Jamie H. Von Roenn MD
Judith A. Paice PhD, RN
Michael E. Preodor MD
Internists care for a variety of patients with life-threatening illnesses, including those with cancer, cardiac disease, neuromuscular disorders, and many other illnesses. The number of these patients will grow as the population ages, increasing the need for physicians who can provide care to persons with advanced disease. Although usually provided in the context of an interdisciplinary team of physicians, nurses, social workers, chaplains, and other professionals, these formal services are not yet available in all health care settings. As a result, all physicians must be able to address some of the basic components of palliative care, including aggressive symptom management.
Of the many symptoms that occur during the end of life, pain is one of the most feared. Yet, the majority of patients can obtain relief, even during the final hours of life. In fact, despite concerns that high-dose infusions of parenteral opioids will be necessary, many patients remain on relatively low oral doses of these agents even until the time of death. An awareness of the common pain syndromes seen during this time will assist the physician to determine the underlying cause and devise an appropriate treatment plan.
Not unexpectedly, the prevalence of pain at the end of life varies with the underlying diagnosis as well as the setting of care. In a retrospective review of 400 patients referred for palliative care services in London, pain was the most common symptom, experienced by 64% of patients; most (90%) had cancer. Other common symptoms in this study included anorexia (34%), constipation (32%), weakness (32%), and dyspnea (31%). This prevalence is consistent with other studies of patients with advanced cancer.
Pain in HIV-infected persons is well documented as is the undertreatment of pain in this population. Unfortunately, the prevalence of pain associated with other life-threatening illnesses has not been studied in sufficient detail.
Patients referred to palliative care or hospice generally have a greater symptom burden, particularly increased prevalence of pain. For example, one study of lung cancer outpatients revealed that 27% had pain, compared with 76% of those referred to palliative care. However, after 2 weeks in hospice, pain usually diminishes significantly.
With the exception of cancer, few studies have explored specific pain syndromes associated with life-threatening illnesses. Table 9-1 lists pain syndromes that are common at the end of life.
Most patients experience continuous pain, with episodes of escalation. Breakthrough or transient pain is common at the end of life in persons with cancer and nonmalignant disease, though rapid escalation of pain in the last days and hours of life is not. Breakthrough pain is often spontaneous (40%)or related to movement (36%), to the analgesic regimen (35%), to coughing (11%), or to other factors (18%). In a recent study of patients seen by a palliative care service, breakthrough pain occurred in 75% of persons who had continuous pain. Of these, 30% were exclusively incidental, 26% were not related to a particular movement or other factors, and 16% were due to end-of-dose failure.
The assessment of pain in palliative care includes the principles discussed in Chapter 2. A thorough history and physical examination is critical when evaluating a
new pain complaint, with ongoing reassessment as warranted. Laboratory and imaging studies are conducted based on the patient's goals of care. If these tests yield information that will guide and inform treatment, they may be considered. However, if they are not likely to provide meaningful information, empiric management of the pain is warranted. Additionally, these tests can be painful, expensive, and can provide a false sense of hope to patients and families who believe the results may lead to some new cure.
Table 9-1. Pain Syndromes in Palliative Care.
Key aspects of pain assessment in palliative care include the following:
A variety of circumstances may confound pain assessment in patients with life-threatening illness. Diseases, such as dementia, stroke, Parkinson disease, and others, may limit self-report. As patients approach the end of life, the risk of-or potential for-cognitive impairment (including delirium) increases, making the use of standard, self-report tools difficult. Internists may also see patients in the intensive care unit who are ventilated and unable to respond. There is little research regarding pain assessment in palliative care patients with greater cognitive impairment or in those who have no ability to self-report. In the absence of standardized measures, these challenges can be addressed in several ways:
For many patients and their families, having a diagnosis of a life-threatening illness leads to significant existential distress. Although some patients and family members find this time a period of great personal growth, for others, futility, hopelessness, and anxiety are common. Spiritual issues and a sense of loss of meaning may arise. These are intertwined with the grief and distress experienced by loved ones and other caregivers.
Assessment includes the following:
Because physical symptoms, particularly pain, can increase suffering, it is critical to aggressively manage pain. This not only builds trust with patients and their families, but allows them to direct their energies toward addressing the other factors contributing to distress and suffering.
Prolonged pain (weeks to months) due to any etiology may change in character with time. For example, chronic abdominal pain due to advanced colon cancer with intraperitoneal spread begins as an achy pain, typical of nociceptive pain. It may assume a squeezing, pulling, neuropathic character that may become less responsive to opioid therapy. This underscores the need for frequent reassessment of pain and its prescribed management. Treatment of pain that has undergone neuropathic transformation follows the same principles of treatment as classic neuropathic pain (see Chapter 10).
Gutgsell T et al. A prospective study of the pathophysiology and clinical characteristics of pain in a palliative medicine population. Am J Hosp Palliat Care. 2003;20:140 .
Mercadante S et al. Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer. 2002;94:832 .
Potter J et al. Symptoms in 400 patients referred to palliative care services: prevalence and patterns. Palliat Med. 2003;17:310 .
World Health Organization. Cancer pain relief and palliative care. Geneva: World Health Organization, 1990.
The EPECTM Project. Education in Palliative and End-of-life Care. Available at http://www.epec.net (accessed August 27, 2005).
Pain is by far a more complex phenomenon than once believed. A number of factors (ie, personal, social, and cultural) interact to impact the perception of pain. Relieving pain in palliative care requires knowledge and utilization of multiple therapeutic modalities. Pharmacologic interventions, extensively discussed here, are more efficacious if usedin combination with other modalities (Table 9-2).
While some modalities, such as rigorous physical therapy, may be difficult or seemingly impossible due to advanced illness and poor functional status, similar interventions, such as massage and gentle stretching, can complement pharmacologic interventions.
Table 9-2. Multiple Treatment Modalities for Pain.
Table 9-3. Palliative Medical Therapies.
Effective pain management is complemented by concurrent disease-modifying treatment. For example, ongoing medical management of painful, preexisting, chronic conditions, such as gout or osteoarthritis, is an essential component of optimal pain management in palliative situations (Table 9-3). Complications of advanced illness, such as bowel, biliary, or urinary tract obstruction, may require surgical intervention to effectively relieve pain (Table 9-4).
