++
++
Key Clinical Questions Pain
How do I choose an appropriate opioid dose for my patient?
What adjuvant medications can I use for neuropathic pain?
How do I treat a patient who is experiencing a pain crisis?
When should I consult a palliative care or pain specialist?
Nausea Dyspnea
What nonpharmacologic strategies can I use to relieve my patient’s dyspnea?
What is an appropriate dose of opioid for treating dyspnea?
What do I say to family members who are concerned that opioids may hasten the patient’s death?
Secretions Terminal Delirium
How do I evaluate an agitated dying patient?
How do I identify terminal delirium and distinguish it from other kinds of delirium?
What medications are useful for treating terminal delirium?
Nutrition and Hydration
How do I counsel family members who are upset that the patient is no longer eating?
Are there any clinical situations in which artificial nutrition and hydration may be helpful for patients with advanced disease?
Complementary Medicine
++
Studies of patient perspectives on end-of-life care consistently report pain control as a major priority. Nonetheless, the literature shows that many patients experience poor pain control. In one well-known study (SUPPORT trial: Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments), approximately 40% of hospitalized patients experienced severe pain in the last 3 days before death.
++
When the focus of care is quality of life and comfort, any poorly controlled symptom should be treated urgently. Many patients already fear that pain will be an inevitable part of their disease process and that “nothing can be done.” Hospitalists play a vital role in correcting this misconception and ensuring that patients with advanced illnesses receive adequate pain control.
++
Pain can be described as nociceptive or neuropathic in origin. In nociceptive pain, peripheral nociceptors in the skin, musculoskeletal system, or viscera detect noxious stimuli and send impulses via afferent A-delta or C fibers to the dorsal horn of the spine. These signals are transmitted through ascending spinothalamic tracts to the thalamus and then to the cortex. Neuropathic pain occurs when the peripheral or central nervous system itself suffers damage or develops pathologic changes in sensitization. Neuropathic pain is generally more difficult to control than nociceptive pain. In reality, however, any type of chronic pain can significantly alter the sensory pathways and cause pathologic activation of the nervous system even after the initial pain stimulus has dissipated. The mechanisms of activation are quite complex and can involve central sensitization pathways, including multiple neurotransmitters (substance P, amino acid ligands), receptors (mu opioid, neurokinin-1, N-methyl-D-aspartate [NMDA]), and intracellular pathways (nitric oxide, protein kinase C).
++
The patient ultimately experiences pain not just as a physical phenomenon, but as an emotional experience. The International Association for the Study of Pain (IASP) has defined pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. While it is unquestionably a sensation in part or parts of the body, it is always unpleasant and, therefore, an emotional experience.” Patients with life-threatening illness are especially vulnerable to emotional and cognitive factors that can influence their experience of pain.
++
Assessment of pain begins with a thorough history, including location, onset, duration, intensity, quality, and aggravating or ameliorating factors. The evaluation should also include a history of any associated functional decline, a psychosocial assessment (including exploration of any associated fears and concerns about disease progression), and a careful physical exam. The clinician should formulate a differential diagnosis of the clinical etiology of pain, which may include processes unrelated to the patient’s known terminal disease. For example, chest pain in a patient with breast cancer could be due to bony metastases, postradiation skin changes, cardiac ischemia, pulmonary embolism, costochrondritis, or gastroesophageal reflux disease.
++
The clinician should also determine the type of pain a patient is experiencing, as this will guide the appropriate treatment strategy.
++
Nociceptive pain can be categorized as somatic or visceral. Somatic pain includes skin, musculoskeletal, or bone pain. It may be described as sharp, constant, throbbing, aching, and exacerbated by movement. It is usually well localized. Unlike somatic pain, visceral pain is generally poorly localized and arises from injury to organs or the lining of body cavities. It may be described as cramping, aching, tearing, deep, or a pressure sensation. Examples of visceral pain include symptoms from bowel obstruction, cholecystitis, or cardiac ischemia.
Neuropathic pain can result from injury to any part of the nervous system, such as the peripheral nerves or spinal cord. Examples include postherpetic neuralgia, radiation-related brachial plexus injury, post-thoracotomy pain, and phantom limb pain. Neuropathic pain is frequently described as burning, tingling, stabbing, electric, or shooting. It may also be described as aching. Physical findings may include allodynia, which is pain caused by a normally painless stimulus such as light touch. Neuropathic pain may also radiate.
Some pathologic processes can cause a mixed pain syndrome with both nociceptive and neuropathic pain. One example is bone metastases to the spine, which may incite nociceptive, somatic bone pain as well as neuropathic pain from nerve root compression.
++
When a patient is unable to communicate, the clinician must then rely on the family or caregiver’s report and careful observation for nonverbal cues, such as guarding or grimacing with movement, to assess pain. One common misconception is that a patient who exhibits no physiologic signs of discomfort (such as tachycardia or hypertension) is unlikely to be experiencing pain. In fact, patients with chronic pain rarely show these signs of sympathetic arousal. These physiologic changes are more typically seen in acute pain, though even some patients with acute pain do not exhibit these signs.
++
Several pain scales have been developed to monitor pain intensity and efficacy of treatment (Figure 216-1). Some patients may have no difficulty with the numerical pain scale, whereas others find it easier to report simplified categories of mild, moderate, or severe pain. Patients with mild cognitive deficits may be able to utilize the Faces Pain Scale, which was originally developed for pediatric patients.
++
++
Diagnostic tests should be tailored appropriately to a patient’s overall goals of care. Generally, if a study has good potential to lead to therapies (such as radiation) that would enhance a patient’s comfort, then the study may be indicated even in the setting of advanced disease.
++
++
The World Health Organization (WHO) has developed a well-known analgesic ladder that recommends nonopioid analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for mild pain, with the addition of opioids for moderate and severe pain. The WHO ladder also recommends consideration of adjuvant therapies such as antidepressants and anticonvulsants at any level of pain if appropriate. One should keep in mind that many patients with terminal illness have at least moderate to severe pain and thus will need an opioid immediately in addition to nonopioid analgesics.
++
Medication choice should also be guided by the type of pain. Opioids are generally effective for nociceptive pain, including both somatic and visceral types. Somatic pain such as musculoskeletal or bone pain may also be quite responsive to NSAID therapy. Bone pain may require a combination of additional therapies including bisphosphonates, corticosteroids, calcitonin, or radiation therapy. Visceral pain from bowel obstruction may warrant an antisecretory agent such as a somatostatin analogue (octreotide) or an anticholinergic agent with antispasmotic activity (hyoscyamine, glycopyrrolate, scopolamine). Neuropathic pain is often less responsive to opioids and requires the addition of adjuvant medications. Table 216-1 shows common adjuvant medications for neuropathic pain.
++
++
The mainstays in neuropathic pain therapy include anticonvulsants (gabapentin, pregabalin) and antidepressants (tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors). Topical agents such as lidocaine and capsaicin can be helpful. Depending on the etiology of pain, second-line agents such as corticosteroids and autonomic drugs (clonidine, prazosin, terazosin) may have a role. NMDA receptor antagonists such as ketamine can be considered for intractable pain but would require administration by a pain specialist.
++
The side-effect profile may greatly influence one’s choice of pain medication. NSAIDs are not recommended for those with significant risk of renal compromise, including patients who are elderly or have chronic kidney disease. Patients with multiple myeloma and a normal creatinine still carry a substantial risk for renal failure with NSAIDs. NSAIDs may also be contraindicated in patients at risk for gastrointestinal bleed or those on concomitant blood-thinning agents. Tricyclic antidepressants should be used cautiously in the elderly due to anticholinergic side effects. Nortriptyline is well studied and is generally considered the best-tolerated tricyclic agent for the elderly, as it has the least anticholinergic activity. Opioids have some well-known side effects including constipation and sedation. However, because many patients with terminal illness will eventually need an opioid for adequate pain control, the clinician should become adept at dosing opioids and managing their side effects.
