Palliative and End-of-Life Care

77CHAPTER 12

will and designates a proxy is often used, and the directive should

indicate clearly whether the specified patient preferences or the proxy’s

choice takes precedence if they conflict. Some states have begun to

put into practice a “Physician Orders for Life-Sustaining Treatment

(POLST)” directive, which builds on communication between providers and patients by including guidance for end-of-life care in a

color-coordinated form that follows the patient across treatment

settings. The procedures for completing advance care planning documents vary according to state law.

A potentially misleading distinction relates to statutory, as opposed

to advisory, documents. Statutory documents are drafted to fulfill relevant state laws. Advisory documents are drafted to reflect the patient’s

wishes. Both are legal, the former under state law and the latter under

common or constitutional law.

LEGAL ASPECTS As of 2021, 48 states and the District of Columbia

had enacted living will legislation. Massachusetts and Michigan are the

two states without living will legislation. Indiana has a life-prolonging

procedures declaration. States differ in the requirements for advanced

directives, including whether they need to be witnessed and, if so, by

how many witnesses and whether they need to be notarized. Importantly, in 25 states, the laws state that the living will is not valid if a

woman is pregnant. All states except Alaska have enacted durable

power of attorney for health care laws that permit patients to designate

a proxy decision-maker with authority to terminate life-sustaining

treatments. Only in Alaska does the law prohibit proxies from terminating life-sustaining treatments for pregnant women.

The U.S. Supreme Court has ruled that patients have a constitutional

right to decide any issues related to refusing or terminating medical

interventions, including life-sustaining interventions, and that mentally incompetent patients can exercise this right by providing “clear

and convincing evidence” of their preferences. Since advance care

directives permit patients to provide such evidence, commentators

agree that they are constitutionally protected. Most commentators

believe that a state is required to honor any clear advance care directive,

regardless of whether it is written on an “official” form. Many states

have enacted laws for the explicit purpose of honoring out-of-state

directives. If a patient is not using a statutory form, it may be advisable

to attach a statutory form to the advance care directive being used.

State-specific forms are readily available free of charge for health care

providers, patients, and families through the website of the National

Hospice and Palliative Care Organization (http://www.nhpco.org).

REIMBURSEMENT As of January 1, 2016, the Centers for Medicare

and Medicaid Services amended the physician fee schedule to reimburse discussions of advance care planning under Current Procedural

Terminology codes 99497 and 99498. The session must be voluntary

and include an explanation of advance care planning but need not

include a completed advance care document. There can be multiple

bills for the discussion if it extends over several encounters. A study

found that patients who engaged in a billed advance care planning

encounter were more likely to be enrolled in hospice and less likely to

receive intensive therapies, despite being more likely to be hospitalized in the ICU. However, a billing incentive in and of itself may not

increase advance care planning discussions by clinicians. In 2016, just

1.6% of Medicare Advantage patients had a discussion of advance care

planning that was billed. Factors beyond reimbursement, such as clinicians’ lack of comfort and skill in carrying out advance care planning

discussions and lack of time, appear to impede discussions of advance

care planning.

INTERVENTIONS

■ PHYSICAL SYMPTOMS AND THEIR MANAGEMENT

Great emphasis has been placed on addressing dying patients’ pain.

In order to emphasize its importance, pain assessment has frequently

been included as the fifth vital sign. Heightened consideration of pain

has been advocated by large health care systems such as the Veterans’

Administration and accrediting bodies such as The Joint Commission. Although this embrace of pain has been symbolically important,

available data suggest that making pain the fifth vital sign does not lead

to improved pain management practices. In light of the opioid crisis in

the United States, the emphasis on pain management has begun to be

reexamined. For instance, in 2017 draft standards, The Joint Commission recommends nonpharmacologic pain treatment as well as identification of psychosocial risk factors for addiction. Importantly, good

palliative care requires much more than good pain management. The

frequency of symptoms varies by disease and other factors. The most

common physical and psychological symptoms among all terminally ill

patients include pain, fatigue, insomnia, anorexia, dyspnea, depression,

anxiety, nausea, and vomiting. In the last days of life, terminal delirium

is also common. Assessments of patients with advanced cancer have

shown that patients experienced an average of 11.5 different physical

and psychological symptoms (Table 12-4).

