Key Points

Opioid therapy is the mainstay for pain and dyspnea management inthe actively dying patient.

It is recommended that pain medication is given on a standing basis, with “prn” doses available for exacerbations of pain at end of life when pain is generally experienced on a constant basis.

A thorough history and physical examination can help one determine the likely cause and pathway involved in nausea and vomiting, and can help guide appropriate pharmacologic management.

Anticholinergic medications can help reduce secretions at end of life.

Additional Reading

Steinhauser KE, Christakis NA, Clipp EC, McNeilly M, McIntyre L, Tulsky JA. Factors considered important at the end of life by patients, family, physicians and other care providers. JAMA. 2000;284(19):2476-2482.

Qaseem A, Snow V, Shekelle P, et al. Evidence-based interventions to improve the palliative care of pain, dyspnea, and depression at the end of life: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;148(2):141-146.

Whitecar PS, Jonas AP, Clasen ME. Managing pain in the dying patient. Am Fam Physician. 2000;61(3):755-764

Tyler LS. Nausea and vomiting in palliative care. In: Lipman AG, Jackson KC, Tyler LS, eds. Evidence-Based Symptom Control in Palliative Care. New York: The Hawthorn Press; 2000.

Case

A 58-year-old male with colon cancer metastatic to the liver and lungs presents with vomiting, dyspnea, and abdominal pain. His disease has progressed through third-line chemotherapy and his care is now focused entirely on symptom management. He has not had a bowel movement in five days and he began vomiting two days ago.

Overview

The majority of patients in the United States die in acute-care hospitals. The Study to Understand Prognosis and Preferences for Outcomes and Risks of Treatments (SUPPORT), which evaluated the courses of close to 10,000 hospitalized patients with serious and life-limiting illnesses, illustrated that patients’ end-of-life (EOL) experiences often are characterized by poor symptom management and invasive care that is not congruent with the patients’ overall goals of care.¹ Studies of factors identified as priorities in EOL care have consistently shown that excellent pain and symptom management are highly valued by patients and families. As the hospitalist movement continues to grow, hospitalists will play a large role in caring for patients at EOL and will need to know how to provide adequate pain and symptom management so that high-quality care can be achieved.

Pain: A Basic Tenet

A basic tenet of palliative medicine is to evaluate and treat all types of suffering.² Physical pain at EOL is frequently accompanied by other types of pain, such as psychological, social, religious, or existential pain. However, this review will focus on the pharmacologic management of physical pain.

Pain management must begin with a thorough evaluation of the severity, location, and characteristics of the discomfort to assess which therapies are most likely to be beneficial (see Table 1).³ The consistent use of one scale of pain severity (such as 0-10, or mild/moderate/severe) assists in the choice of initial dose of pain medication, in determining the response to the medication, and in assessing the need for change in dose.⁴

Table 1. Medications beneficial in treating pain at end of life3

Opioids are the foundation of pain management in advanced diseases because they are available in a number of formulations and, when dosed appropriately, they are effective and safe. Starting doses and equianalgesic doses of common opioids are presented in Table 2. Guidelines recommend the use of short-acting opioids for dose titration to gain control of poorly controlled pain.³ If a patient is experiencing mild pain on a specific regimen, the medication dose can be increased up to 25%; by 25% to 50%, if pain is moderate; and 50% to 100%, if severe.⁵ When the pain is better-controlled, the total amount of pain medication used in 24 hours (24-hour dose) can be converted to a long-acting formulation for more consistent pain management. Because there is a constant component to most advanced pain syndromes, it is recommended that pain medication is given on a standing basis, with as-needed (prn) doses available for exacerbations of pain.³ Prn doses of short-acting medication (equivalent to approximately 10% of the 24-hour dose of medication) should be available at one- or two-hour intervals prn (longer if hepatic or renal impairment is present) for IV or PO medications, respectively.

Opioids often are categorized as low potency (i.e. codeine, hydrocodone) and high-potency (i.e. oxycodone, morphine, hydromorphone, fentanyl). When given in “equianalgesic doses,” the analgesic effect and common side effects (nausea/vomiting, constipation, sedation, confusion, pruritis) of different opioids can vary in different patients. Due to differences in levels of expressed subtypes of opioid receptors, a given patient might be more sensitive to the analgesic effect or side effects of a specific medication. Therefore, if dose escalation of one opioid is inadequate to control pain and further increases in dose are limited by intolerable side effects, rotation to another opioid is recommended.⁴ Tables documenting equianalgesic doses of different opioids are based on only moderate evidence from equivalency trials performed in healthy volunteers.6 Due to interpatient differences in responses, it is recommended that the equianalgesic dose of the new medication be decreased by 25% to 50% for initial dosing.⁵

Certain treatments are indicated for specific pain syndromes. Bony metastases respond to NSAIDs, bisphosphonates, and radiation therapy in addition to opioid medications. As focal back pain is the first symptom of spinal cord compression, clinicians should have a high index of suspicion for compression in any patient with malignancy and new back pain. Steroids and radiation therapy are considered emergent treatments for pain control and to prevent paralysis in this circumstance. Pain due to bowel obstruction is usually colicky in nature and responds well to octreotide as discussed in the section on nausea and vomiting. Steroids (such as dexamethasone 4 mg PO bid-tid) might be an effective adjuvant medication in bone pain, tumor pain, or inflammation.