Prophylactic therapies also may provide a measure of palliation. For example, ablation of the celiac plexusat the time of exploration for pancreatic cancer reduces the likelihood and severity of subsequent abdominal pain. Antimicrobial prophylaxis for opportunistic infections such as Mycobacterium avium-intracellulare (MAC) in patients with advanced HIV disease may prevent MAC-associated abdominal pain.
Nonopioid analgesics (Table 9-5) are the initial treatment of choice for mild pain. These agents are free of significant central nervous system (CNS) adverse effects. When caring for patients with advanced illness, there is often a rush to initiate opioids before a trial of nonopioids. Aspirin, acetaminophen, and NSAIDs have proved effective for mildly painful conditions.
Acetaminophenis an effective analgesic at standard doses, though not an anti-inflammatory agent. Because of its relative safety, acetaminophen is a useful tool to manage mild pain in the palliative and end-of-life care setting. It is effective for the musculoskeletal aches and pains that often accompany advanced age and, in particular, is useful for the generalized stiffness associated with reduced mobility in the frail elderly or bedridden patient.
Table 9-4. Palliative Surgical Therapies.
Acetaminophen is available as tablets, a liquid, or as rectal suppositories. No parenteral preparation is available. Use the minimally effective dose of acetaminophen. Efficacy increases little above the ceiling dose of 2.6 g/d. The maximally tolerated dose is 4 g/d in healthy persons. The likelihood of liver or renal toxicity increases with higher doses. This may or may not be an important consideration, depending on the patient's overall medical condition. The dose is reduced by 50 to 75% if the patient has a history of chronic alcohol intake (more than three drinks per day) or significant hepatic impairment.
Nonsteroidal Anti-Inflammatory Drugs
The NSAIDs are analgesic via their inhibition of prostaglandins (Table 9-5). Like acetaminophen, NSAIDs are widely used in combination with opioids for patients with moderate to severe pain at the end of life. Their usefulness, especially for bone pain and inflammatory syndromes, is well established. NSAIDs are also appropriate for treating the generalized body aches, joint stiffness, and pain due to periods of immobility that are common in advanced illness.
Table 9-5. Nonopioids: Nonsteroidal Anti-Inflammatory Drugs and Acetaminophen.a
The analgesic effects are dose-dependent but with a ceiling effect. There are individual variations in the effectiveness of the various products. When faced with diminished or absent effectiveness with one agent, try an alternate preparation.
The use of NSAIDs for palliation may be limited by toxicity. Their toxicity (gastrointestinal and renal) is particularly relevant when used in patients who, due to advanced illness, may be more susceptible to gastric irritation, especially if multiple oral medications accompany NSAID therapy. Careful attention to prior episodes of gastrointestinal upset or bleeding with NSAIDs may prevent inappropriate use of these drugs in sensitive persons. However, a high percentage (75-80%) of patients with gastrointestinal bleeding due to NSAIDs have no prior gastrointestinal symptoms. The renal effects may be problematic due to compromised renal function or decreased renal perfusion as a consequence of longstanding illness, dehydration, or the normal decline in renal function with advancing age.
NSAIDs diminish platelet function and increase the risk of bleeding and bruising. There is also a modest interaction between warfarin and NSAIDs, requiring appropriate monitoring of the international normalized ratio (INR) and adjustment of warfarin dose as necessary, depending on the clinical setting.
The cardiovascular risks of NSAIDs, particularly the cyclooxygenase-2 (COX-2) inhibitors, are well documented. Whether this should preclude their use in end-of-life care depends on the relative benefits and risks in a particular clinical setting and the patient's and family's goals. All NSAIDs are available as oral preparations. Ketorolac is the only parenteral NSAID available in the United States. In the face of opioid toxicity, ketorolac is a good adjunct to opioid therapy. Ketorolac 30 mg IV has the approximate analgesic effect of morphine 12 mg IV. Its renal toxicity limits the recommended duration of use to fewer than 5 days. The dose is reduced to 15 mg in patients over 65 years of age. Oral ketorolac appears to be no more effective than other NSAIDs.
Acetaminophen Plus Opioid Combinations
Acetaminophen is available in fixed combination with multiple opioids (Table 9-6). These agents are effective for treating moderate pain (eg, local pain due to tissue damage without neuropathic qualities). They are widely prescribed in seriously ill patients because of their somewhat lower incidence of sedation and confusion, compared with the stronger opioids. Care should be taken to avoid escalating combination preparations to acetaminophen doses that are toxic. Changing to an opioid without acetaminophen is safer and more effective in this circumstance. As a practical matter, the regulatory environment in many countries (ie, the United States) allows combination products to be ordered by telephone, thus facilitating their use. All combination preparations are oral. Tablet and liquid formulations are available for many. The usual opioid side effects of constipation and, less frequently, nausea may be observed and should be anticipated.
The two adult strengths of acetaminophen, 325 mg and 500 mg (regular and extra strength, respectively), are present in most combination pain products, eg, acetaminophen with codeine (Tylenol #3 and #4) and acetaminophen with hydrocodone (Vicodin). The
acetaminophen component limits the safe dose of these products to 8 tablets per day for products containing 500 mg of acetaminophen and 12 tablets daily for those containing 325 mg of acetaminophen.
Table 9-6. Opioid Equianalgesic Dosing Guidelines.a
Since the birth of the modern hospice and palliative care movement, opioids have been an essential element of pain management in patients with life-threatening illness. Oral opioids are effective for controlling pain when administered in adequate doses on a regular schedule rather than on an as-needed basis (see Chapter 3).
Patients and families often worry that use of strong opioids will result in addiction or “feeling high.” There also may be reluctance to use adequate doses due to fears that the opioid will become ineffective, thus making it necessary to “save” the drugs for more severe
circumstances. Educating and reassuring patients and families about the safety and efficacy of opioids and pointing out the low likelihood of addiction in palliative care settings provide reassurance and may enhance adherence to the opioid regimen.