In the vast majority of cases, evaluations to determine the etiology

of these symptoms should be limited to the history and physical examination. In some cases, radiologic or other diagnostic examinations will

provide sufficient benefit in directing optimal palliative care to warrant

the risks, potential discomfort, and inconvenience, especially to a seriously ill patient. Only a few of the common symptoms that present difficult management issues will be addressed in this chapter. Additional

information on the management of other symptoms, such as nausea

and vomiting, insomnia, and diarrhea, can be found in Chaps. 45,

31, and 46, respectively. Information on the management of patients

with cancer is provided in Chap. 69.

Pain • FREQUENCY The frequency of pain among terminally ill

patients varies significantly. Cancer (~85%), congestive heart failure

(CHF; ~75%), and AIDS have been associated with a higher prevalence of pain compared to other advanced illnesses, such as COPD

(~45%), chronic kidney disease (~40%), and dementia (~40%). One

meta-analysis of adults with advanced or terminal illness found pain

prevalence of 30–94% in patients with cancer, compared to 21–77% for

COPD, 14–78% for CHF, 11–83% for end-stage renal disease, 14–63%

for dementia, and 30–98% for AIDS.

ETIOLOGY There are two types of pain: nociceptive and neuropathic.

Nociceptive pain is further divided into somatic or visceral pain.

Somatic pain is the result of direct mechanical or chemical stimulation

of nociceptors and normal neural signaling to the brain. It tends to

be localized, aching, throbbing, and cramping. The classic example

is bone metastases. Visceral pain is caused by nociceptors in gastrointestinal (GI), respiratory, and other organ systems. It is a deep or

colicky type of pain classically associated with pancreatitis, myocardial

infarction, or tumor invasion of viscera. Neuropathic pain arises from

TABLE 12-4 Common Physical and Psychological Symptoms of

Terminally Ill Patients

PHYSICAL SYMPTOMS PSYCHOLOGICAL SYMPTOMS

Pain Anxiety

Fatigue and weakness Depression

Dyspnea Hopelessness

Insomnia Meaninglessness

Dry mouth Irritability

Anorexia Impaired concentration

Nausea and vomiting Confusion

Constipation Delirium

Cough Loss of libido

Swelling of arms or legs

Itching

Diarrhea

Dysphagia

Dizziness

Fecal and urinary incontinence

Numbness/tingling in hands/feet

78PART 1 The Profession of Medicine

disordered nerve signals. It is described by patients as burning, electrical, or shock-like pain. Classic examples are post-stroke pain, tumor

invasion of the brachial plexus, and herpetic neuralgia.

ASSESSMENT Pain is a subjective experience. Depending on the

patient’s circumstances, perspective, and physiologic condition, the

same physical lesion or disease state can produce different levels of

reported pain and need for pain relief. Systematic assessment includes

eliciting the following: (1) type: throbbing, cramping, burning, etc.; (2)

periodicity: continuous, with or without exacerbations, or incident; (3)

location; (4) intensity; (5) modifying factors; (6) effects of treatments;

(7) functional impact; and (8) impact on patient. Several validated pain

assessment measures may be used, including the Visual Analogue Scale

(VAS), the Brief Pain Inventory (BPI), or the Numerical Pain Rating

Scale (NRS-11). Other scales have been developed for neuropathic

pain, such as the Neuropathic Pain Scale and the DN4 Questionnaire.

Frequent reassessments on a consistent scale are essential to assess the

impact of and need to readjust interventions.

INTERVENTIONS Interventions for pain must be tailored to each

individual, with the goal of preempting chronic pain and relieving

breakthrough pain. At the end of life, there is rarely reason to doubt

a patient’s report of pain. With the opioid crisis in the United States,

there is more emphasis on making opioids one component of multimodal analgesia. Nevertheless, at the end of life, pain medications,

especially opioids, remain the cornerstone of management (Fig. 12-2).

