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Optimal symptom control is an important cornerstone of palliative medicine, because uncontrolled symptoms increase patients’ and caregivers’ distress. Poorly controlled symptoms often detract from patients’ quality of life, impair their interactions with loved ones, and limit their ability to attend to important issues at the end of life. Many studies have documented the high frequency of symptoms in patients with serious illnesses and the tendency for symptoms to increase in intensity as a disease progresses. The following discussion reviews management of some common symptoms. As with most medical problems, successful management of symptoms starts with a careful history and physical examination, with therapy directed at identifiable underlying causes.
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Pain can be classified physiologically as nociceptive (somatic or visceral) or neuropathic. (Table 67-1). Pain can occur directly from the underlying illnesses (such as tumor involvement, cytokine release, and vasculopathy), as a consequence of therapy (particularly chemotherapy, radiation therapy, and invasive procedures), or from pathologies that are not directly related to the primary disease processes. It is important to remember that pain is a subjective experience, and it is essential to respect and accept the complaint of pain as characterized by the patient. Pain is influenced by psychosocial and spiritual issues, and effective pain management requires a multidisciplinary approach.
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Unlike opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen have an analgesic ceiling effect. The use of opioid-nonopioid combinations therefore is limited by the dose of the NSAIDs or acetaminophen. Despite this fact, NSAIDs are effective pain medication, especially for inflammatory conditions. Their use can decrease the amount of opioids required and hence decrease the incidence of opioid side effects. Unless contraindicated, all pain protocols should include a NSAID or acetaminophen.
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The general principles of pain management with opioids are as follows:
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Assess pain using a standardized pain scale: Most commonly used is a 0–10 scale, where 0 indicates no pain and 10 represents the worst pain imaginable. Numerous validated scales can be used for patients who cannot communicate–either because they are intubated, are preverbal children, or are cognitively impaired adults.
In opioid-naive patients, start with a short-acting opioid (such as morphine, oxycodone, or hydromorphone) to control acute, moderate to severe pain. Unless there are contraindications, morphine is the agent of choice given its low costs and variable routes of administration [oral (PO), intravenous (IV), subcutaneous (SQ), intramuscular (IM), or rectal (PR)]. Short-acting opioids can be given as frequently as the time to peak onset of action: every 60–90 minutes for oral immediate-release formulations and every 10–15 minutes for IV formulations. For severe pain, IV administration is recommended given the faster onset of action and greater ease of titration. Conversion to oral opioids can occur once the pain is controlled.
Determine whether the dose is adequate, and adjust accordingly: The dose should be titrated at least every 24 hours if the pain is moderate, and as often as every 4 hours if the pain is severe, particularly while using intravenous opioids. Dose increases should be made by 25–50% for moderate pain, and by 50–100% for severe pain. There is no specific limit to opioid doses. These agents should be titrated until pain is controlled or side effects develop.
Further titration or rotation of opioids is achieved by first calculating the oral morphine equivalent (OME) of the previous 24 hours’ worth of opioid use. Equianalgesic tablets for opioids are readily available (Table 67-2); however, these tablets often differ slightly. It is important to remember that oral and parenteral doses are not equal because of oral medicines’ first-pass hepatic metabolism– for example, 1 mg of IV morphine sulfate equals 3 mg of oral morphine sulfate, and 1 mg of parenteral hydromorphone equals 4 mg of oral hydromorphone.
Determine the dosing schedule: Chronic pain deserves scheduled pain medication, not just as-needed dosing: 66–75% of the patient’s stable 24-hour OME needs should be given as a long-acting formulation.
Determine the breakthrough dose. Breakthrough pain is defined as a transitory exacerbation of pain that occurs on top of an otherwise stable persistent pain. An adequate breakthrough dose is calculated as 10–15% of the total daily long-acting opioid, and it should be given every 3 hours as needed. Whenever possible, the same opioid agent should be used for both short- and long-acting administration [eg, sustained-release morphine 150 mg PO Q12h (by mouth every 12 hours) and immediate-release morphine 30–45 mg PO Q3h, as needed).
During administration of opioid therapy, the patient’s renal function should be closely monitored, as toxic metabolites can accumulate with decreased kidney function, leading to alterations in mental status, myoclonic jerks, and seizures. Opioids that are safe to use in renal failure include hydromorphone, fentanyl, and methadone.
Reasons for rotating to a different opioid include renal failure, side effects, and a need to change the route of administration (such as changing from oral morphine to transdermal fentanyl). When rotating to a different opioid, the dose should be reduced by 25–50% to account for incomplete cross-tolerance.