Use of opioids in advanced illness is safe and effective if prescribed appropriately. The adage, “start low and go slow,” is germane. An “opioid naïve” patient (a patient not recently treated with opioids) should be given the lowest possible dose that is then titrated upward. For the patient who has been taking one or more opioids, equianalgesic principles are applied to identify the starting dose. To relieve severe pain, opioids are delivered on an around-the-clock schedule.
Most of the commonly prescribed oral opioids (see Table 9-6) have a 4-hour half-life under usual physiologic circumstances. Therefore, routine oral dosing is every 4 hours; after 4 to 5 half-lives, or slightly less than a day, steady state is achieved. Therefore, if pain control is inadequate after 24 hours, dose adjustment is required. Once the daily dose requirement for pain control is established, patient convenience is enhanced by the introduction of long-acting preparations. There are both 12 hourly and daily long-acting opioid preparations available. If pain is not well controlled, the dose of opioid may be increased by 25 to 50% for mild to moderate pain and by 100% if the pain remains severe. During this titration phase, reassess pain at least every 4 hours and adjust the opioid dose. There is no total dose that is too high. The dose that is effective to control pain is the “right” dose for a given patient. Morphine does not have a ceiling effect. Knowledge of the pharmacology of opioids in this very ill group of patients will provide pain relief without unacceptable toxicity.
Once on a stable opioid dose, breakthrough dosing is generally necessary to allow “rescue” doses of opioid to be given during times of increased activity or pain escalation during the day or night. The recommended dose of opioid for breakthrough pain, based on opioid pharmacodynamics, is equal to 10 to 20% of the 24-hour total dose. The peak analgesic effect occurs when Cmax, the peak serum concentration, is achieved. For most opioids, the Cmax occurs 1 hour after oral dosing. Opioids administered by intravenous bolus peak in 10 to 15 minutes, and when delivered subcutaneously, in 15 to 20 minutes. Therefore, a breakthrough dose may be repeated after 1 hour by mouth, 10 to 15 minutes by IV, and after 15 to 20 minutes subcutaneously.
If breakthrough doses are required three or more times in 24 hours, the total dose used in the 24-hour period is added up and the daily dose is adjusted upward. A breakthrough dose of 10 to 20% is recalculated as the new total daily dose for continued effectiveness.
Opioids are the mainstay of therapy for severe pain. Morphine is one of the most versatile drugs available and can be delivered via multiple routes: oral, intravenous, subcutaneous, rectal, intramuscular (although not recommended due to variable uptake and pain upon injection), sublingual, epidural, and intranasal. Intravenous and subcutaneous opioid administration follows first order kinetics; therefore, the opioid blood concentration is in linear proportion to the dose administered. Opioids are metabolized by the liver, and 90 to 95% is excreted by the kidneys. When using the oral route, first-pass metabolism by the liver reduces opioid potency by about two-thirds. As advanced illness, age, or intrinsic disease reduce renal or liver function, the serum level of the opioid rises proportionally. As patients approach death and renal function declines, the opioid dose may require reduction. Opioid metabolites, such asmorphine-6 glucuronide and morphine-3 glucuronide, accumulate in patients with renal impairment. Many of these metabolites are centrally acting and have the potential to increase side effects, particularly sedation.
Successful analgesia, defined as adequate pain control without unacceptable adverse effects, is achieved in 70 to 90% of patients. There are several frequently encountered situations in palliative medicine where adverse effects of opioids are more common and may forestall adequate opioid dosing:
Opioids Not Recommended for Use in Palliative Medicine
Table 9-7 lists the opioids that should be avoided. Propoxyphene, a synthetic derivative of methadone, is a weak opioid of limited use in palliative care. It has low analgesic potency and a prolonged half-life. Propoxyphene is biotransformed by the liver to norpropoxyphene, a metabolite with the potential to cause CNS excitation (ie, tremors, myoclonus, twitches, seizures). Because norpropoxyphene is renally excreted, its use is not recommended in persons with renal impairment.
Table 9-7. Opioids Not Recommended.
Tramadol is a weak opioid agonist and blocks reuptake of serotonin and noradrenalin. The significance of the latter is unclear. Its use in palliative care is limited due to its psychomimetic effect, a ceiling effect (doses greater than 300 to 400 mg/d are not recommended), and significant cost. However, compared with codeine and related compounds, constipation appears to be less prominent with this agent.
Meperidine is an opioid with erratic oral absorption, a relatively short half-life, and toxic metabolites. Meperidine is metabolized in the liver to normeperidine. This metabolite has half the analgesic effect of the parent compound but twice the potential for CNS toxicity. The neurotoxicity of normeperidine may occur rapidly, particularly in the face of renal toxicity. Other factors that may contribute to meperidine-induced CNS excitation include long-term treatment, high-dose therapy, a prior history of seizures, or coadministration with other potentially neurotoxic agents (eg, methylphenidate, phenothiazines).
Mixed agonist-antagonist agents (eg, pentazocine, butorphanol) cannot be recommended. Dose escalation leads to psychomimetic effects for a significant number of patients and, in addition, there is a ceiling to their analgesic effect. Furthermore, all of these agents have the potential to precipitate withdrawal in opioid-dependent patients.
Routes of Administration
The versatility of opioids allows for the provision of adequate analgesia when the oral route of administration is not feasible. For situations in which the oral route is not available, alternatives are indicated and summarized in Table 9-8. Opioids for palliation are currently available in multiple formulations to facilitate administration. The optimal route of opioid administration is oral. In general, the route that is simplest, most cost effective, and most convenient should be used.
Most opioids, with the exception of fentanyl and related compounds (eg, sufentanil), are available by mouth. Morphine, hydromorphone, oxycodone, and methadone are available in liquid preparations. Morphine, hydromorphone, and oxycodone are available as long-acting preparations. The long-acting preparations have the added convenience of being taken fewer times a day (one to three times), compared with short-acting preparations that are usually taken six times a day.
Sublingual and buccal application of opioids may be used with some success. However, the effectiveness of this administration route is primarily from swallowing the opioid rather than through direct oral absorption. This is particularly true for morphine. Due to its low lipid solubility, the bioavailability of sublingual morphine is about 18%. Highly lipid-soluble opioids, such as fentanyl and methadone, have significantly greater transmucosal absorption. For example, oral transmucosal fentanyl citrate, a fentanyl-containing matrix that dissolves when rubbed against the buccal mucosa, provides rapid relief of pain (within 5 to 10 minutes). About 25% of the total fentanyl dose is absorbed through the buccal mucosa, avoiding first-pass metabolism, while the remainder is swallowed.