++
Many clinicians have received little formal training in pain management and do not feel fully confident selecting and dosing opioids. This discomfort may be exacerbated by misconceptions about opioids on the part of both clinicians and patients. Opioids rarely cause respiratory depression when dosed appropriately for pain. Studies have shown that patients with underlying lung disease such as chronic obstructive pulmonary disease (COPD) can safely use opioids if dosed appropriately.
++
True opioid addiction is uncommon in terminally ill patients. Providers sometimes mistake behaviors like clock-watching or irritability as signs of addiction, but usually these are manifestations of an inadequate pain regimen. These apparent drug-seeking behaviors (termed pseudoaddiction) tend to cease when patients are given adequate doses at regular intervals.
++
Some patients and family members may not readily articulate their fears of opioid addiction. They may also worry that their disease is progressing or that they are “giving up” if they take opioids. Many patients directly associate morphine with dying. Clinicians should be attuned to these fears and educate their patients accordingly. It is also important to emphasize that pain medications will not advance one’s disease, and may in fact improve function by reducing pain.
++
Commonly used opioids include morphine, oxycodone, hydromorphone, fentanyl, and methadone. For most patients being initiated on opioids, there is not a compelling reason to choose, for example, hydromorphone over morphine. For certain patient populations, however, the choice of opioid does matter. Patients with significant renal failure should generally avoid morphine. The metabolites of morphine can accumulate in renal failure and cause neurotoxic side effects including myoclonus and delirium. Fentanyl and methadone are the safest opioids to use in renal failure patients including those on dialysis. Hydromorphone and oxycodone may be used cautiously in those with mild to moderate renal failure, with consideration of a reduction in dose or decrease in frequency. Similarly, patients with liver failure may need dose and frequency adjustments, but it is not clear that one particular opioid is significantly safer than the others in this setting.
++
Methadone may be effective for patients with severe pain who have responded poorly to other opioids or who have developed intolerable side effects. In addition to its opioid receptor activity, methadone is also believed to act as an NMDA receptor antagonist. It has good bioavailability and no known active metabolites (thus accounting for its safety in renal failure). However, due to its long half-life and complexities in dosing, it should generally be initiated by clinicians with prior training or in consultation with a specialist.
++
Certain opioids are almost never recommended. Both meperidine and propoxyphene should be avoided because their metabolites can accumulate with repeated dosing and cause serious neurotoxicity such as seizures. Codeine should not be used for severe pain because it has a “ceiling effect” whereby further titration results only in increased side effects without improved pain relief. Furthermore, codeine must first be metabolized to morphine to provide analgesia, and approximately 10% of the population lacks the appropriate hepatic enzyme. These patients derive no benefit from codeine.
+++
Principles of opioid dosing
++
++
Different opioids have different potencies (ie, dose required to achieve a certain effect). Equianalgesic doses of two different opioids should achieve a similar degree of pain relief for most patients, although some patients may have idiosyncratic responses to different opioids due to genetically determined variations in metabolism. Table 216-2 shows equianalgesic doses of commonly used opioids. Looking at the table, morphine 10 mg intravenously should achieve similar pain relief as morphine 30 mg orally and oxycodone 20 mg orally. Misconceptions that “morphine does not work but hydromorphone does” may arise from a lack of knowledge of equianalgesic doses. A patient who finds no relief with morphine 4 mg intravenously but responds well to hydromorphone 1 mg intravenously may have in fact needed a higher dose of morphine (hydromorphone 1 mg intravenously is equianalgesic to approximately morphine 6.6 mg intravenously).
++
++
General opioid dosing guidelines:
++
Table 216-3 lists reasonable starting doses and dosing intervals for moderate to severe pain in opioid-naïve patients.
Figure 216-2 demonstrates opioid conversions using simple mathematical ratios.
Many clinicians find it helpful to consult an opioid calculator program. One commonly used opioid calculator is available through Global RPh: www.globalrph.com/narcotic.cgi.
When switching between different opioids, most experts recommend a 25% to 50% dose reduction after one has calculated the equianalgesic dose. This is to account for incomplete cross tolerance. A patient who has developed some tolerance to the old opioid may not have the same degree of tolerance to the new opioid. The dose reduction is intended to reduce the risk of undesired side effects.
Patients with chronic pain will generally need a long-acting pain medication (eg, sustained-release oxycodone or morphine, fentanyl patch, or methadone), not just short-acting medications. Figure 216-2 demonstrates the initiation of a long-acting opioid in a patient with metastatic bone pain. If unable to use a long-acting pain medication, chronic pain patients should at least receive a standing pain regimen with additional as-needed availability.
Patients on sustained-release medications should also have a short-acting medication for breakthrough pain. Each dose of breakthrough opioid should be approximately 10% to 20% of the total daily requirement of the sustained-release opioid.
If greater than three doses of breakthrough pain medications are needed in a 24-hour period, one may consider increasing the amount of sustained-release opioid. An appropriate increase would be 50% to 100% of the total amount used for breakthrough pain in 24 hours.
++
++
++
Patients with terminal illness, particularly those with cancer, may suffer severe exacerbations of pain from bone metastases, pathologic fractures, bowel obstruction, or other manifestations of progressive disease. When a patient presents with severe, uncontrolled pain (7-10 intensity), this is considered an acute pain crisis or palliative care emergency. Clinicians should treat these symptoms aggressively while determining the underlying cause. The National Comprehensive Cancer Network has published guidelines for rapid titration of opioids to treat severe pain (Figures PAIN-4 and PAIN-5 in NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain. To access: www.nccn.org/professionals/physician_gls/f_guidelines.asp).
++
++
PRACTICE POINT
Consider a pain or palliative consult in patients with uncontrolled pain or intolerable side effects. Also consider a consult in patients with unusual dosing needs due to a history of chronic opioid use, illicit drug use, or methadone maintenance. Such patients are at great risk of undertreatment due to high opioid tolerance and psychosocial or behavioral issues.
++
Infusions can be useful in certain settings but require a good understanding of basic principles.
++
Opioid infusions should be used only when there is a specific indication. They should not be automatically started in a dying patient who is “comfort care” unless the patient has symptoms of discomfort and has demonstrated an ongoing need for opioids.
Patients who were previously on sustained-release oral regimens but are now unable to take pills (eg, surgery, bowel obstruction) will need another means of fulfilling their baseline opioid requirement. For most inpatients, an opioid infusion is appropriate. The total daily opioid requirements should be converted into intravenous morphine or hydromorphone equianalgesic units, then divided by 24 hours for an hourly infusion rate. Consider a 25% to 50% dose reduction for incomplete cross-tolerance if switching between opioids. Fentanyl patch (discussed later) may be an option for those without intravenous access, but it is not appropriate for acute pain due to the time required to reach peak effect.
Patients with severe pain who have required multiple opioid doses to control their symptoms may also be potential candidates for an opioid infusion. The initial infusion rate should be calculated based on the prior total documented 24-hour needs, or if in an acute pain crisis, projected from their needs over the past 4 hours.
Opioid infusion orders should not be written as broad ranges of “morphine 2 to 20 mg/h, titrate to comfort.” This type of order places the patient at risk for inappropriate titration of the infusion. Many clinicians do not realize that it takes at least 8 to 12 hours to achieve new steady-state blood levels of morphine or hydromorphone after a change in the basal infusion rate. If one simply continues titrating up an infusion in a symptomatic patient without administering as-needed boluses, this patient is at risk for undertreatment of symptoms in the immediate setting, as well as overdose in several hours once the opioid reaches a new steady state. Many experts therefore recommend that opioid infusions be written as a specific rate without any range, with an additional order for as-needed boluses, either nurse-administered or through patient-controlled analgesia (PCA).
Bolus orders can be rapidly titrated for poorly controlled pain. Peak effect for morphine and hydromorphone boluses occurs within 15 to 30 minutes. If a particular bolus dose is inadequate, the dose can be safely increased every 15 to 30 minutes without needing to rapidly titrate up the basal infusion rate.