If they are failing and nonpharmacologic interventions—including

radiotherapy and anesthetic or neurosurgical procedures such as

peripheral nerve blocks or epidural medications—are required, a pain

consultation is appropriate.

Pharmacologic interventions still largely follow the World Health

Organization three-step, “analgesic ladder” approach, which involves

nonopioid analgesics, “mild” opioids, and “strong” opioids, with or

without adjuvants (Chap. 13). Nonopioid analgesics, especially nonsteroidal anti-inflammatory drugs (NSAIDs), are the initial treatments for

mild pain. They work primarily by inhibiting peripheral prostaglandins

and reducing inflammation but may also have central nervous system

(CNS) effects. Additionally, NSAIDs have a ceiling effect. Ibuprofen,

up to 2400 mg/d qid, has a minimal risk of causing bleeding and renal

impairment and is a good initial choice. In patients with a history of

severe GI or other bleeding, however, ibuprofen should be avoided.

In patients with a history of mild gastritis or gastroesophageal reflux

disease (GERD), acid-lowering therapy, such as a proton pump inhibitor, should be used. Acetaminophen is an alternative in patients with

a history of GI bleeding and can be used safely at up to 4 g/d qid. In

patients with liver dysfunction due to metastases or other causes and in

patients with heavy alcohol use, doses should be reduced.

If nonopioid analgesics are insufficient, opioids should be introduced. Opioids primarily work by interacting with μ opioid receptors

to activate pain-inhibitory neurons in the CNS, although they also

interact variably with δ and κ receptors. Receptor agonists, such

as morphine, codeine, and fentanyl, produce analgesia by activating pain-inhibitory neurons in the CNS. Partial agonists, such as

buprenorphine, have a ceiling effect for analgesia and a lower potential

for abuse. They are useful for postacute pain but should not be used for

chronic pain in end-of-life care. Pure antagonists, such as naloxone and

methylnaltrexone, are used for reversal of opioid effects.

Traditionally, “weak” opioids such as codeine were used first. If they

failed to relieve pain after dose escalation, “strong” opioids like morphine were used in doses of 5–10 mg every 4 h. However, this breakdown between “weak” and “strong” opioids is no longer commonly

accepted, with smaller doses of “stronger” opioids frequently being

preferred over similar or larger doses of “weaker” opioids, and different

pain syndromes having different preferred therapies. Regardless, nonopioid analgesics should be combined with opioids, as they potentiate

the effect of opioids.

Importantly, the goal is to prevent patients from experiencing pain.

Consequently, for continuous pain, opioids should be administered on

a regular, around-the-clock basis consistent with their duration of analgesia, and the next dose should occur before the effect of the previous

dose wears off. They should not be provided only when the patient

MILD PAIN

Acetaminophen: 500 mg 2 tablets every 4–6 h

Ibuprofen: 400 mg every 6 h; max 8 tablets per day

(2400 mg/d qid)

MODERATE PAIN

Codeine: 30–60 mg every 4–8 h; maximum daily

dose for pain 240 mg

Tramadol: 25 mg PO every 6 h; max 400 mg/d

Add to acetaminophen, NSAIDs

SEVERE PAIN

Morphine: 2.5–5 mg every 3–6 h orally

Hydromorphone: 1–2 mg every 3–6 h orally

Fentanyl transdermal: 1000-µg patch for 72 h

Hydrocodone: 5–10 mg every 3–6 h orally

Add to acetaminophen, NSAIDs

Pain persists or increases

Difficult to Control Pain

Specialist Consultation

(Consideration of surgical procedures such as nerve

blocks)

Pain persists or increases

NEUROPATHIC PAIN

burning, electrical, shock-like

e.g., poststroke pain, tumor invasion of brachial plexus, herpetic

neuralgia

Treatment

Gabapentin: 100–300 mg bid or tid, with 50–100% dose increments

every 3 days; 3600 mg/d in 2 or 3 days

NOCICEPTIVE PAIN

cramping, throbbing, aching, sharp, prickling, stabbing, deep and

constant, dull and gnawing

e.g., pancreatitis, bone metastases, tumor invasion, obstruction (of

ureters, colon, gastric outlet, gallbladder, etc.)