Continuous subcutaneous administration of opioids is approximately equianalgesic to continuous parenteral
opioid infusions. A cannula can be readily inserted in the subcutaneous tissue of the abdomen or chest without the need for multiple injections or placement of a venous catheter. The ability of the subcutaneous tissue to absorb fluid is the dose-limiting factor. For patients requiring higher opioid doses to maintain effective analgesia, hydromorphone, rather than morphine, is preferred. Hydromorphone is more soluble than morphine, allowing administration of a higher dose, in a smaller volume. For patients with terminal illness who require large doses of opioids for adequate pain relief and who cannot tolerate oral administration, subcutaneous infusion is often the administration route of choice.
Table 9-8. Alternatives to Oral Administration of Opioids.
Fentanyl is available as a transdermal patch, releasing an amount of fentanyl per hour proportional to the surface area of the patch. Steady-state blood levels are not reached until 17 to 24 hours after application of the patch. Once achieved, 17 to 24 hours is required after patch removal before the dermal fentanyl deposits are eliminated. Transdermal fentanyl is useful after the opioid requirement for pain control is established but not during the dose titration period. Equipotent conversion to the transdermal system is made after titration (Table 9-9). While the recommended dosing interval is 72 hours, about 25 to 30% of patients experience end-of-dose failure and require a dosing interval of 48 hours to maintain analgesia.
Rectal opioid administration is approximately equivalent to absorption via the oral route. Long-acting morphine matrix preparations may be administered per rectum with the desired sustained-release effect, but higher oral doses may be required. The absorption of rectal opioids is decreased by the presence of feces in the rectum and altered by characteristics of the opioid preparation.
These routes of administration are options for drug delivery when systemic opioids, in doses necessary to control pain, result in unacceptable side effects. Spinal opioid delivery systems may be especially useful, particularly when combined with a local anesthetic, when pain is present in the lower body. These routes require catheter placement. If prolonged therapy is contemplated (longer than 3 months) and the patient's life expectancy and condition warrant, surgical implantation of an epidural catheter is necessary. This increases the initial cost but has been shown to be cost effective overall when used for more than 3 months.
Important considerations include the following:
Methadone is an atypical opioid. It is particularly useful in patients with opioid toxicity and in situations in which its blocking of N-methyl-D-aspartate (NMDA) may provide an advantage (eg, neuropathic pain syndromes). However, it is not generally the first drug of choice; it is frequently given late in the course of illness. Problems arise because of methadone's long half-life (20 to 100 hours). In addition, because it is metabolized by cytochrome P450, plasma levels of methadone can be increased or decreased by other drugs metabolized
by this enzyme system. Conversion from standard opioids to methadone does not conform to a fixed dose ratio. When converting an oral morphine equivalent of 20 mg/d to methadone, the conversion is 10 mg/d methadone (1:2). However, when converting oral morphine equivalent of 300 mg/d to methadone, the conversion is 30 to 60 mg/d of methadone (1:5 to 1:10). Monitoring the effects of methadone closely for the first few weeks of treatment is important. Dose adjustments of methadone should not be made more often than every 3 to 5 days.
Table 9-9. Use of the Fentanyl Patch.
Management of Opioid Adverse Effects
To manage adverse effects of opioids consider the following:
Respiratory depression, although feared, is extremely uncommon. Tolerance to this adverse effect
develops rapidly. Naloxone is effective in reversing respiratory depression but should be used with extreme caution in the opioid-dependent patient with chronic pain to avoid precipitating an acute abstinence syndrome. Naloxone is rarely indicated in the palliative care setting. A patient may be comfortable with a respiratory rate of 10 breaths per minute. If the patient is arousable, naloxone is not indicated. However, if naloxone is necessary, start with a very low dose and monitor respiratory status and reoccurrence of pain. Dilute one ampule of naloxone 0.4 mg in 10 mL of normal saline. Give 1 mL (0.04 mg) as a frequent injection, as often as every 5 minutes, or by continuous infusion if necessary until the patient is arousable. Overzealous administration of naloxone will result in an opioid withdrawal syndrome that is highly unpleasant for the patient and associated with reemergence of severe pain.
Table 9-10. Management of Opioid Toxicity.
Sedation is another manifestation of opioid toxicity. Psychostimulation with methylphenidate may be useful. Start with a low dose, 2.5 to 5 mg orally each morning and at noon. Titrate the dose to desired effect or toxicity. Titrate dose by 5 mg/dose to effect.
Nausea and vomiting is covered in detail later in this chapter, since they are frequent symptoms in patients with terminal illness. Opioids are just one potential cause of nausea in the palliative care setting. When opioids do play a role, opioid rotation is sometimes helpful.
Due to the prevalence of constipation, anticipating this adverse effect and prescribing softeners and cathartics with initiation of opioid therapy is recommended. This is covered in greater detail later in this chapter.
Myoclonus may occur with any opioid secondary to the accumulation of neuroexcitatory opioid metabolites in the CNS. If an option, a 25% reduction of the opioid dose or opioid rotation may alleviate the symptom. However, if myoclonus is disturbing for the patient, benzodiazepines, such as clonazepam, are useful.
Coanalgesics are useful when added to opioids for controlling pain. Coanalgesic medications enhance pain control when opioid therapy is not adequate to control pain. This combination therapy is particularly useful for neuropathic pain and for pain due to pleural disease (Table 9-11). The principles governing their use in the palliative care setting are not significantly different from other situations, except as noted below. The use of coanalgesics is described in detail in Chapter 3.
Corticosteroids are potent anti-inflammatory medications. They are effective in treating pain secondary to edema (CNS disease and increased intracranial pressure) and in managing prostaglandin-mediated pain (eg, arthritis, bone metastases). The usual starting dose is dexamethasone 10 mg orally each morning. Other conditions in which 10 mg/d of dexamethasone may be used include capsular distention of the liver from tumor, sub-capsular hemorrhage, or liver infiltration.