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Fentanyl patches should not be used alone for acute severe pain. Because of the delayed onset of effect (12 hours) and long half-life of this formulation, which allows for titrations only every 48–72 hours, it cannot be titrated quickly for rapid pain control. If the pain is severe or unpredictable, or if opioid requirements are unknown or increasing rapidly, patient-controlled analgesia (PCA) may be indicated. With PCA infusion pumps, opioids can be infused intravenously or subcutaneously at a continuous basal rate programmed by the care provider, while the administrations of bolus doses are controlled by the patient. There is theoretically no risk of overdose since the patient will fall asleep before serious signs of overdose occur, and for this reason, the patient’s family or visitors should be carefully educated to avoid pushing the PCA button on the patient’s behalf.
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Guidelines on management of opioid-induced side effects are as follows:
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Nausea/vomiting: Opioids can cause nausea and vomiting by decreasing gastrointestinal motility. Patients usually develop a tolerance to these side effects. It may be helpful to schedule an antiemetic for a few days, then change to as-needed administration. Dopamine receptor antagonists are most effective (haloperidol 0.5–2 m Q6–12h or metoclopramide 10–40 mg Q6h).
Sedation: This is a commonly encountered side effect, although tolerance typically develops over time to this as well. Downtitration of opioids, rotation of opiates, and use of adjuvant, nonopioid pain therapies should be considered. Other sedating agents should be eliminated whenever possible. If sedation persists despite these interventions, the addition of a central nervous system (CNS) stimulant can be helpful (methylphenidate 2.5–5 mg in the morning and at noon, or modafinil 100–200 mg daily).
Constipation: This is one of the most common side effects. Since patients rarely develop tolerance, if at all, a bowel regimen must be started for most patients with initiation of opioid therapy. A bowel stimulant (senna) is the most commonly used agent. Methylnaltrexone is a peripherally acting opioid receptor antagonist that has been approved for refractory constipation in patients receiving opioid therapy. It does not reverse central analgesia.
Delirium/confusion/hallucinations: In this setting, opioid dose reduction, rotation to a different opioid, and initiation of neuroleptic therapy (haloperidol 0.5–1 mg BID-QID or olanzapine 2.5–5 mg daily BID should be considered).
Allergic reaction: True allergic reactions are rare. Allergylike symptoms are usually secondary to mast cell activation and subsequent histamine release.
Respiratory depression: Tolerance to the respiratory depressant effects occurs rapidly; thus, opioids can be used safely when titrated to pain control, even in patients with underlying emphysema. Naloxone administration is indicated if (a) the patient is somnolent and difficult to arouse or (b) respiratory rate is <8/min or oxygen saturation is <92% and the respiratory rate is <12/min. A dilution of 0.4 mg naloxone (one ampoule, 1 mL) in 9 mL of normal saline to yield 0.04 mg naloxone per milliliter should be prepared, with administration of this diluted nalxone in 1–2-mL increments (0.04–0.08 mg) over 1–2-minute intervals until a change in alertness is observed. Giving naloxone in this way should not cause pain to return or opioid withdrawal. Remember that the half-life of naloxone is shorter than the half-life of most opioids, so respiratory depression may recur and a naloxone drip may be needed.
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A challenge in prescribing opioid pain medications is to correctly differentiate a patient in pain from a patient with a substance abuse disorder. The key lies in understanding the specific characteristics of tolerance, physical and psychological dependence, and pseudoaddiction. Tolerance is a state of adaption in which exposure to a drug induces changes that result in a decreased effect of the drug dose over time. Physical dependence is a state of adaption that is manifested by a specific withdrawal syndrome when the drug is discontinued suddenly. Most patients on chronic opioids will develop physical dependence. If the need arises for a rapid decrease in opioid dose, administering 25–50% of the stable dose can prevent withdrawal symptoms. Both tolerance and physical dependence cannot be used to differentiate between a patient in pain and a patient with a substance abuse disorder. Psychological dependence or addiction is a primary, chronic, neurobiological disease with genetic and psychosocial factors influencing its development. It is characterized by certain behaviors, including loss of control, compulsive drug use, craving, and continued use of the drug despite harm. Research suggests that opioids used to treat pain rarely lead to psychological dependence. Pseudoaddiction describes a patient’s behavior when the pain is undertreated. Some of these behaviors, such as “clock watching” or having “excessive pain,” may mimic addiction. However, a distinguishing feature of pseudoaddiction not seen in true addiction is the resolution of these behaviors when pain is effectively treated.