Treatment

NSAIDs or acetaminophen with opioids

FIGURE 12-2 Terminal pain management flow chart. NSAIDs, nonsteroidal anti-inflammatory drugs.

Palliative and End-of-Life Care

79CHAPTER 12

experiences pain. Patients should also be provided rescue medication,

such as liquid morphine, for breakthrough pain, generally at 20% of

the baseline dose. Patients should be informed that using the rescue

medication does not obviate the need to take the next standard dose

of pain medication. If the patient’s pain remains uncontrolled after

24 h and recurs before the next dose, requiring the patient to utilize

the rescue medication, the daily opioid dose can be increased by the

total dose of rescue medications used by the patient, or by 50% of the

standing opioid daily dose for moderate pain and 100% for severe pain.

It is inappropriate to start with extended-release preparations.

Instead, an initial focus on using short-acting preparations to determine how much is required in the first 24–48 h will allow clinicians to

determine opioid needs. Once pain relief is obtained using short-acting

preparations, the switch should be made to extended-release preparations. Even with a stable extended-release preparation regimen, the

patient may experience incident pain, such as during movement or

dressing changes. Short-acting preparations should be taken before

such predictable episodes. Although less common, patients may have

“end-of-dose failure” with long-acting opioids, meaning that they

develop pain after 8 h in the case of an every-12-h medication. In

these cases, a trial of giving an every-12-h medication every 8 h is

appropriate.

Due to differences in opioid receptors, cross-tolerance among opioids is incomplete, and patients may experience different side effects

with different opioids. Therefore, if a patient is not experiencing pain

relief or is experiencing too many side effects, a change to another opioid preparation is appropriate. When switching, one should begin with

50–75% of the published equianalgesic dose of the new opioid.

Unlike NSAIDs, opioids have no ceiling effect; therefore, there is no

maximum dose, no matter how many milligrams the patient is receiving. The appropriate dose is the dose needed to achieve pain relief. This

is an important point for clinicians to explain to patients and families.

Addiction or excessive respiratory depression is extremely unlikely in

the terminally ill; fear of these side effects should neither prevent escalating opioid medications when the patient is experiencing insufficient

pain relief nor justify using opioid antagonists.

Opioid side effects should be anticipated and treated preemptively.

Nearly all patients experience constipation that can be debilitating (see

below). Failure to prevent constipation often results in noncompliance

with opioid therapy. The preferred treatment is prevention. Cathartics

(senna 2 tbsp qHS), stool softeners (docusate 100 mg PO qd), and/or

laxatives (laxtulose 30 mL qd) are considered first-line treatment. For

refractory cases, opioid antagonists or other therapies, such as lubiprostone, should be considered.

Methylnaltrexone is the best-studied opioid antagonist for use in

refractory opioid-induced constipation. It reverses opioid-induced

constipation by blocking peripheral opioid receptors, but not central

receptors, for analgesia. In placebo-controlled trials, it has been shown

to cause laxation within 24 h of administration. As with the use of

opioids, about a third of patients using methylnaltrexone experience

nausea and vomiting, but unlike with opioid usage, tolerance usually

develops within a week. Therefore, when one is beginning opioids, an

antiemetic such as metoclopramide or a serotonin antagonist is often

prescribed prophylactically and stopped after 1 week. Olanzapine has

also been shown to have antinausea properties and can be effective

in countering delirium or anxiety, with the advantage of some weight

gain.

Drowsiness, a common side effect of opioids, also usually abates

within a week. For refractory or severe cases, pharmacologic therapy

should be considered. The best-studied agents are the psychostimulants dextroamphetamine, methylphenidate, and modafinil, although

evidence regarding their efficacy is weak. Modafinil has the advantage

of once-a-day dosing compared to methyphenidate’s twice daily dosing.

Seriously ill patients who require chronic pain relief rarely become

addicted. Suspicion of addiction should not be a reason to withhold

pain medications from terminally ill patients. Nonetheless, patients

and families may withhold prescribed opioids for fear of addiction

or dependence. Physicians and health care providers should reassure

patients and families that the patient will not become addicted to

opioids if they are used as prescribed for pain relief; this fear should

not prevent the patient from taking the medications around the clock.