In addition, corticosteroids enhance appetite (short-term), ameliorate nausea, malaise, and improve sense of well-being. The potential for multiple beneficial effects from a single agent suggests its usefulness in the palliative care setting.
Lidocaine infusion for treatment of neuropathic pain may be used in the palliative care setting. A lidocaine trial using a bolus dose of 100 mg IV (1 to 3 mg/kg), administered over 30 minutes in a concentration of 8 mg/mL, should provide pain relief. Vital signs should
be monitored at least every 15 minutes during the loading period. An infusion, 0.5 mg/kg, is titrated to comfort. Perioral paresthesias or lightheadedness suggest the need for dose reduction (use therapeutic cardiac levels), but clinical evaluation is generally adequate. Minor sedative adverse effects are noted in 30% of patients with no significant severe adverse reactions. Dose adjustment should take place in obese patients with liver disease.
Table 9-11. Adjuvant Analgesics.a
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In the palliative care setting, particularly at the end of life, patients often carry a significant symptom burden. Pain, and its treatment, may be associated with a multitude of symptoms, including nausea and vomiting, constipation, delirium, and myoclonus. The evaluation and treatment of these symptoms are an essential component of palliative care.
Delirium is a frequent neuropsychiatric complication at the end of life, occurring in 28 to 83 of patients depending on the population studied and the criteria used. Delirium has been defined as a transient, global disorder of cognition and attention. It is characterized by an acute
onset and a fluctuating course, unlike the insidious, progressive nature of dementia. Impairment of attention is the central feature of delirium, while in dementia, attention is relatively preserved until late in the course. Speech is often incoherent, and the level of consciousness is disturbed with delirium, with decreased ability to focus, sustain, or shift attention.
Delirium may present as one of three major types: hyperactive, hypoactive, or mixed. Hyperactive, or agitated, delirium is characterized by agitation and often hallucinations. In contrast, hypoactive delirium presents as a decreased level of consciousness with somnolence and may be mistaken for sedation secondary to opioids or other medications. The third type, mixed delirium, alternates between agitation and quiet and may be difficult to recognize.
The standard approach to the management of delirium involves a search for reversible, underlying causes in concert with management of the symptoms and signs of the disorder (Table 9-12). Reversibility of delirium depends on identification of reversible etiologies. Medications are a common cause of delirium, and opioids, in particular, are a concern in the patient with pain. Adjuvant analgesics, such as tricyclic antidepressants, other anticholinergic agents, neuroleptics, and corticosteroids also may cause delirium. Other psychoactive medications, such as selective serotonin reuptake inhibitors, antihistamines, H2-blockers, and ciprofloxacin, also are potential culprits.
The laboratory evaluation of a patient with delirium may identify reversible causes of delirium. Laboratory tests include blood counts, as severe anemia may cause delirium; renal function; or alterations in calcium, magnesium, phosphorus, and glucose. Oxygen saturation also should be evaluated because hypoxia is another potential, treatable cause of delirium.
The intensity of the evaluation and treatment of the delirium should depend on the goals of therapy and the patient's status overall. The distress of the delirium needs to be evaluated in the context of the patient's overall symptom complex, and the advantages and disadvantages of evaluation and intervention need to be discussed with the patient's family.
In patients with advanced disease, delirium is often multifactorial, and the likelihood of identifying a reversible, underlying etiology varies but has been reported to be as high as 50 to 60%, even in patients with advanced cancer. In patients with pain, opioids as a cause of alterations in mental status or delirium should always be considered. Particularly in the face of decreased renal function or underlying renal failure, the risk of delirium is high, as active opioid metabolites may lead to delirium.
Table 9-12. Etiology and Work-up of Delirium.
Delirium is often unrecognized and most commonly misdiagnosed as either depression or dementia. Table 9-13 identifies differences in these diagnostic categories.
According to the criteria of the Diagnostic and Statistical Manual for Mental Disorders, 4th edition, published by the American Psychiatric Association, the diagnosis of delirium is characterized by the following:
Table 9-13. Distinguishing Delirium, Dementia, and Depression.
Frequently, there are disorders of the sleep/wake cycle, altered psychomotor activity, and emotional lability, but these are not required for the diagnosis.
Recognized risk factors for delirium include advanced age, underlying cognitive impairment, advanced illness, and select clinical findings. A multifactorial model for delirium in the hospitalized elderly distinguishes between “baseline vulnerability” and “precipitating factors or insults.” Predisposing factors present at the time of admission to the hospital define the “vulnerability factors” in this model and include visual impairment, severe illness, cognitive impairment, and dehydration. The precipitating factors or insults identified in this model include the use of physical restraints, malnutrition, the addition of more than three new medications, bladder catheter, and iatrogenic events. Additional factors suggested by other studies include age, dementia, depression, alcohol use, and poor functional status.
Underlying neurocognitive dysfunction increases the risk of delirium. Both primary and metastatic tumors of the brain as well as leptomeningeal disease may trigger delirium. A postictal state is occasionally associated with delirium as well. Organ failure of any major organ system, infection, and dehydration are all potential causes of delirium. Delirium may be the presenting sign of life-threatening sepsis.
Other metabolic disorders that may cause or contribute to the development of delirium include hypercalcemia, hyponatremia, hypomagnesemia, and hypoglycemia.
Treatment interventions, both pharmacologic and non-pharmacologic, have been used to treat delirium. Non-pharmacologic interventions include supportive measures, such as a well-lighted room, familiar sounds and music, and presence of family members and friends. While these interventions may be helpful, the mainstay of therapy remains as pharmacologic intervention.
Treatment of opioid-related delirium involves decreasing the dose of the opioid if the patient's symptoms will allow. Alternatively, consider opioid rotation, although this is based more on practice and consensus than clinical trial data. Medications that may contribute to the delirium should be changed when possible. For example, discontinue cimetidine and replace it with an alternate H2-blocker, or taper the corticosteroid dose if feasible.