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A. Adjuvant Pain Therapies
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Patients with neuropathic pain occasionally respond to opioids alone; however, many require the addition of adjuvant pain medications. Commonly used adjuvants for neuropathic pain include tricyclic antidepressants (TCAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, and antiarrhythmics. The choice of an adjuvant is usually dictated by the individual drug side effect profile, the potential for drug interactions, and the previous drug therapy. The secondary amines, nortriptyline and desipramine, are generally better tolerated than amitriptyline. The analgesic effects of TCAs occur at lower doses and usually within several days, as compared with the antidepressant effects. Data on use of selective serotonin reuptake inhibitors (SSRIs) for neuropathic pain are not convincing; however, recent studies suggest that SNRIs may be as beneficial at tricyclic agents for pain control. Of the anticonvulsants, gabapentin, pregabalin, carbamazepine, and valproic acid are commonly used for neuropathic pain. Carbamazepine and valproic acid are cost-effective but have a higher risk of drug interactions and toxicity compared with gabapentin and pregabalin. Gabapentin requires more frequent dosing, slower titration secondary to sedation, and dose adjustments for renal insufficiency. Antiarrhythmics, topical lidocaine, and oral mexiletine have also been used successfully for neuropathic pain. For adjuvant pain medications, standard initial dosing and titration guidelines should be followed, although lower-than-usual doses have been effective for pain control. In elderly patients, it is generally safer to start at low doses and titrate at a slower rate.
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Corticosteroids, benzodiazepines, and anticholinergics are also used as adjuvant pain medication. Corticosteroids, by decreasing tumor-associated edema and by their anti-inflammatory effects, are useful for pain because of multiple pathologies, including bone metastasis, liver capsule distention from metastasis, and conditions in which the tumor is compressing sensitive structures. Benzodiazepines and baclofen are indicated for pain from spasticity. Anticholinergics can relieve colic due to intestinal obstruction.
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In addition to drug therapy for pain control, interventions such as palliative radiation therapy for bone metastasis, nerve blockage (eg, celiac plexus block for pancreatic cancer), palliative surgical resection, or immobilization of fractures should be considered. Before undertaking such interventions, the patient’s overall prognosis and the effectiveness of less invasive measures should be considered. Complementary therapies are often used in hospice and palliative care for treatment of pain and other symptoms. Some of these therapies are described in Table 67-3.
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Nausea and vomiting entail complex physiologic processes and are triggered by activation of one of four main pathways. An understanding of these pathways may aid in choosing an effective antiemetic regimen.
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The chemoreceptor trigger zone (CTZ) is located at the area postrema of the medulla. It lies outside the blood-brain barrier and is therefore able to sample emetogenic toxins, drugs, or metabolic abnormalities such as uremia or hypercalcemia. It further receives input from the gastrointestinal tract. The main receptors involved include dopamine type 2 receptors (D2), 5-hydroxytryptamine type 3 receptor (5-HT-3), and neurokinin type 1 receptor (NK1).
Pathways from the vestibular apparatus respond to vertigo and visuospatial disorientation. The main receptors involved include muscarinic acetylcholine receptors (m-Ach) and histamine type 1 receptors (H1).
Peripheral pathways (vagus nerve and splanchnic nerves) mediate nausea triggered by activation of visceral chemoreceptors (local toxins) and serosal mechanoreceptors (stretch of organs and capsules). The main receptors involved include H1 and m-Ach receptors. Enterochromaffine cells release 5-HT-3 when damaged by interventions such as chemotherapy or radiation therapy.
Cortical pathways respond to increased intracranial pressure, sensory stimuli (smell, pain), and psychogenic stimuli (anxiety, memory, conditioning).
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Each of these pathways sends signals to the vomiting center (VC), which triggers nausea and vomiting when thresholds are reached. The main receptors involved at the VC are H1, m-Ach, and 5-HT-2.
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Treatment should focus on correcting underlying causes as well as choosing antiemetics to target specific receptors and pathways involved. Commonly used antiemetics are described in Table 67-4. If nausea or vomiting is persistent, severe, or refractory, it is recommended to schedule regular administrations of an antiemetic agent. A second or third antiemetic targeting a different receptor may be added (scheduled dosing, or dosed as needed).
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Nausea and vomiting also may be presenting symptoms of a malignant gastrointestinal obstruction. The patent should be evaluated for invasive procedures such as venting gastrostomy, intraluminal stent, or surgical diversion. With partial obstruction, the use of metoclopramide and dexamethasone along with a low-fiber diet can provide significant symptom relief for several weeks or longer. When an obstruction becomes complete, therapy is directed at decreasing intestinal motility and decreasing secretions using anticholinergics and somatostatin analogs. Metoclopramide is contraindicated in complete bowel obstruction as it increases gastrointestinal motility and leads to exacerbation of painful abdominal cramping.