However, diversion of drugs for use by other family members or illicit

sale may occur. It may be necessary to advise the patient and caregiver

about secure storage of opioids. Contract writing with the patient and

family can help. If that fails, transfer to a safe facility may be necessary.

Tolerance describes the need to increase medication dosage for the

same pain relief without a concurrent change in disease. In the case of

patients with advanced disease, the need for increasing opioid dosage

for pain relief usually is caused by disease progression rather than tolerance. Physical dependence is indicated by symptoms resulting from

the abrupt withdrawal of opioids and should not be confused with

addiction.

In recent years, the potential dangers of opioid drugs have become

increasingly apparent. To help mitigate the risk of these powerful

drugs, several strategies should be used to reduce the risk of aberrant

drug use. To start, all patients should be assessed for their individual

levels of risk. While there are multiple surveys available, including the

Opioid Risk Tool, none have gained widespread use or validation. In

general, however, it is important to screen for prior substance abuse

and major psychiatric disorders.

For patients deemed to be high risk, a multidisciplinary effort

should be pursued to reduce the risk of adverse consequences, such

as addiction and diversion. Prescribing strategies include selecting

opioids with longer durations of action and lower street values, such

as methadone, and prescribing smaller quantities with more frequent

follow-up. Monitoring options include periodic urine screening and

referral to pain specialists. In some cases, it may also be reasonable to

consider not offering short-acting opioids for breakthrough pain. In no

situation, however, should adequate pain relief be withheld due to risk.

Adjuvant analgesic medications are nonopioids that potentiate the

analgesic effects of opioids. They are especially important in the management of neuropathic pain. Gabapentin, an anticonvulsant initially

studied in the setting of herpetic neuralgia, is now the first-line treatment for neuropathic pain resulting from a variety of causes. It is begun

at 100–300 mg bid or tid, with 50–100% dose increments every 3 days.

Usually 900–3600 mg/d in two or three doses is effective. The combination of gabapentin and nortriptyline may be more effective than gabapentin alone. Two potential side effects of gabapentin to be aware of are

confusion and drowsiness, especially in the elderly. Other effective

adjuvant medications include pregabalin, which has the same mechanism of action as gabapentin but is absorbed more efficiently from

the GI tract. Lamotrigine is a novel agent whose mechanism of action

is unknown but has been shown to be effective. It is recommended

to begin at 25–50 mg/d, increasing to 100 mg/d. Carbamazepine, a

first-generation agent, has been proven effective in randomized trials

for neuropathic pain. Other potentially effective anticonvulsant adjuvants include topiramate (25–50 mg qd or bid, rising to 100–300 mg/d)

and oxcarbazepine (75–300 mg bid, rising to 1200 mg bid).

Glucocorticoids, preferably dexamethasone given once a day, can be

useful in reducing inflammation that causes pain, while also elevating

mood, energy, and appetite. Its main side effects include confusion,

sleep difficulties, and fluid retention. Glucocorticoids are especially

effective for bone pain and abdominal pain from distention of the GI

tract or liver. Other drugs, including clonidine and baclofen, can be

effective in providing pain relief. These drugs are adjuvants and generally should be used in conjunction with—not instead of—opioids.

Methadone, carefully dosed because of its unpredictable half-life in

many patients, has activity at the N-methyl-D-aspartamate (NMDA)

receptor and is useful for complex pain syndromes and neuropathic

pain. It is generally reserved for cases in which first-line opioids

(morphine, oxycodone, hydromorphone) are either ineffective or

unavailable.

Radiation therapy can treat bone pain from single metastatic lesions.

Bone pain from multiple metastases can be amenable to radiopharmaceuticals such as strontium-89 and samarium-153. Bisphosphonates,

such as pamidronate (90 mg every 4 weeks) and calcitonin (200 IU

intranasally once or twice a day), also provide relief from bone pain but

have multiday onsets of action.