The basal infusion rate should be reassessed every 8 hours but not more frequently. The infusion rate can be increased based on the amount of boluses required, but generally should not be increased by more than 100% at a time.
When using an opioid infusion to treat a patient who is not at the final stages of illness, the clinician should be attuned to potential fears that the patient may be actively dying. Many people associate a “morphine drip” with dying.
Seek the advice of a pain expert before starting an infusion for a patient who is opioid-naïve.
+++
Patient-controlled analgesia
++
Patient-controlled analgesia (PCA) may be used for patients with significant pain who are alert and able to use the equipment appropriately. PCAs should not be used by patients who have delirium, dementia, or other cognitive deficits. Table 216-4 shows commonly used PCA doses and lockout intervals in opioid-naïve patients. Higher doses may be needed in patients who have previously been on opioids. PCA pumps can be programmed to deliver patient-controlled boluses, a basal infusion, or both, although opioid-naïve patients generally should not be started on a basal infusion without the advice of a pain expert.
++
++
The fentanyl transdermal patch is another option for patients who cannot reliably take pills, but it is important to understand appropriate dosing and limitations of use:
++
Equianalgesic dosing for the fentanyl patch compared with oral morphine appears earlier in this chapter (Table 216-2). Note that the commonly used fentanyl 25 mcg/h patch is equianalgesic to approximately 50 mg oral morphine per day. Elderly or opioid-naïve patients should not be initiated on the 25 mcg/h dose unless there is demonstrated need for this quantity of opioid. A 12 mcg/h patch is available for patients with lesser needs, but in general fentanyl patches should only be initiated in patients with chronic pain and well-documented opioid requirements.
The patch can take greater than 24 hours to reach peak effect. It is not appropriate for acute pain or if frequent titration is needed.
Fentanyl patches are not recommended for patients with significant cachexia. The patch requires subcutaneous fat for effective absorption and release of drug.
Fentanyl patches generally should not be used in febrile patients, as the uptake of medication may increase with temperature and cause unexpected side effects (such as sedation) or poor analgesia if the patch runs out early.
++
Concerns about side effects from opioids often lead to undertreatment of pain. Clinicians should make it a priority to recognize and treat opioid-induced side effects.
++
Many patients complain about mild sedation or “fogginess” when initiating opioids or immediately after dose titration, but the effect usually wanes after 2 to 7 days. If a patient complains of persistent symptoms and other causes of sedation have been ruled out (eg, other medications, metabolic disturbances, or central nervous system processes), one can consider several options:
++
Reduce opioid dose (10%-25%) if pain symptoms allow. Consider adding nonopioid adjuvant pain medications to facilitate dose reduction.
Rotate to another opioid.
Add a psychostimulant such as methylphenidate, with a starting dose of 2.5 mg orally twice a day and titrate up to a maximum of 1 mg/kg/d in divided doses. Psychostimulants should be avoided in patients with significant anxiety, arrhythmias, delirium, or psychosis.
++
Like sedation, opioid-induced nausea usually improves after the first week. This symptom is discussed in greater detail in the nausea section of this chapter. First-line therapies for opioid-induced nausea include dopamine antagonists such as prochlorperazine and haloperidol.
++
Unlike other opioid side effects, constipation does not wane with time. Patients taking opioids should be given a standing bowel regimen. Even patients with regular bowel movements should have a bowel regimen in place to prevent future constipation. The combination of docusate sodium (stool softener) with senna (laxative) is one option. Many patients will need an additional laxative, such as polyethylene glycol or lactulose, to maintain regular bowel function. Methylnaltrexone, a selective opioid antagonist, can be considered for more severe cases of opioid-induced constipation that have not responded to laxatives and enemas. Unlike naloxone, methylnaltrexone does not cross the blood-brain barrier and provides effective relief of constipation without opioid withdrawal or reduction in analgesia. Methylnaltrexone can be given subcutaneously every other day as needed.
++
Any mental status change in a patient taking opioids should be taken seriously. Delirium can cause a myriad of complications including patient and family distress, uncertainty in overall prognosis, injury, and a delay in discharge. Delirium can be particularly distressing because it compromises a patient’s sense of self. Patients may find this quite frightening, and families often struggle with a heightened sense of loss, feeling like they are losing their loved one even before death.
++
However, one should not automatically blame opioids for every new mental status change, especially if a patient has been on a stable dose for some time. Workup for delirium should include an evaluation for other reversible causes, including other medications, infection, central nervous system disease, hypoxemia, metabolic/electrolyte disorders, and renal or liver failure.
++
If the delirium ultimately seems attributable to opioids but the patient needs continued pain control, consider the following options:
++
Reduce opioid dose (10%-25%) if pain symptoms allow. Use nonopioid adjuvants if needed.
Treat concurrently with an antipsychotic such as haloperidol or olanzapine.
Rotate to a different opioid.
Use nonpharmacologic strategies, including environmental cues for day and night, glasses and hearing aids, and family presence.
++
Patients on chronic opioids can develop neurotoxic side effects from opioid metabolites, especially in the setting of high opioid doses, dehydration, or renal failure. Myoclonus is a common manifestation of this neuroexcitatory state. Symptoms may be mild, such as an occasional jerking of extremities, but with continued opioid administration patients may develop frequent twitching of muscle groups in the extremities and face. Other signs of neurotoxicity include delirium, hyperalgesia (increased sensitivity to pain), and allodynia (pain from non-noxious stimuli). In severe neurotoxicity, patients may even develop generalized seizures. Hyperalgesia is particularly confusing because clinicians may mistake this as worsened pain from an underlying disease process. Further opioid escalation actually worsens the hyperalgesia.
++
Treatment strategy depends on both the severity of symptoms and overall prognosis. In an imminently dying patient with mild myoclonus, it may be appropriate to simply monitor the patient for any worsening symptoms. For patients with ongoing need for opioids and concerning manifestations of neurotoxicity, consider several strategies:
++
Reduce opioid dose (10%-25%) if neurotoxic symptoms are mild (only occasional myoclonus). Consider adding nonopioid adjuvant pain medications to facilitate opioid dose reduction.
Rotate to another opioid if there are signs of significant neuroexcitation, including myoclonus, allodynia/hyperalgesia, delirium, or hallucinations. The new opioid should be initiated at 25% of the equianalgesic dose. Methadone and fentanyl are particularly good options in severe neurotoxicity because they do not have active metabolites. Clinicians without specific training in pain management should consult an expert for any cases of significant neurotoxicity and when initiating methadone or fentanyl, due to complexities of dosing in this setting.
Add medications to reduce myoclonus. Options include benzodiazepines (lorazepam, clonazepam, midazolam) and muscle relaxants (baclofen, nifedipine).
++
+++
Respiratory depression
++
Though respiratory depression remains a commonly feared side effect, clinically significant respiratory depression is actually quite rare when opioids are dosed appropriately. Respiratory depression is a late effect, and patients should exhibit signs of somnolence before their respiratory function is compromised. Naloxone should be reserved for those with life-threatening respiratory depression. To prevent sudden reversal of analgesia (and almost certain pain crisis), an incremental dosing approach is recommended. Mix 0.4 mg (1 mL ampule) of naloxone into 9 mL of saline to make a diluted 0.04 mg/mL naloxone solution. Administer 1 to 2 mL of this diluted solution intravenously approximately every 1 to 2 minutes until respiratory depression resolves. Repeated doses may be necessary due to the short duration of naloxone, and a continuous infusion may be required if the patient was on long-acting opioids.
++
Does the patient understand how to use pain medications appropriately, including the difference between long-acting and breakthrough medications? Create a written pain management plan, review it with the patient and family members, and confirm that they know who to contact for uncontrolled symptoms.
Is your patient on a standing bowel regimen to prevent opioid-induced constipation?
Is the responsible outpatient clinician aware that you have initiated opioids or changed doses during this hospitalization? Has the outpatient provider agreed to continue writing for these controlled substances?