There is insufficient data to guide the selection of treatment for delirium. Haloperidol is the most widely used agent, though only one randomized, controlled trial suggests its superiority to benzodiazepines for hyperactive and hypoactive delirium in patients with AIDS. Haloperidol has the advantages of having a fairly wide therapeutic window and the availability as an oral, intravenous, intramuscular, subcutaneous, or rectal preparation. Start with 0.5 to 1.0 mg every hour as needed. The drug is associated with minimal risks for respiratory depression and is less sedating than benzodiazepines. Although generally safe, haloperidol is associated with the risk of dystonia and the potential for initial worsening of delirium symptoms, particularly the agitation.
The short-acting benzodiazepines are another choice for the treatment of delirium, either lorazepam or midazolam. However, it is noteworthy that benzodiazepines may actually exacerbate the delirium state and need to be used and titrated with caution.
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McNicol E et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain. 2003;4:231 .
Ross DD et al. Management of common symptoms in terminally ill patients: Part II. Constipation, delirium and dyspnea. Am Fam Physician. 2001;64:1019 .
Nausea & Vomiting
Nausea and vomiting are among the most common and distressing symptoms of patients in the palliative care setting and can be particularly disturbing at the end of life. Earlier in the trajectory of disease, the incidence of nausea and vomiting varies somewhat with diagnosis and treatment. In the setting of cancer, chemotherapy- and radiation-related nausea and vomiting are frequent but generally self-limited. In patients with terminal cancer, nausea and vomiting occur in nearly two-thirds of patients, although its prevalence during the last 6 weeks of life is lower than 50% and rarely develops as a new symptom during the last days of life.
Nausea is an unpleasant, subjective feeling that can only be determined by self-report. It is generally felt in the back of the throat and the epigastrium and is accompanied by decreased gastric tone, duodenal contractions, and reflux of intestinal contents into the stomach. Many patients describe it as feeling “sick to their stomach.” It is frequently associated with loss of appetite and may be described as a vague, unpleasant feeling in the epigastric region. Chronic nausea is defined as nausea lasting for more than 2 weeks without the presence of mechanical bowel obstruction or a well-identified, self-limiting cause of the symptom.
Vomiting is the forceful expulsion of gastric contents from the mouth, resulting from contraction of the abdominal muscles, descent of the diaphragm, and opening of the gastric cardia. Vomiting is an objective phenomenon that can be quantified. Both nausea and vomiting may be associated with other symptoms. A recent study concluded that patients with nausea and dyspnea actually experienced more pain than patients without these symptoms. This may be, in part, due to the frequent use of opioids in patients at the end of life. Clinical evaluation should include identification of potentially readily reversible causes of nausea and vomiting.
The etiology of nausea and vomiting in the palliative care setting varies and is often multifactorial. Blood tests to rule out hyponatremia, renal failure, or hypercalcemia, and liver function tests to rule out liver disease as causes of nausea may be helpful. Imaging studies are ordered as indicated by physical examination.
Bowel obstruction is a clinically important cause of nausea and vomiting in the setting of advanced disease, particularly in patients with advanced ovarian or colon cancer or a history of multiple abdominal surgeries. Characteristic clinical findings include nausea and vomiting without normal bowel movements; frequently, the patient has a distended, tender abdomen with high-pitched bowel sounds on physical examination, and a flat plate of the abdomen demonstrates dilated loops of bowel, with or without air-fluid levels.
Increased intracranial pressure may present with nausea and vomiting, often associated with severe headache occurring upon awakening. Papilledema, or focal neurologic findings, new cranial nerve abnormalities, or evidence of meningeal carcinomatosis may all be associated with nausea and vomiting.
Other findings that may lead to a specific explanation for nausea and vomiting include signs and symptoms of myocardial ischemia. An electrocardiogram would be the evaluation of choice as well as serum troponin levels. Constipation or obstipation, identified by history as well as physical examination, is another cause of nausea and vomiting, particularly in patients with advanced illness.
Review of the patient's current medications often suggests contributing factors. Both anticonvulsants and digoxin are prescribed frequently and may be reversible causes of nausea and vomiting. Patients taking NSAIDs may have gastric irritation, resulting in nausea and vomiting, readily treated with antacids or cytoprotective agents. Similarly, gastrointestinal tract infections may cause nausea and vomiting as well. Specific treatment for the underlying infection is the ultimate treatment for the nausea and vomiting.
Opioid-induced nausea and vomiting is estimated to occur in 10 to 40% of opioid-treated patients. It occurs most frequently shortly after and at the time of initiation of opioids. The mechanism of opioid-induced nausea includes stimulation of the chemoreceptor trigger zone on the floor of the fourth ventricle, gastric stasis, and enhanced vestibular sensitivity. Long-term dosing generally results in decreased nausea and vomiting, usually over 2 weeks of therapy. Slow titration upward of the opioid dose may also prevent nausea. If the nausea is severe and the analgesic cannot be altered or reduced, parenteral administration of an antiemetic is preferred until the symptom is improved. Once improved, the oral route remains the preferred route of opioid administration.
Pharmacologic treatment of nausea and vomiting in the palliative care setting, whenever possible, should be selected based on an understanding of the underlying pathophysiology. For nausea and vomiting arising from stimulation of the chemoreceptor trigger zone, such as
with opioid-induced nausea, a dopamine antagonist, such as prochlorperazine or haloperidol, should be considered first. These are cost-effective agents that are generally well-tolerated and available for use by multiple administration routes (Table 9-14). If ineffective, the more expensive serotonin antagonists are also generally useful for chemoreceptor trigger zone-stimulated nausea and vomiting. If gastric stasis appears to be a major component (eg, in the patient with diabetes, ascites, or significant opioid use), then a prokinetic agent is the treatment of choice. Metoclopramide in doses of 10 to 20 mg every 6 hours is generally prescribed, although in patients with decreased creatinine clearance, the dose must be reduced.
Table 9-14. Treatment of Nausea and Vomiting.
For nausea exacerbated by motion or vestibular toxicity, an acetylcholine antagonist, such as transdermal scopolamine, is helpful. Other potentially useful agents are the histamine blockers (diphenhydramine, meclizine, hydroxyzine, hydrochloride, and promethazine).