Table 2. Starting doses and equianalgesic doses of common opioids
*Half this dose should be used in renal or liver dysfunction and in the elderly.
Preferred in renal dysfunction.
SOURCES: Adapted from Assessment and treatment of physical pain associated with life-limiting illness. Hospice and Palliative Care Training for Physicians: UNIPAC. Vol 3. 3rd ed. Glenview, IL: American Academy of Hospice and Palliative Medicine; 2008, and Evidence-based standards for cancer pain management. J Clin Oncol. 2008;26(23):3879-3885.

Back to the Case

At home, the patient was taking 60 mg of extended-release morphine twice daily and six doses per day of 15-mg immediate-release morphine for breakthrough pain. This is the equivalent of 210 mg of oral morphine in 24 hours. His pain is severe on this regimen, but it is unclear how much of this medication he is absorbing due to his vomiting. Using the IV route of administration and a patient-controlled analgesia (PCA) system will enable rapid dose titration and pain control. The equivalent of the 24-hour dose of 210 mg oral morphine is 70 mg IV morphine, which is equivalent to a drip basal rate of approximately 3 mg IV morphine per hour. This basal rate with a bolus dose of 7 mg (10% of the 24-hour dose) IV morphine q1 hour prn is reasonable as a starting point.

Review of the Data: Nausea and Vomiting

Nausea and vomiting affect 40% to 70% of patients in a palliative setting.⁷ A thorough history and physical exam can enable one to determine the most likely causes, pathways, and receptors involved in the process of nausea and vomiting. It is important to review the timing, frequency, and triggers of vomiting. The oral, abdominal, neurologic, and rectal exams, in addition to a complete chemistry panel, offer helpful information. The most common etiologies and recommended medications are included in Table 3. It is worthwhile to note that serotonin-antagonists (i.e. ondansetron) are first-line therapies only for chemotherapy and radiation-therapy-induced emesis. If a 24-hour trial of one antiemetic therapy is ineffective, one should reassess the etiology and escalate the antiemetic dose, or add a second therapy with a different (pertinent) mechanism of action. Although most studies of antiemetic therapy are case series, there is good evidence for this mechanistic approach.⁸

Table 3. Common etiologies of pain and recommended medication treatment options
*EPS: extrapyramidal symptoms

The various insults and pathways that can cause vomiting are quite complex. The medullary vomiting center (VC) receives vestibular, peripheral (via splanchnic and vagal nerves), and higher cortical inputs and is the final common pathway in the vomiting reflex. The chemoreceptor trigger zone (CTZ) near the fourth ventricle receives input from the vagal and splanchnic nerves, and generates output to the VC.

General dietary recommendations are to avoid sweet, fatty, and highly salted or spiced foods. Small portions of bland foods without strong odors are best tolerated.⁷ Constipation commonly contributes to nausea and vomiting and should be managed with disimpaction, enemas, and laxatives as tolerated. Imaging may be required to make the important distinction between partial and complete bowel obstruction, as the treatments differ. Surgical procedures, such as colostomy or placement of a venting gastrostomy tube, can relieve pain and vomiting associated with complete bowel obstruction.

Back to the Case

The patient is found to have a fecal impaction on rectal exam, but vomiting persists after disimpaction and enema use. Imaging documents a complete bowel obstruction at the site of a palpable mass in the right upper quadrant and multiple large hepatic metastases. Octreotide is initiated to decrease intestinal secretions and peristalsis. Steroids are given to decrease tumor burden and associated inflammation in the intestine and liver, as well as to relieve distension of the hepatic capsule. Haloperidol is used in low doses to control episodes of nausea.

Review of the Data: Dyspnea

Dyspnea is a common symptom faced by patients at EOL. An estimated 50% of patients who are evaluated in acute-care hospitals seek treatment for the management of this often-crippling symptom.¹⁰ Unfortunately, as disease burden progresses, the incidence of dyspnea increases towards EOL, and the presence and severity of dyspnea is strongly correlated with mortality.

It is imperative for providers to appreciate that dyspnea is a subjective symptom, similar to pain. The presence and severity of dyspnea, therefore, depends on patient report. Given its subjective nature, the degree of dyspnea experienced by a patient might not correlate with objective laboratory findings or test results. In practice, the severity of dyspnea is commonly assessed with a numeric rating scale (0-10), verbal analogue scale, or with verbal descriptors (mild, moderate, severe). It is important to determine the underlying etiology of the dyspnea and, if possible, to target interventions to relieve the underlying cause. However, at the end of life, the burdens of invasive studies to determine the exact cause of dyspnea might outweigh the benefits, and invasive testing might not correlate with patients’ and families’ goals of care. In that instance, the goal of treatment should be aggressive symptom management and providers should use clinical judgment to tailor therapies based on the patient’s underlying illness, physical examination, and perhaps on noninvasive radiological or laboratory findings. Below are nonpharmacological and pharmacological interventions that can be employed to help alleviate dyspnea in the actively dying patient.