Have you communicated with the case manager and home care agency (visiting nurse agency, hospice agency) about the current pain medication plan? Have you considered a contingency plan if the patient is no longer able to take oral medications?
++
Symptoms of nausea and vomiting are common in patients with advanced illnesses, including cancer, congestive heart failure, end-stage renal disease, and AIDS. For patients and families facing a life-threatening illness, nausea and vomiting can cause substantial distress due to concerns about maintaining adequate nutrition and worries that these symptoms indicate disease progression.
++
Evaluation should include a thorough history and physical exam, with careful attention to common causes of nausea in the terminally ill, including medications (chemotherapy, opioids), constipation, electrolyte abnormalities, liver and kidney failure, radiation therapy, central nervous system lesions, bowel obstruction, and anxiety. It is important to try to identify the likely mechanism or pathway responsible for a patient’s nausea, as this can guide the therapeutic approach.
++
Nausea and vomiting can be triggered by activation of any of four general pathways:
++
Cortex: Activation can occur due to meningeal irritation, increased intracranial pressure, or cognitive/emotional factors such as anxiety.
Chemoreceptor trigger zone: This area is located in the floor of the fourth ventricle and lacks a blood-brain barrier. It is easily activated by metabolic abnormalities, toxins, and medications present in the cerebrospinal fluid (CSF). Activation of the chemoreceptor trigger zone is mediated primarily by the dopamine (D2) receptor, but others include neurokinin-1 (NK1) and serotonin (5HT3).
Vestibular system: Motion or inner ear disease can activate the vestibular apparatus via histamine (H1) and muscarinic acetylcholine (ACh) receptors.
Peripheral pathways: Activation can occur through mechanoreceptors and chemoreceptors in the gastrointestinal tract and heart, as well as 5HT3 receptors in the gastrointestinal tract. These signals are then transmitted along afferent tracts including the vagus, glossopharyngeal, splanchnic, and sympathetic nerves.
++
Each of these four pathways can then activate the vomiting center, a specific area of the medulla that coordinates the final act of vomiting via the parasympathetic system and gastrointestinal tract. Activation of the vomiting center is believed to be mediated by H1 receptors or muscarinic ACh receptors.
+++
Nonpharmacologic treatment
++
Nonpharmacologic strategies may be helpful for many patients. Patients should avoid strong smells and eat small, frequent meals as they are able. Relaxation techniques may be useful for patients with significant anxiety or anticipatory nausea (nausea that occurs prior to chemotherapy sessions due to a conditioned response). Acupuncture appears to be helpful for chemotherapy-related nausea and vomiting. Although further research is needed, there have been a few randomized controlled trials demonstrating that acupuncture-point stimulation reduces the incidence of acute chemotherapy-induced vomiting.
+++
Pharmacologic treatment
++
Most patients with nausea or vomiting will need some type of pharmacologic therapy. Table 216-5 shows common clinical etiologies of nausea and recommended first-line pharmacologic therapies based on likely mechanisms and receptors. Table 216-6 lists common antiemetics, doses, and side effects.
++
++
++
PRACTICE POINT
Determine the clinical etiology of nausea and select a first-line antiemetic based on the likely mechanism.
Use the first-line agent on a scheduled basis initially until nausea symptoms are controlled, and then consider tapering to as-needed dosing.
If symptoms persist, consider adding another agent in a different class while keeping the first-line agent. Nausea is frequently multifactorial and may need therapy directed at multiple sources.
Recognize the side-effect profiles of different antiemetics and use them to the patient’s advantage, not disadvantage.
Avoid using multiple agents in the same class simultaneously.
+++
Opioid-induced nausea
++
Opioid-induced nausea warrants further discussion because it is particularly common and troublesome in this population. Opioids cause nausea through multiple mechanisms, including decreased gut motility (constipation, gastroparesis), stimulation of the chemoreceptor trigger zone via dopamine receptors, and enhanced vestibular sensitivity. Symptoms of opioid-induced nausea usually improve after the first week of opioid use. One strategy is to use a dopamine antagonist such as prochlorperazine, haloperidol, or metoclopramide on a scheduled basis for several days. The antiemetic may be subsequently be tapered as the patient develops tolerance to the opioid side effects. Another effective agent is olanzapine, which has mixed dopamine, acetylcholine, histamine, and serotonin activities. Patients with persistent nausea may require an opioid dose reduction (10%-20%) or rotation to another opioid. Patients taking opioids should be on a scheduled bowel regimen to prevent constipation.
+++
Malignant bowel obstruction
++
Malignant bowel obstruction is a common complication in patients with advanced abdominal and pelvic malignancies. In patients who are not surgical candidates, medical management should include several concurrent mechanical and pharmacologic strategies:
++
Pain control is a priority and generally requires the use of opioids.
Decompression with a nasogastric tube may provide rapid relief of nausea and abdominal distension. A percutaneous gastrostomy tube may be considered in patients with persistent obstruction since patients can be transitioned home with a gastrostomy tube in place.
Patients should be given a scheduled antiemetic to relieve associated nausea. Metoclopramide is recommended for patients with partial obstruction, but it should be discontinued if the patient develops worsened abdominal pain or cramping. It should not be used in patients with complete bowel obstruction. Haloperidol may be used for nausea in patients with complete obstruction or those with symptoms of colic. Dexamethasone 4 mg orally or intravenously two to three times a day may be useful for both its antiemetic and anti-inflammatory properties, including treating tumor-associated inflammation and potentially reducing the obstruction.
Anticholinergic agents may be helpful for reducing abdominal distension and cramping. Hyoscyamine can be given 0.125 to 0.25 mg sublingually four times a day or scopolamine can be administered through a patch.
Octreotide is a somatostatin analogue that inhibits motility and reduces gastrointestinal secretions. It can be administered subcutaneously 50 to 150 mcg three times a day. Patients who respond well to subcutaneous octreotide may be candidates for a monthly depot injection of octreotide for longer-term palliation of bowel obstruction.
Studies have demonstrated successful symptom management of malignant bowel obstruction using a combined regimen of metoclopramide, octreotide, and dexamethasone, including the recovery of bowel transit in some patients with partial obstruction.
++
Antiemetics may cause a number of side effects. Sedation is common with antihistamines and neuroleptic agents, including dopamine antagonists and atypical antipsychotics. Sedation may be a desired effect for some patients nearing the end of life, but a dose adjustment or medication change may be necessary for patients who find this problematic. Almost all classes of antiemetics can cause delirium, including antihistamines, benzodiazepines, anticholinergics, corticosteroids, and cannabinoids. The elderly are especially vulnerable and should be monitored closely. Patients on dopamine antagonists may develop extrapyramidal symptoms such as akathisia and dystonia. Management includes treatment with diphenhydramine or benztropine and discontinuation of the offending agent. Serotonin antagonists such as ondansetron may cause constipation and patients may need prophylactic laxatives. Clinicians should also be aware that many antiemetics (such as haloperidol, metoclopramide, ondansetron) may prolong the QT interval. EKG monitoring may be warranted, depending upon the patient’s clinical situation and overall goals of care.
++
Patients with persistent nausea and vomiting often develop dehydration and electrolyte disturbances, which can further exacerbate symptoms of nausea. It may be reasonable to consider intravenous hydration, even in patients with a limited prognosis, with the goal of relieving symptoms. Consider referring patients with persistent bowel obstruction for surgical evaluation, depending on the stage of illness and overall prognosis. Additionally, patients and families may struggle with news that disease-modifying therapies (such as chemotherapy) are no longer possible due to intractable symptoms, poor functional status, or advanced disease. Their psychosocial distress should be addressed with the assistance of the primary outpatient clinician, palliative care clinician, social worker, or chaplain.
