstruction, and hemorrhoids; metabolic disturbances, such as hypercalcemia, hypokalemia, hypothyroidism, and diabetes; and neurologic disorders, such as Parkinson s disease and spinal cord lesions. Ruling out impaction or obstruction while assessing a patient for constipation is of key importance. Impaction occurs when a large fecal mass cannot move through the colon. The result is liquid stool formed by bacteria in the colon that surrounds the mass; the end result presents as diarrhea with fecal and, at times, urinary incontinence. Tumors or adhesions in the colon can result in bowel obstruction and can present as a combination of alternating constipation and diarrhea, colic, and nausea and vomiting. This should be suspected in patients with intraabdominal malignancies or previous abdominal surgeries. General treatment measures are important to aid in the resolution of constipation. As such, mobility should be encouraged to the extent possible to increase colon peristalsis. Patients should be encouraged to increase their oral intake of fluids to prevent dehydration. Attempts should be made to increase the fiber content; however, the priority should be placed on increasing caloric intake of foods the patient enjoys. Increasing fiber alone will not correct severe constipation. If possible, medications that are constipating should be avoided. Finally, it is important to encourage daily routine toileting. 43 Medication Therapy Several classes of cathartic medications are available (etable 9-3). These medications are grouped based on their mechanisms of action. Many of these are used for general constipation management. Further details pertaining to constipation can be found in Chapter 23. Stimulant laxatives are considered first-line treatment in palliative care. By stimulating the myenteric plexus, peristalsis is induced. Examples include senna and bisacodyl. Because these agents may induce colic, they are not recommended in bowel obstruction. Osmotic laxatives such as sorbitol and lactulose are indigestible sugars that cause an increase in fluid in the intestines to dilute sugars. The increase in water results in a softer stool and distension etable 9-3 Medications for Constipation in Palliative Care Laxative Adult Dose Onset of Action Comments Bulk Forming Methylcellulose PO (powder or capsules): 3 times per day 2 48 h Source of fiber; less gas formation compared with psyllium Polycarbophil PO (caplets): 4 times per day 2 48 h May be ineffective if patient has preexisting constipation or is nonambulatory Psyllium PO (powder, wafer or capsule): 3 times per day 2 48 h Source of fiber; adequate water ingestion required (,000,500 ml/day) Osmotic Lactulose Oral (liquid): 5 60 ml/day h More expensive than sorbitol Polyethylene glycol Oral (powder): 7 g in 8 oz water daily h Lacks salty taste, making it a good option; more expensive than sorbitol Sorbitol Oral (liquid):5 60 ml per day h 70% solution; sweet taste Saline Magnesium citrate Oral (liquid): 8 oz PO once; repeat as needed h Saline laxatives more useful on an as-needed basis; electrolyte imbalances are possible with all of the saline laxatives; use caution when prescribing to patients with declining renal function Magnesium hydroxide PO (liquid): 5 60 ml once; repeat as h needed Sodium phosphate PR: one adult enema Within 30 min Stimulant Bisacodyl PO: 0 5 mg to 3 times per day PO: 6 2 h PR: suppository per day PR: 5 60 min Senna PO (liquid or tablet): 2 to 4 tablets or 2 times per day Stool Softener Docusate sodium PO (capsule or liquid): 00 to 400 mg 2 times per day 6 2 h Good first-line agent, especially in those receiving chronic opioids hours Not as effective when used as monotherapy and is best when combined with other laxatives PO, by mouth; PR, per rectum. Adapted or Reprinted with permission from Management of Common Opioid-Induced Adverse Effects, October 5, 2006, American Family Physician. Copyright 2006 American Academy of Family Physicians. All Rights Reserved.