Small studies have suggested that in ambulatory cancer patients who initiate opioid therapy, labyrinthine hypersensitivity to motion may play a greater role in the initiation of nausea than in those who are bedridden. In a pilot study, the majority of ambulatory cancer patients with opioid-induced nausea responded to scopolamine patches. Similarly, in a study of ambulatory cancer patients with chronic nausea and vomiting, patients identified the histamine antagonist, cyclizine 50 mg, to significantly reduce the incidence of vomiting, though it was less effective for the treatment of nausea.
In general, anticholinergic medications are the choice first-line for patients with nausea and vomiting related to colic or mechanical bowel obstruction. These agents may provide some symptomatic relief for patients with increased intracranial pressure but are secondary agents after corticosteroids. In the older population, anticholinergics may cause cardiovascular toxicity. In ambulatory patients, the xerostomia associated with anticholinergics may be dose limiting.
Corticosteroids are the treatment of choice for increased intracranial pressure but also produce an addictive effect when combined with a variety of other antiemetics. For chemotherapy-induced nausea and vomiting, they are part of the standard antiemetic regimen, in concert with serotonin antagonists. While there is no evidence-based data for identification of a dose of corticosteroid for nausea and vomiting, most people choose doses of dexamethasone in the range of 6 to 20 mg orally once daily. Dexamethasone is generally the corticosteroid of choice due to its limited mineralocorticoid activity, the availability of multiple dosage forms, and its long half-life. In patients with multiple symptoms, particularly pain, dexamethasone may provide an important anti-inflammatory, and therefore analgesic, effect.
For the patient with nausea and vomiting related to bowel obstruction, in addition to anticholinergics, octreotide, a somatostatin analogue, is useful for control of nausea and vomiting as well as abdominal discomfort. Octreotide decreases gastrointestinal secretions, stimulates absorption of water and electrolytes, and inhibits intestinal peristalsis. Octreotide is generally initiated at a dose of 50 to 150 mcg intravenously or subcutaneously every 8 to 12 hours with titration over 24 to 48 hours to maintain maximum benefit.
Nonpharmacologic therapies are an essential component of the treatment and prevention of nausea.
For patients with nausea, the odor of foods may be unpleasant. Room temperature or cold foods tend to have less aroma. In addition, for patients with nausea related to early satiety, small, frequent meals may be better tolerated and result in improved control of symptoms. The major nonpharmacologic antiemetic therapies include acupuncture, acupressure, and transcutaneous electrical acupoint stimulation.
Bruera E et al. Dexamethasone in addition to metoclopramide for chronic nausea in patients with advanced cancer: a randomized controlled trial. J Pain Symptom Manage. 2004;28:381 .
McNicol E et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain. 2003;4:231 .
Rhodes VA et al. Nausea, vomiting, and retching: complex problems in palliative care. CA Cancer J Clin. 2001;51:232 .
Ross DD et al. Management of common symptoms in terminally ill patients: Part I. Fatigue, anorexia, cachexia, nausea and vomiting. Am Fam Physician. 2001;64:807 .
Constipation is frequently seen in hospitalized patients and is the most common adverse effect of opioids in patients receiving long-term opioid therapy. While opioids account for only 25% of the constipation identified in terminally ill cancer patients in hospice, the need for laxatives and softeners in those patients who require opioids is greater than 75%. In patients with pain, the most likely etiology of constipation is opioid related, though the cause for a given patient is generally multifactorial.
By definition, constipation is evacuation of hard stools less frequently than is normal for a particular person or a subjective sensation of difficulty or discomfort with bowel movements that occur at decreased frequency compared with baseline.
Treatment focuses on both dietary and fluid changes as well as pharmacologic interventions. Prevention remains an essential component of treatment for patients receiving opioid therapy.
First, establish what the patient means by constipation. Are the stools too hard, too infrequent, or too difficult to expel? Is there pain with bowel movements? Is there an incomplete sense of emptying after defecation? Is there intermittent watery stool and hard stool, suggesting impaction with overflow?
Symptoms that may be associated with constipation, and may be the presenting symptoms, include bloating, nausea, loss of appetite, abdominal pain, and even early satiety. Physical examination should focus on the presence of abdominal masses, distention, the quality of bowel sounds and, of course, the rectal examination. In addition, evidence of neurologic symptoms and signs should be sought. Parkinson disease, spinal cord lesions, and autonomic neuropathies are all associated with an increased likelihood of constipation.
Physical examination should consider all causes of constipation in patients with advanced disease. Digital examination of the rectum may reveal an impaction or a mass, rectal ulcerations or anal stenosis, loss of anal sphincter tone, or loss of anal sensation. Palpation of the abdomen may reveal fecal masses in the left iliac fossa. These are usually nontender and relatively mobile and can be altered in shape with gentle pressure, unlike other causes of mass lesions.
If the diagnosis of constipation is not clearly explained by physical examination, an abdominal radiograph is useful to distinguish constipation from obstruction. Assessment also includes a review of the patient's current medications (eg, antidepressants, antiemetics). Many of the medications used for the treatment of symptoms associated with advanced illness cause constipation. Anticholinergics, the serotonin antagonist class of antiemetics, and diuretics all induce constipation. Selective 5-HT3 receptor antagonists cause constipation by antagonizing the ability of 5-HT to stimulate cholinergically mediated contractions of the intestinal longitudinal muscle. The anticholinergic activity of antidepressants and some antihypertensive agents are also important to consider. Patients treated with carbamazepine for neuropathic pain or seizures may develop severe constipation that does not appear to be dose-related. It may be refractory to oral laxatives and necessitate discontinuation of the agent.
In patients with pain, however, opioid-related constipation is the primary concern. Opioids cause constipation by binding to opioid receptors on gut smooth muscle as well as in the CNS. Opioids delay gastric emptying, decrease peristalsis, increase oral cecal transit time, and desiccate the intraluminal contents. It is generally believed that patients do not build tolerance to opioid-induced constipation.
There is no apparent correlation between the dose of opioids and the dose of laxatives, though as opioid doses are titrated up, generally the same is required of the laxatives. There is significant variability among patients with regard to the laxative dose needed with a particular opioid dose. While few data are available, there is at least one prospective, open-label study that compared laxative use and frequency of bowel movements in patients receiving morphine versus transdermal fentanyl. Although the same number of patients had bowel movements in each arm of the trial, lesser amounts of laxative were used by patients in the transdermal fentanyl arm versus the oral morphine-treated group.