++
Dyspnea, defined as the subjective experience of difficult or uncomfortable breathing, is a very common and distressing symptom for patients. Dyspnea has been reported in up to 78% of cancer patients, 70% of patients with congestive heart failure, 70% of patients with dementia, 56% of COPD patients, and 62% of patients with AIDS. Of note, studies show that patients with higher dyspnea scores report decreased quality of life indices. Despite its prevalence and impact on quality of life, dyspnea often goes untreated. One study reported that over 60% of patients with advanced cancer had dyspnea for greater than 3 months, yet most had not received any treatment for their symptoms.
++
The pathophysiology of dyspnea is complex and not yet fully understood. The respiratory center, located in the medulla and pons, coordinates the movements of the diaphragm and chest wall muscles during breathing. The respiratory center receives sensory input from several sources, including pulmonary vagal afferents, peripheral and medullary chemoreceptors, and peripheral mechanoreceptors from respiratory muscles and joints. The pulmonary vagal afferents include pulmonary stretch receptors, alveolar C fibers that respond to interstitial and capillary pressure, and pulmonary irritant receptors.
++
Several mechanisms appear to trigger the sensation of dyspnea:
++
Increased work of breathing: This can be caused by increased airway resistance, such as in COPD or asthma, or weakened musculature, as occurs in neurodegenerative disorders or severe cachexia.
Chemoreceptor activity: Receptors in the medulla primarily detect hypercapnia, and those in the carotid and aortic bodies detect hypoxemia. Hypercapnia appears to have a greater role in triggering dyspnea than hypoxemia.
Neuromechanical dissociation: Researchers have described an important relationship between the brain’s efferent motor output for respiration and the afferent information it receives in response to these efforts. Dyspnea can occur when there is a mismatch, or neuromechanical dissociation, between what the brain desires from respiration and the sensory feedback from pulmonary vagal afferents and peripheral mechanoreceptors. A patient with amyotrophic lateral sclerosis (ALS) may experience dyspnea because the brain is not receiving the expected feedback in chest wall expansion. In another example, normal subjects became dyspneic when researchers limited the inspiratory flow rate despite no change in respiratory work or oxygenation status.
++
The gold standard for diagnosis is always the patient’s report of symptoms. Studies have demonstrated that there is no clear correlation between symptoms of dyspnea and respiratory rate, oxygen saturation, and accessory muscle use. Interestingly, some patients feel dyspneic despite normal oxygen saturations, while others do not feel dyspneic even though they are hypoxemic. It is therefore important to screen all patients for dyspnea, since patients may have no obvious signs of respiratory compromise or distress.
++
Common etiologies should be considered, including pneumonia, pleural effusion, space-occupying lung lesions, bronchospasm, pulmonary embolism, COPD, cardiac ischemia, congestive heart failure, anemia, and ascites. Patients with cancer may also have disease-specific processes such as radiation or chemotherapy-induced pneumonitis, malignant pericardial effusion, superior vena cava syndrome, or lymphangitic spread of tumor. Patients with primary neurologic or neuromuscular disorders may have symptoms of dyspnea associated with progressive muscle weakness.
++
The decision of whether to pursue diagnostic studies should take into account the patient’s overall goals of care, disease trajectory, and the likelihood that the study results will enhance management of dyspnea symptoms. For some patients, workup to rule out pneumonia, pleural effusion, or pulmonary embolism may still be appropriate as there are specific treatments that can help their symptoms. Sometimes no clear etiology for dyspnea can be found. The National Hospice Study, which followed terminal cancer patients during their last 6 weeks of life, found that 24% of patients with dyspnea had no signs of lung involvement or cardiac disease.
++
Treatment of dyspnea should be directed at the etiology, if known. Patients with advanced illness may still be considered candidates for procedures like thoracentesis for a large pleural effusion and pleural catheter for recurrent effusions. The ultimate goal in all cases should be the subjective relief of symptoms rather than the correction of any single parameter, such as oxygen saturation or respiratory rate. Patients may need further nonpharmacologic and pharmacologic therapies if treatment of the underlying etiology of dyspnea does not fully relieve their symptoms.
+++
Nonpharmacologic treatment
++
Placing patients in an upright position improves the mechanics of the intercostal muscles and lessens the work of breathing. A cool fan or moist cloth over the face can improve symptoms, possibly through stimulation of the V2 branch of the trigeminal nerve, which may then inhibit dyspnea perception centrally. The presence of a family member or volunteer at the bedside can help relieve anxiety associated with dyspnea. Cognitive and behavioral interventions, similar to those used in pulmonary rehabilitation for COPD patients, can also improve symptoms of dyspnea. Several trials of nursing-led interventions, which included relaxation techniques, breathing control, activity pacing, and psychosocial support, demonstrated a reduction in dyspnea scores.
++
Oxygen is frequently used in patients with dyspnea, though evidence to support its use is mixed. There is strong evidence to support oxygen use in COPD patients, for both symptomatic relief and improved survival. However, the role of oxygen in cancer patients with dyspnea is less clear. A meta-analysis of cancer-related dyspnea did not demonstrate any clear symptom improvement with oxygen compared to air. In the palliative care population, a trial of supplemental oxygen seems reasonable if the patient has had insufficient relief with other approaches. The potential benefits and risks of oxygen therapy should be considered before discharging a patient with home oxygen. Considerations include the degree of symptom relief, the risk of falls with tubing, and the presence of smokers in the home.
+++
Pharmacologic treatment
++
Opioids are the first-line agents in pharmacologic therapy for dyspnea near the end of life. Their exact mechanism is not fully understood, but opioids are believed to decrease the chemoreceptor response to hypercapnia and increase preload through cardiovascular vasodilation. Opioids have been shown to reduce dyspnea in patients with advanced cancer, congestive heart failure, and COPD, and can also increase exercise tolerance in patients with COPD and congestive heart failure. Doses required to control dyspnea are usually lower than those required for pain (Table 216-7). A reasonable starting dose of morphine for an opioid-naïve patient is morphine 1 to 2 mg intravenously every 2 hours or 2 to 5 mg orally every 4 hours. For patients already on opioids for pain, consider a 25% increase in their usual opioid dose to treat dyspnea. Other opioids such as hydromorphone and oxycodone can be used. There is no evidence to suggest any substantial differences in efficacy between opioids in the treatment of dyspnea. Patients who require frequent opioid doses may need initiation of either long-acting opioids or an opioid infusion. Principles for ordering and titrating infusions can be found in the section on pain management.
++
++
++
Dyspnea can be closely associated with anxiety, with each symptom exacerbating the other. Anxiolytics may be a helpful adjunct to opioids for treating dyspnea (Table 216-8). Lorazepam can offer rapid relief and is available in oral concentrate form. Clonazepam can be beneficial for chronic dyspnea due to its longer half-life. One trial has shown that midazolam can improve dyspnea control when added to a morphine regimen, though in practice its use is generally reserved for severe symptoms. Midazolam can be given 0.2 to 0.5 mg intravenously slowly for severe dyspnea or for refractory symptoms of panic or anxiety.
++
+++
Respiratory depression
++
Some clinicians or patients may be hesitant to use opioids due to fears that they will cause respiratory depression and hasten death. These fears are largely unfounded. Many studies have shown that opioids improve dyspnea without compromising respiratory function when dosed appropriately. One meta-analysis that included COPD, congestive heart failure, cancer, and interstitial lung disease patients reported statistically significant improvement in dyspnea with no deaths attributable to opioids. It is also important to recognize that major changes in respiratory status such as apnea or periodic breathing may be indicative of imminent death from natural disease progression, rather than opioid-induced.
++
In the rare instance of respiratory depression due to accidental opioid overdose, naloxone can be used, but it should be diluted to avoid complete reversal of analgesia in palliative care patients. One ampule (0.4 mg in 1 mL) should be diluted with 9 mL saline to create a 0.04 mg/mL solution and then given in 1 mL doses every 1 to 2 minutes until respiratory depression is reversed. Further doses may be needed if long-acting opioids were used. If the only manifestation of opioid overdose is somnolence with intact respiratory function, naloxone should not be given and the patient should just be monitored closely.