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Dyspnea, like pain, is a subjective experience, and can be present with or without hypoxia. With a broad differential existing for dyspnea, reversible causes should always be considered first. The optimal therapy is aimed at the presumed etiology. Palliative therapy can involve chemotherapy, radiotherapy, thoracentesis, pericardiocentesis, and bronchial stent placement. General measures such as providing a fan, keeping the room temperature cool, use of relaxation techniques, or using a careful trial of supplemental oxygen (for hypoxic patients) can help dyspneic patients. Available palliative drug therapies include steroids, opioids, bronchodilators, diuretics, anxiolytics, antibiotics, and anticoagulants. All these drugs can be used in combination, depending on the etiology of dyspnea.
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Opioids can relieve breathlessness, although the mechanism is unclear. Opioid administration, dose, frequency, and titration are the same as for pain control. The use of nebulized morphine sulfate is not more effective than placebo. Opioids can increase exercise tolerance and reduce dyspnea in patients with chronic obstructive airways. Fear of addiction or fear of respiratory depression should not preclude a trial of opioids in this population. Starting at low doses, carefully titrating the dose to achieve symptom control, and close monitoring allow for safe and effective use.
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Steroids are useful for dyspnea from bronchospasm and tumor-associated edema. Specific indications include malignant bronchial obstruction, carcinomatous lymphangitis, and superior vena cava syndrome. Dexamethasone can be started at 4 mg twice daily and subsequently reduced to the lowest effective dose. Dexamethasone is more potent and has lower mineralocorticoid activity than other steroids, resulting in less fluid retention.
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Some patients with dyspnea express disturbing fears of suffocation and choking. Understandably, anxiety often coexists with chronic dyspnea. Anxiety can heighten breathlessness, making symptom control more difficult. The use of anxiolytics such as benzodiazepines and phenothiazines can help treat dyspnea associated with a high component of anxiety. Lorazepam, 0.5–1 mg, can be tried initially. If patients show benefit, long-acting diazepam or clonazepam can then be prescribed. Low-dose chlorpromazine has also shown benefit in relieving both dyspnea and anxiety.
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Anorexia (poor appetite) and cachexia (involuntary weight loss regardless of caloric intake or appetite) are prevalent distressing symptoms in patients with advanced illnesses. Mechanisms of the anorexia-cachexia syndrome include an aberrant inflammatory response, generated by disease-host reactions, as well as neurohormonal dysfunction. Exacerbating factors include delayed gastric emptying, constipation, nausea, depression, mucositis, thrush, and even ill-fitting dentures.
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Little effective drug therapy is available. Megestrol acetate, a progestin, has been shown to increase appetite and result in weight gain; however, weight gain is due largely to accumulation of adipose tissue and not lean muscle mass. Doses start at 160 mg/day and can be titrated to 800 mg/day if required. Side effects include thromboembolic events and adrenal insufficiency on abrupt cessation. Corticosteroids, such as dexamethasone, can be prescribed as an appetite stimulant for patients in whom side effects of long-term steroid use are of less concern. Beneficial effects tend to be limited to several weeks. Significant weight gain is not seen with corticosteroids in this population. Dexamethasone can be started at 2–4 mg daily, with titration to 16 mg daily if required. The lowest effective steroid dose should always be used. Androgens dronabinol and growth hormones have been effective for patients with AIDS-associated anorexia and cachexia.
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Nutritional support, parenteral and enteral, has not been shown to prolong survival in patients with advanced cancer who are not candidates for disease-specific therapy. Exceptions include patients with head and neck cancer undergoing radiation therapy or patients with gastrointestinal dysfunction and otherwise good performance status.
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Asthenia is well described in patients with cancer, but it also affects patients with end-stage organ dysfunction. It is one of the most disabling symptoms yet at the same time remains underrecognized and poorly treated. It is characterized by excessive physical, emotional, and cognitive fatigue that is not relieved by rest. Etiologies are often multifactorial, and treatment should be aimed at treating underlying and reversible causes, including hypoxia, anemia, electrolyte disturbances, dehydration, insomnia, or uncontrolled symptoms (such as pain, nausea, vomiting, and constipation). Unfortunately, when disease-specific therapy is not effective, asthenia is difficult to palliate. Education of the patient and family, normalization of the experience, counseling about energy conservation, mild exercise programs, light exposure therapy, and cognitive behavioral therapy can be effective. Symptomatic drug therapy includes corticosteroids (dexamethasone 2–4 mg PO once or twice daily) and psychostimulants (methylphenidate 2.5–5 mg PO once or twice daily). To lessen potential insomnia at night, these drugs should be administered early in the day.