Table 9-15. Treatment of Constipation.
It is important to remember that in the palliative care setting, even in the absence of opioid use, constipation is common, occurring in as many as 64% of patients enrolled in a hospice and not receiving opioid analgesia. This highlights the importance of other contributing factors, such as immobility, dehydration, concomitant medications, and neurologic diseases.
Constipation is managed with both pharmacologic and nonpharmacologic measures. In the setting of advanced disease, the nonpharmacologic interventions are generally not helpful. These include increased activity, dietary manipulation (eg, fruit juices, increased fluid intake, bran), and increased dietary fiber. Bulking agents, such as methylcellulose or cilium, are relatively ineffective and may worsen constipation for patients who are bedridden. These agents require physical activity as well as adequate fluid intake to increase stool water content. Prophylactic laxatives are essential for patients at increased risk for constipation. Commonly identified factors in the setting of palliative care include the use of long-term opioids, being elderly or bedridden, and a variety of medications, as noted above. Alow rectal impaction should be evacuated manually. Manual disimpaction is uncomfortable, and the patient should be premedicated either with lorazepam 1 mg intravenously or midazolam 5 mg subcutaneously as well as with analgesics as necessary. After disimpaction, the patient is likely to require enemas to reach stool that is higher up in the colon.
Therapeutic and prophylactic measures for the treatment of constipation can be administered orally or rectally (Table 9-15). The clinical situation, patient preference, and potential side effects dictate which type of medication should be chosen. The osmotic or emollient laxatives are surfactant substances that act as a detergent and facilitate the interface between aqueous and fatty acid components of stool. They increase the luminal water and salt. These agents, which are not absorbed in the gut, are the most commonly prescribed medications to treat constipation. As noted in Table 9-15, representative agents include senna, cascara, bisacodyl, and phenolphthalein. These agents directly stimulate the myenteric plexus, increasing peristalsis and decreasing water absorption in the small and large intestine. Recommended starting doses of commonly prescribed laxatives are shown in Table 9-16.
Lubricant laxatives are used to soften the fecal mass. They are primarily used for fecal impaction but are otherwise of little use for chronic constipation. Mineral oil is a representative of this group. Its use may interfere with the absorption of fat-soluble vitamins, and it may, as a result, increase the prothromb in time if used long term.
Hyperosmotic agents, as with the emollients, are not broken down or absorbed in the small bowel. Laxatives representative of this group include lactulose, sorbitol,
and magnesium citrate. These agents have the potential to cause significant cramping as well as diarrhea. Lactulose, in particular, may result in bloating, colic, and flatulence. These agents directly stimulate peristalsis and increase water secretion, adding to their effectiveness. They should be used with caution in the face of congestive heart failure or renal insufficiency due to increased absorption of salt and magnesium. If given rectally, these agents work extremely rapidly (within 15 minutes) due to their stimulation of rectal peristalsis.
Table 9-16. Recommended Starting Doses of Commonly Prescribed Laxatives.
An overall strategy for use of laxatives is similar philosophically to the treatment of other symptoms. Doses of laxatives should be titrated to effect. The best example of this is opioid-induced constipation. When the dose of opioid is increased, the prescription for laxatives generally needs to be increased as well. Frequently, combination treatment with a softener and stimulant, for example, is most effective for opioid-induced constipation.
Different clinical scenarios suggest alternate approaches. For example, a patient with severe constipation, abdominal distention, nausea, vomiting, and stool palpability, both on abdominal and rectal examination, requires treatment rectally first with a glycerin suppository to soften the fecal mass and oral laxatives as tolerated. Oral laxatives are the treatment of choice if the patient is able to tolerate them. Agents with different modes of action should be used if constipation is not responding to prescribed management. For example, constipation with colicky pain may require either an increase in the softener or use of an osmotic agent, like sorbitol or lactulose. If a stimulant is not working, addition of an osmotic agent is worth considering. As with all symptoms, reassessment is an essential component of management.
Ross DD et al. Management of common symptoms in terminally ill patients: Part II. Constipation, delirium and dyspnea. Am Fam Physician. 2001;64:1019 .
Sykes NP. The relationship between opioid use and laxative use in terminally ill cancer patients. Palliat Med. 1998;12:375 .
Myoclonus presents as sudden, uncontrollable, non-rhythmic jerking or twitching of the extremities, which initially may be confused with seizure activity or restlessness. While there are multiple causes of myoclonus, a common etiology near the end of life is opioid-induced myoclonus; the prevalence of which ranges anywhere from 2.7 to 87%. It can exacerbate pain significantly in the setting of widespread bone metastases and may progress to more significant neurologic dysfunction, such as grand mal seizures and, therefore, requires rapid identification and treatment.
Opioid-induced myoclonus is thought to occur secondary to the formation of neural excitatory metabolites that are poorly excreted in the face of progressive renal dysfunction. The byproducts of opioid glucuronidation, both morphine-3 glucuronide and hydromorphone-3 glucuronide, are believed to be responsible for the excitatory behaviors, myoclonus, and seizures. Limited data suggest that the plasma levels of these glucuronidation by products are significantly increased in the presence of renal insufficiency, with the ratio of metabolite to parent compound four times greater than the ratio seen in patients with normal renal function.
Myoclonus and seizures have been seen with other opioid compounds, including methadone and acute administration of fentanyl in the operating room. Other reported nonopioid causes of myoclonus include the following:
The primary treatment of opioid-related myoclonus is opioid rotation, particularly if the patient has renal insufficiency. Increased use of adjuvant analgesics may reduce the opioid dose necessary for adequate pain
control and reduce or eliminate myoclonus. While there are few data, an alternative approach is the use of benzodiazepines, including clonazepam, diazepam, and midazolam. Start with clonazepam 0.5-1.0 mg at night or 0.5 mg two or three times a day for mild myoclonus. For patients with severe myoclonus near the end of life, where opioid rotation or opioid dose reduction is not feasible or appropriate, a continuous infusion of either midazolam or lorazepam may be appropriate. Begin with 0.5 to 1.0 mg per hour and titrate to symptom control.
Cherny N et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol. 2001;19:2542 .
Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol. 2000;27:524 .