+++
EVALUATION AND MANAGEMENT
++
As their level of consciousness diminishes, many dying patients lose the ability to clear oropharyngeal secretions and develop noisy respirations, also known as the “death rattle.” Some family members and providers may find the noise distressing, though patients are generally obtunded and are thought to be undisturbed by it.
++
Management strategies include placing the patient in a lateral or semiprone position to promote drainage of secretions. Gentle suctioning may be helpful for secretions that are easily accessible, but deep suctioning is generally ineffective and may cause discomfort to the patient. Intravenous fluids can increase the production of secretions and should be minimized or discontinued.
++
Anticholinergic agents are often used in an attempt to reduce oropharyngeal secretions, though studies have not shown any clear benefit. Table 216-9 lists commonly used agents. Anticholinergics may cause significant side effects including sedation, delirium, urinary retention, constipation, and dry mouth. Patients receiving anticholinergic agents should receive scheduled mouth care including lip balm and mouth swabs.
++
++
Noisy secretions may be difficult to control despite the above interventions, and family education is paramount to minimize emotional distress. Clinicians should explain that as patients become less alert, the oropharyngeal muscles relax and patients are no longer able to swallow secretions. The loud respirations occur when air moves past the pooled secretions and relaxed muscles. Some family members may need reassurance that the patient is receiving adequate air and that this is not a sign of drowning. It is especially important to emphasize that these symptoms are normal and an expected part of the dying process.
+++
EVALUATION AND TREATMENT
++
Nearly half of all dying patients will display signs of restlessness or agitation in their last days of life due to delirium. Symptoms include grimacing, moaning, mumbling speech, hallucinations, twitching or jerking, and changes in the level of arousal. Because delirium is common in hospitalized patients both with and without terminal illness, it is important to recognize other physiologic signs that may indicate a patient is in the dying phase. Manifestations can include decreased perfusion with cool extremities or cyanosis, tachycardia or bradycardia, hypotension, respiratory changes such as Cheyne-Stokes breathing or apnea, decreased urine output, and progressive somnolence.
++
Many of the general principles of delirium assessment and treatment still apply in the dying patient. Medications such as anticholinergic drugs (antiemetics, antisecretion agents, tricyclic antidepressants), opioids, sedatives, and corticosteroids are common precipitants for delirium in this population. The offending medications should be discontinued or weaned if possible, keeping in mind that delirious patients should not be left with undertreated pain, dyspnea, or other symptoms. Certain drugs such as opioids may need to be rotated (ie, a patient with severe renal insufficiency and signs of opioid neurotoxicity from morphine may need to be rotated to fentanyl or methadone). Other common and reversible causes of delirium include untreated pain, full bladder, or fecal impaction. If a patient appears to be nearing the end of life, it is often appropriate to forgo a full evaluation of delirium and transition instead to comfort-focused care.
++
Nonpharmacologic interventions for delirium may be helpful, including family presence at the bedside, gentle reminders to help with reorientation, hearing or visual devices, and psychosocial/spiritual support. Antipsychotic medications are the primary pharmacologic treatment for terminal delirium. Common medications are listed in Table 216-10. Antipsychotics can cause varying levels of sedation, with haloperidol causing the least sedation and chlorpromazine causing the most sedation.
++
++
Most clinicians recognize that benzodiazepines are generally discouraged in delirious patients due to the potential for paradoxical worsening of symptoms and agitation. One exception is the dying patient with significant agitation despite treatment with strong doses of antipsychotic medications. In this situation, benzodiazepines may be added for their sedative effect. Lorazepam can be given 0.5 to 2 mg intravenously, orally, or subcutaneously every 2 hours as needed. Diazepam is available rectally and can be given 10 mg rectally 6 hours. If these measures prove ineffective, consider contacting a palliative care specialist to discuss the possibility of further sedating medications.
+++
NUTRITION AND HYDRATION
++
Patients and families can experience tremendous emotional distress when nutritional issues arise. For many, nutrition may become a symbolic battleground of the fight against death. Many families express their love through food. When patients do not eat, well-intentioned family members may struggle with feelings of rejection or fear that their loved one has “given up.” Clinicians are sometimes pressed with questions about artificial nutrition and hydration (ANH) in the setting of advanced illness.
+++
ANOREXIA-CACHEXIA SYNDROME
++
Patients may show signs of anorexia-cachexia, a complex wasting syndrome mediated by cytokine and neurohormonal factors. This syndrome is well recognized in cancer and AIDS patients, but is also seen in patients with advanced chronic illnesses such as congestive heart failure and COPD. It is important to explain to patients that this decline is a natural part of the disease process and not due to any deficiency on their part. Patients or family members may focus on weight loss as a sign that they have not done enough to ensure adequate calories. Although patients appear malnourished, this catabolic condition is generally not reversible even with aggressive nutrition.
++
Clinicians should screen for treatable causes of poor intake that may masquerade as anorexia-cachexia. These conditions include oral mucositis or candidiasis, esophagitis, reflux disease, gastrointestinal dysmotility, constipation, nausea, chronic pain, or depression. If a reversible cause for anorexia is not found, management of the anorexia-cachexia syndrome includes behavioral and pharmacologic strategies.
++
Referral to a nutritionist may provide guidance to patients and families. Patients should be empowered to determine their own eating habits, including eating the foods that are most appealing and deciding the quantity and frequency of intake. Patients who are easily nauseated or have early satiety should eat small portions only as they are able. Families should be advised to refrain from any comments and behavior that pressure the patient to consume more. Patients can liberalize dietary restrictions, including those that were previously important for management of long-standing conditions such as diabetes or hyperlipidemia, provided that doing so will not cause uncomfortable symptoms such as edema. Some patients and family members may need tremendous support and education as they make this transition. Many have spent years doing everything “right” to fight their illness, maintaining their caloric intake, eating specific foods while undergoing chemotherapy, or carefully adhering to a diabetic diet. Patients and family members may find themselves having to acknowledge for the first time that the disease is advancing and incurable. Clinicians should be attuned to these psychosocial concerns and may need to facilitate appropriate support systems for their patients, such as social work, chaplaincy, palliative care, and hospice.
++
Patients or family members may ask if there is a role for appetite stimulants. Pharmacologic agents can be considered, but appetite stimulants have demonstrated only modest or limited benefit at best, and all have certain contraindications and side effects. Before starting an agent, it is important to discuss specific goals (such as a small amount of weight gain or increased appetite) and a clear timeframe in which to assess whether the goals are being met. If there is no obvious benefit after 2 or 3 weeks, the drug should be discontinued. Table 216-11 lists common appetite stimulants and doses. These include the following:
++
Megestrol acetate (Megace) is a synthetic progestational agent that has been shown to increase appetite and weight in randomized control trials of patients with cancer and AIDS. Weight gain manifests as increased fat stores but not lean muscle mass. The data for improved quality of life indices is less clear than the effects on appetite and weight. Potential adverse effects include fluid retention, adrenal insufficiency, hypertension, and thromboembolic events. Megestrol should not be used in patients with a history of thromboembolism and is generally not recommended for patients with congestive heart failure.
Corticosteroids such as dexamethasone and prednisone have been shown in randomized controlled trials to improve subjective appetite and overall sense of well-being, though patients did not demonstrate any significant weight gain. Corticosteroids are most appropriate for patients with a shorter life expectancy or for those who cannot receive megestrol due to history of thromboembolism. They should not be used longer than a few weeks due to the potential for significant side effects including peptic ulcer disease, cushingoid changes, and myopathy.
Dronabinol (Marinol) is a synthetic cannabinoid that has demonstrated modest benefit in appetite stimulation in AIDS patients, but unconvincing effect on weight gain. For cancer patients with anorexia, studies have not demonstrated any improvement in appetite or weight gain. Adverse effects of dronabinol are primarily central nervous system related and include dizziness, euphoria, and confusion. Cannabinoids should be avoided in elderly patients, as they are particularly sensitive to the side effects.
++
++
Other agents that are still undergoing study as potential appetite stimulants include mirtazapine, thalidomide, COX-2 inhibitors, and L-carnitine.