Nonpharmacological Management

A handheld fan aimed near the patient’s face has been shown to reduce the sensation of dyspnea.¹¹ This relatively safe and inexpensive intervention has no major side effects and can provide improvement in this distressing symptom.

Often, the first line of therapy in the hospital setting for a patient reporting dyspnea is the administration of oxygen therapy. However, recent evidence does not show superiority of oxygen over air inhalation via nasal prongs for dyspnea in patients with advanced cancer or heart failure.^12,13

Pharmacological Management

Opioids are first-line therapy for alleviating dyspnea in patients at EOL. The administration of opioids has been shown in systematic reviews to provide effective management of dyspnea.^14,15 Practice guidelines by leading expert groups advocate for the use of opioids in the management of dyspnea for patients with advanced malignant and noncancer diseases.^10,16 Fear of causing unintended respiratory sedation with opioids limits the prescription of opioids for dyspnea. However, studies have not found a change in mortality with the use of opioids appropriately titrated to control dyspnea.¹⁷

Studies examining the role of benzodiazepines in dyspnea management are conflicting. Anecdotal clinical evidence in actively dying patients supports treating dyspnea with benzodiazepines in conjunction with opioid therapy. Benzodiazepines are most beneficial when there is an anxiety-related component to the dyspnea.

Many patients with advanced disease and evidence of airflow obstruction will benefit from nebulized bronchodilator therapy for dyspnea. Patients with dyspnea from fluid overload (i.e. end-stage congestive heart failure or renal disease) might benefit from systemic diuretics. An increasing number of trials are under way to evaluate the efficacy of nebulized furosemide in the symptomatic management of dyspnea.

Back to the Case

The patient’s clinical course decompensates, and he begins to report worsening dyspnea in addition to his underlying pain. He becomes increasingly anxious about what this new symptom means. In addition to having a discussion about disease progression and prognosis, you increase his PCA basal dose to morphine 4 mg/hour to help him with this new symptom. You also add low-dose lorazepam 0.5 mg IV q8 hours as an adjunct agent for his dyspnea. The patient reports improvement of his symptom burden.

Review of the Data: Secretions

Physiological changes occur as a patient enters the active phase of dying. Two such changes are the loss of the ability to swallow and a reduced cough reflex. These changes culminate in an inability to clear secretions, which pool in the oropharynx and the airways. As the patient breathes, air moves over the pooled secretions and produces a gurgling sound that is referred to as the “death rattle.” The onset of this clinical marker has been shown to have significant prognostic significance for predicting imminent death within a period of hours to days. Proposed treatments for the symptom are listed below.

Nonpharmacological Management

Nonpharmacological options include repositioning the patient in a manner that facilitates postural draining.¹⁸ Careful and gentle oral suctioning might help reduce secretions if they are salivary in origin. This will not help to clear deeper bronchial secretions. Suctioning of deeper secretions often causes more burden than benefit, as this can cause repeated trauma and possible bleeding.

Family and caregivers at the bedside can find the “death rattle” quite disturbing and often fear that their loved one is “drowning.” Education and counseling that this is not the case, and that the development of secretions is a natural part of the dying process, can help alleviate this concern. Explaining that pharmacological agents can be titrated to decrease secretions is also reassuring to caregivers.

Pharmacological Management

Pharmacological options for secretion management include utilizing anticholinergic medications to prevent the formation of further secretions. These medications are standard of care for managing the death rattle and have been found to be most efficacious if started earlier in the actively dying phase.^19,20 Anticholinergic medications include glycopyrrolate (0.2 mg IV q8 hours), atropine sulfate ophthalmological drops (1% solution, 1-2 drops SL q6 hours), hyoscyamine (0.125 mg one to four times a day), and scopolamine (1.5 mg patch q72 hours). These medications all have possible side effects typical of anticholinergic agents, including delirium, constipation, blurred vision, and urinary retention.

Back to the Case

The patient becomes increasingly lethargic. You meet with his family and explain that he is actively dying. His family reiterates that the goals of medical care should focus on maximizing symptom management. His family is concerned about the “gurgly” sound they hear and want to know if that means he is suffering. You educate the family about expected changes that occur with the dying process and inform them that glycopyrrolate 0.2 mg IV q8 hour will be started to minimize further secretions.

Bottom Line

Pain, nausea, dyspnea, and secretions are common end-of-life symptoms that hospitalists should be competent in treating.

Dr. Litrivis is an associate director and assistant professor at the Mount Sinai School of Medicine in New York, and Dr. Neale is an assistant professor at the University of New Mexico School of Medicine in Albuquerque.