9 of the bowel, which stimulates peristalsis. The onset of action occurs within 24 to 48 hours. Surfactant laxatives, also called emollient laxatives or stool softeners, increase water penetration into the stool, thereby softening it and allowing easier passage through the bowel. Effects are seen within 24 to 72 hours. An example is docusate sodium. Bulk-forming laxatives increase stool size. This causes distension of the intestinal lumen, induces peristalsis, and decreases transit time through the intestine. The net result of these effects is an increased frequency of defecation. Use of bulk-forming agents should, however, be limited in the palliative care patient population. Patients ingesting bulk laxatives with relatively little activity and decreased fluid intake are at risk of forming an obstruction. Bulk-forming laxatives are also not effective for severe constipation. Last, they have a grainy, unfavorable texture that may be nauseating to some patients. Methylcellulose, polycarbophil, and psyllium are examples of bulk-forming laxatives. Suppositories and various enemas may be necessary for refractory constipation 44 because many newer agents, such as the opioid antagonists naloxone and methylnaltrexone, interrupt the constipating effects mediated by opioid receptors in the gut. They are effective in about 50% of patients with severe opioid-induced constipation within 4 hours of administration. 44,45 These medications have limited use in palliative care because of their expense and the need for subcutaneous administration. Delirium Delirium is a common neuropsychiatric symptom in patients with advanced terminal diseases. It is defined as an acquired syndrome of disordered consciousness and cognition that develops over a short period of hours or days. It is often worse at night. 46 Hallmark features of delirium include an acute onset and fluctuating course; inattention, with difficulty focusing and easy distraction; an altered level of consciousness; and cognitive impairment, impaired memory, disorientation, delusions, or hallucinations. Because delirium is classified as a disorder of arousal and cognition, 47 the patient s activity level can vary. There are three subtypes of delirium. Hyperactivity (i.e., hyperaroused, agitated) is marked by hypervigilance, agitation, restlessness, and hallucinations; hypoactivity (i.e., hypoaroused, hypoalert) is marked by slow psychomotor activity, lethargy, and apathy (it is often mistaken for sedation caused by opioids in the final hours of life); and mixed (i.e., fluctuates between hyperactive and hypoactive types). 48 In palliative care, hypoactive delirium is more common than the other two subtypes, affecting up to 80% of patients with delirium. As such, delirium is often mistaken for fatigue or depression. Terminal delirium occurs in the final hours to weeks of life. To some extent, terminal delirium is experienced by most, if not all, dying patients. Because of the similarity of symptoms in dementia, depression, and delirium, the differential diagnosis can be difficult. Although all three can occur simultaneously, each has a different pathophysiology and therefore requires different treatment measures. 6 Delirium can be very disturbing and distressing to patients, family, caregivers, and staff, making education important. Families need to be aware of the disease process and how their loved one is experiencing it. Because delirium is often a preterminal event, it can result from several etiologies simultaneously. Causes include infections (e.g., urinary tract infection, pneumonia, and sepsis); electrolyte and metabolic imbalances; GI complications (e.g., bleeding, constipation, and urinary retention); sensory deprivation, overstimulation, and environmental changes; polypharmacy (e.g., use of anticholinergics, opioids, and sedatives); and cardiopulmonary (e.g., myocardial infarction, hypoxia, and hypotension). 49,50 The goal of managing delirium is to prevent or reverse the course when possible. Although about one-third of delirium episodes are reversible, 5 it is often not reversible in the last 24 to 48 hours of life. Environmental interventions, such as clock and calendar placement; noise minimization; a quiet, well-lit room; and the presence of family, help to improve orientation, decrease sensory overload or deprivation, and provide reassurance for the patient. 52 Discontinuing unnecessary medications can improve symptoms of delirium. Medication Therapy Antipsychotic or neuroleptic agents are the treatment of choice in this setting. Haloperidol is often the first-line treatment for delirium; it is a neuroleptic agent with potent dopamine blockade. Haloperidol has few anticholinergic effects, few metabolites, and a low risk of hypotension during short-term use. The majority of palliative care patients can be successfully managed by oral haloperidol, although it can be administered subcutaneously, IV, and intramuscularly if needed. 53 It is common to add a benzodiazepine such as lorazepam to the antipsychotic regimen to increase sedation and minimize the risk of extrapyramidal symptoms produced by agents such as haloperidol. Second-generation, or atypical, antipsychotic agents are alternatives in patients for whom haloperidol is contraindicated, although the evidence supporting their use is lacking. Newer agents, such as olanzapine, risperidone, and quetiapine, are generally safe but expensive. 54,55 Anorexia and Cachexia Anorexia (loss of appetite) and cachexia (weight loss) are common symptoms in patients receiving palliative care. 56 They may be experienced alone or in conjunction with each other. Although anorexia and cachexia may occur in up to 80% of patients with advanced cancers, 57 they are also common in elderly adults; children; and those 27 e CHAPTER Palliative Care 9