+++
ARTIFICIAL NUTRITION AND HYDRATION
++
When patients and families inquire about a feeding tube or TPN, clinicians should explore their specific concerns and goals. Many people hope that artificial nutrition and hydration (ANH) will improve strength or lengthen survival. For the vast majority of patients with advanced illness, ANH does not improve survival or quality of life.
++
ANH can lengthen survival of patients with certain conditions including extreme short-bowel syndrome, amyotrophic lateral sclerosis, acute phases of stroke or head injury, and those in a permanent vegetative state. The data for cancer patients is more varied due to the heterogeneity of the population. Most clinicians would consider ANH appropriate for patients whose disease location interferes with their ability to swallow or transit food (eg, head and neck cancer, esophageal cancer, proximal bowel obstruction) but who otherwise have good functional status. Some studies suggest that ANH may be useful in patients who are actively undergoing chemotherapy or radiation, while other studies do not support this finding. Patients with cancer-related anorexia-cachexia do not gain weight even when given aggressive calories. When a patient’s disease is no longer responding to disease-modifying treatments, experts agree that the risks of ANH, such as infection, aspiration, or volume overload, generally outweigh the benefits.
++
The literature does not support the use of ANH in patients with advanced dementia. Enteral tube feeds have been shown to increase the risk of aspiration, diarrhea, and gastrointestinal discomfort. Patients with dementia are at risk for pulling on feeding tubes, and studies have shown that the presence of a feeding tube increases the likelihood that patients will be physically restrained. Advanced dementia patients receiving ANH and adequate caloric intake still demonstrate continued weight loss or depletion of lean body mass. There is no evidence to suggest improved healing of pressure ulcers.
++
If a decision is made to pursue ANH, the clinician should discuss
++
Specific goals with the patient and family, such as weight gain or maintenance.
Designate a timepoint at which they will reassess whether ANH is still meeting these goals.
Indications for discontinuing ANH, including any significant complication, such as infection when the risks of ongoing ANH outweigh any potential benefits.
++
Patients, families, and clinicians may have their own deeply rooted beliefs about the role of ANH at the end of life. Cultural or religious traditions may influence an individual’s beliefs, even when medical providers feel that the data does not support the use of ANH. If significant concerns arise, clinicians should include a palliative care clinician, chaplain or clergyperson, social worker, or ethics support staff in these discussions.
++
+++
EDUCATING PATIENTS AND FAMILIES
++
Clinicians play a key role in educating patients and families on nutritional issues at the end of life. Although families may express great concern that their loved one will suffer from hunger, patients in the last stage of life rarely report feeling hungry. Many patients can live comfortably for weeks with minimal food and water. Forcing patients to eat may cause emotional distress, nausea, and aspiration. Many patients and families are also unaware that artificial nutrition and hydration may cause complications including infection, aspiration, and fluid overload with worsened pulmonary edema or ascites, all of which can shorten lifespan.
++
Conversely, families of patients at risk for aspiration may have been instructed not to offer any food or liquids by mouth. In the context of limited prognosis or imminent death, these restrictions may be lifted as long as there are not obvious symptoms of discomfort. Measures such as sitting upright, tucking the chin when swallowing, and using a thickening agent with fluids, may enable patients at risk for aspiration to eat and drink small quantities for pleasure.
++
Palliative care includes helping family members learn other ways of nurturing their loved ones at the bedside. Families may be encouraged to interact with patients through conversation, reading, or music. Thirst is a common complaint at the end of life, and intravenous fluids have not been shown to affect the sensation of thirst. Visitors can learn how to moisten the mouth and provide ice chips to alleviate thirst. Small sips of fluid and candy lozenges can be appropriate if patients are alert and do not show signs of discomfort.
+++
COMPLEMENTARY MEDICINE
++
The National Center for Complementary and Alternative Medicine (NCCAM), an agency of the National Institutes of Health, has defined complementary and alternative medicine as “a group of diverse medical and health care systems, practices, and products that are not generally considered to be part of conventional medicine.” The term complementary medicine refers to therapies that are used together with conventional medicine. Alternative medicine describes practices that are used in place of conventional medicine. The field of complementary and alternative medicine (CAM) includes a wide variety of practices, some of which do not conform to usual biomedical and scientific principles.
++
The NCCAM groups complementary and alternative medicine into several domains:
++
Whole medical systems: These practices are built on complete systems of theory and practice that have evolved separately from conventional medicine. Some have existed longer than Western medical practices. Examples include homeopathy, traditional Chinese medicine, and Ayurveda (practiced on the Indian subcontinent). Systems such as traditional Chinese medicine may incorporate other domains below such as biologically based practices (herbal therapies) and energy-based therapies (acupuncture).
Mind-body medicine: These techniques utilize the mind to affect bodily function and control symptoms. Examples include meditation, guided imagery, music therapy, and hypnosis. Some would include patient support groups and cognitive-behavioral therapies in this category.
Biologically based practices: These therapies are based on substances found in nature including food, herbs, vitamins, and minerals.
Manipulative and body-based practices: These treatments are based on movement of specific body parts. Examples include chiropractic and massage therapy.
Energy-based therapies: These practices focus on energy fields such as electromagnetic fields or biofields, which purportedly surround and penetrate the body. Examples include qi gong, reiki, acupuncture, and magnetic therapy.
++
The use of CAM is very common in the general population. The Centers for Disease Control and Prevention’s (CDC’s) National Center for Health Statistics conducted a National Health Interview Survey in 2012 and found that an estimated 34% of adults had used CAM therapy in the past 12 months. CAM use appears to be particularly high in oncology patients, with studies reporting CAM use in 48% to 88% of patients.
+++
ROLE OF THE CLINICIAN
++
Despite the widespread use of CAM in the general public, most medical providers have limited knowledge about these practices. They may not even be aware that their patients are pursuing CAM. Studies have found that most patients do not mention the use of CAM to their providers unless specifically asked. Clinicians may also struggle with how best to advise patients about certain unproven therapies without alienating those with different personal, cultural, or religious belief systems. Clinicians may encounter patients whose family members or friends are actively encouraging them to use CAM therapies. Studies have shown that friends, families, and mass media are very common sources of information for patients who decide to use CAM.
++
Clinicians can play a key role in advising patients who are considering the use of CAM therapies. Patients should be counseled that overall, research suggests that CAM therapies are most useful when used for alleviation of symptoms and enhancement of quality of life. There is no compelling scientific evidence at this time to support the use of alternative approaches in lieu of conventional therapies. Patients should carefully consider the potential risks and benefits of CAM therapies using reliable sources, including their medical provider and government-sponsored websites that detail current research findings and potential adverse effects.
++
Clinicians should advise patients and their families to consider the following questions before pursuing a CAM therapy:
++
Is there research to support the use of this particular therapy?
Does the therapy require that you stop conventional medical treatments?
Are there substantial side effects that can interfere with your ongoing medical treatments?
Does the treatment or practitioner make unfounded claims such as the ability to cure cancer?
Does the treatment require travel to another country?
Is the treatment available to the general public or is it promoted as a secret, exclusive therapy?
Is the CAM practitioner licensed by the state to provide that specific therapy?
Is the treatment offered by an established medical institution or is it offered only by one individual?
How expensive is the treatment and does it require substantial out-of-pocket expense?
++
A full review of the different CAM therapies is beyond the scope of this discussion, but clinicians should familiarize themselves with the following:
++
Commonly used therapies that might benefit palliative care patients
CAM therapies with potential safety issues
Resources for further education of providers and patients
+++
COMPLEMENTARY AND ALTERNATIVE THERAPIES WITH POTENTIAL BENEFIT
++
There is some clinical data to support the use of CAM in palliative care patients, but the body of evidence is not extensive. Research challenges include small sample sizes, difficulty creating an appropriate control arm, difficulty standardizing the delivery of intervention, short trial duration, and limited funding.
++
Acupuncture has been studied for its potential role in the management of symptoms, including nausea, vomiting, and pain. There has been some positive evidence for its use in chemotherapy-induced nausea and vomiting. Some trials have suggested that acupuncture may also be useful in the treatment of pain, but systematic reviews have concluded that further studies are still needed. The risks of adverse events from acupuncture are minimal, and most complications have been related to lack of sterility of needles. Patients should be advised to only seek treatment from qualified, licensed practitioners who use disposable single-use needles. Although bleeding events are generally minor and localized, it is probably best to advise patients with bleeding disorders or on anticoagulation to avoid acupuncture. There have been case reports of rare serious events such as pneumothorax, but in general acupuncture is a safe complementary therapy.
++
Massage therapy can provide relief of anxiety and fatigue, based on several trials in cancer patients, though the duration of effect is not well established. Massage therapy has also been studied for its effect on pain, with several trials showing statistically significant reductions in pain measures in the immediate setting. Of note, however, pain reduction was not sustained over time. One particular form of massage, manual lymph drainage, was found in a few limited trials to reduce symptoms of lymphedema when used with compressive measures. Massage therapy is generally safe, but clinicians should advise patients with bleeding disorders or bony metastases to exercise caution and avoid all but the gentlest massage techniques.
++
Mind-body therapies such as hypnosis, meditation, guided imagery, and relaxation techniques have increasingly become integrated into the care of palliative care patients. Studies of mind-body interventions demonstrate potential to improve mood, relieve emotional distress, and enhance overall quality of life. Randomized control trials of relaxation training and guided imagery support their use in the treatment of anxiety. Some mind-body interventions also show promise in the treatment of physical symptoms. Hypnosis may have a role in pain and nausea treatment, based on several small randomized controlled trials. Additionally, nursing-led interventions such as breathing and relaxation techniques reduced dyspnea scores in several studies. If a patient reports benefit from mind-body therapies, clinicians can generally support their continued use as long as there is no clear interference with conventional treatments.
++
Clinicians should advise their patients that certain practices carry potential risks. Patients should not initiate any CAM therapies without carefully researching and considering the risks.
++
Quality control for herbal preparations is not standardized, and there is real potential for harm through inconsistencies in preparation and contamination. Clinicians should counsel patients that claims of “natural” ingredients do not necessarily guarantee safety. Patients have developed renal failure necessitating dialysis and even renal transplant after taking herbal preparations containing a nephrotoxic Chinese herb, Aristolochia fang chi. One case series reported a manufacturing error resulted in the substitution of Aristolochia fang chi for the herbal preparation intended for weight loss. Patients taking herbal remedies for ezcema also have developed end-stage renal failure due to contamination from Aristolochia fang chi. This herb is implicated in the development of urothelial cancer. In another example, PC-SPES (“PC” stands for prostate cancer; “spes” means “hope” in Latin), a product containing eight herbs, initially showed promise in the treatment of patients with advanced prostate cancer including decreased serum prostate-specific antigen, but it was recalled due to toxicity and contamination with conventional medications including warfarin and indomethacin. A report of a severe acquired bleeding diathesis after PC-SPES use suggested possible anticoagulant effect from warfarin contamination. The FDA subsequently issued a warning to discontinue use of PC-SPES, and this product is no longer available.
++
Additionally, many agents are pharmacologically active and carry the potential to interact with important conventional therapies. St. John’s wort is an inducer of cytochrome P450 (CYP3A4) and has been found to reduce levels of chemotherapeutic agents including irinotecan. Experts in CAM therapies advise against the use of St. John’s wort with concurrent chemotherapy. Ginseng and ginkgo biloba can also increase cytochrome P450 activity. Green tea (polyphenols) and grapefruit juice are known inhibitors of the cytochrome P450 system. Further information about drug interactions can be found in the resources listed below.
++
Patients at risk for malnutrition should avoid macrobiotic and other highly restrictive diets. Macrobiotic diets are mainly vegetarian, high in grains and low in fat. Some macrobiotic diets are also high in phytoestrogens and may pose some risk for patients with estrogen-positive breast or endometrial cancer. Similarly, the literature recommends that these patients avoid large quantities of soy products and ginseng, as some preparations of ginseng have been found to contain phytoestrogens.
++
Many patients take high doses of vitamins with the hope of slowing cancer progression, but there is no reliable evidence to support this. Additionally, vitamin C has some anticoagulant effect and vitamin E can diminish platelet function. Patients who are thrombocytopenic or taking anticoagulants should avoid high doses of these vitamins.
++
One of the most serious consequences of CAM therapies is the delay of conventional treatment in favor of alternative therapies. Clinicians should strongly caution their patients against pursuing any CAM therapies that interfere with the initiation of recommended conventional therapies.
++
+++
ONLINE RESOURCES FOR PATIENTS AND CLINICIANS
++
Further information is available for both patients and providers on a variety of reputable websites (Table 216-12).
++
+
Abrahm
JL. A Physician’s Guide to Pain and Symptom Management in Cancer Patients. Baltimore: John-Hopkins; 2014.
+
Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. Glenview: American Pain Society; 2008.
+
Abrahm
JL. A Physician’s Guide to Pain and Symptom Management in Cancer Patients. Baltimore: John-Hopkins; 2014.
+
Basch
E, Prestrud
AA, Hesketh
PJ,
et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update.
J Clin Oncol. 2011;29:4189–4198.
[PubMed: 21947834]
+
Ben-Aharon
I, Gafter-Gvili
A, Leibovici
L,
et al. Interventions for alleviating cancer-related dyspnea: a systematic review and meta-analysis. Acta Oncologica. 2012;51:996–1008.
+
Luce
JM, Luce
JA. Management of dyspnea in patients with far-advanced lung disease: “Once I lose it, it’s kind of hard to catch it…” JAMA. 2001;285:1331–1337.
+
Thomas
JR, von Gunten
CF. Management of dyspnea.
J Support Oncol. 2003;1:23–32.
[PubMed: 15352640]
+
Lokker
M, van Zuylen
L, van der Rijt
C,
et al. Prevalence, impact, and treatment of death rattle: a systematic review.
J Pain Symptom Manage. 2014;47:105–122.
[PubMed: 23790419]
+
White
C, McCann
MA, Jackson
N,
et al. First do no harm…terminal restlessness or drug-induced delirium.
J Palliat Med. 2007;10:345–351.
[PubMed: 17472505]
+++
NUTRITION AND HYDRATION
+
Casarett
D, Kapo
J, Caplan
A. Appropriate use of artificial nutrition and hydration—fundamental principles and recommendations.
N Engl J Med. 2005;353:2607–2612.
[PubMed: 16354899]
+
Goldstein
N, Morrison
R. Evidence-Based Practice in Palliative Medicine. Philadelphia: Elsevier; 2013.
+++
COMPLEMENTARY MEDICINE
+
Bardia
A, Barton
DL, Prokop
LJ,
et al. Efficacy of complementary and alternative medicine therapies in relieving cancer pain: a systematic review.
J Clin Oncol. 2006;24:5457–5464.
[PubMed: 17135649]
+
Weiger
WA, Smith
M, Boon
H,
et al. Advising patients who seek complementary and alternative medical therapies for cancer.
Ann Intern Med. 2002;137:889–903.
[PubMed: 12458989]
+++
ADDITIONAL SUGGESTED READINGS
+
Abrahm
JL. A Physician’s Guide to Pain and Symptom Management in Cancer Patients. Baltimore: John-Hopkins; 2014.
+
Center to Advance Palliative Care: Fast Facts and Concepts (peer-reviewed, evidence-based summaries of key palliative care topics). Accessed at
www.capc.org/fast-facts.
+
Goldstein
N, Morrison
R. Evidence-Based Practice in Palliative Medicine. Philadelphia: Elsevier; 2013.
+
Pantilat
S, Anderson
W, Gonzales
M. Hospital-Based Palliative Medicine: A Practical, Evidence-Based Approach. Harrisonburg: Wiley-Blackwell; 2015.