93Pain: Pathophysiology and Management CHAPTER 13

largely preserving the individual’s ability to recognize noxious stimuli

as painful.

■ PAIN MODULATION

The pain produced by injuries of similar magnitude is remarkably variable in different situations and in different individuals. For example,

athletes have been known to sustain serious fractures with only minor

pain, and Beecher’s classic World War II survey revealed that many

soldiers in battle were unbothered by injuries that would have produced

agonizing pain in civilian patients. Furthermore, even the suggestion

that a treatment will relieve pain can have a significant analgesic effect

(the placebo effect). On the other hand, many patients find even minor

injuries such as venipuncture frightening and unbearable, and the

expectation of pain can induce pain even without a noxious stimulus.

The suggestion that pain will worsen following administration of an

inert substance can increase its perceived intensity (the nocebo effect).

The powerful effect of expectation and other psychological variables on the perceived intensity of pain is explained by brain circuits

that modulate the activity of the pain-transmission pathways. One of

these circuits has links to the hypothalamus, midbrain, and medulla,

and it selectively controls spinal pain-transmission neurons through a

descending pathway (Fig. 13-4).

Human brain-imaging studies have implicated this pain-modulating

circuit in the pain-relieving effect of attention, suggestion, and opioid

analgesic medications (Fig. 13-5). Furthermore, each of the component structures of the pathway contains opioid receptors and is

sensitive to the direct application of opioid drugs. In animals, lesions

of this descending modulatory system reduce the analgesic effect of

Anterolateral

tract axon

Skin

Viscus

FIGURE 13-3 The convergence-projection hypothesis of referred pain. According

to this hypothesis, visceral afferent nociceptors converge on the same painprojection neurons as the afferents from the somatic structures in which the pain

is perceived. The brain has no way of knowing the actual source of input and

mistakenly “projects” the sensation to the somatic structure.

Spinal

cord

Medulla

Midbrain

Spinothalamic

tract

Hypothalamus

A B

SS

Thalamus

C

F

Injury

FIGURE 13-4 Pain-transmission and modulatory pathways. A. Transmission system

for nociceptive messages. Noxious stimuli activate the sensitive peripheral ending

of the primary afferent nociceptor by the process of transduction. The message is

then transmitted over the peripheral nerve to the spinal cord, where it synapses

with cells of origin of the major ascending pain pathway, the spinothalamic tract.

The message is relayed in the thalamus to the anterior cingulate (C), frontal insular

(F), and somatosensory cortex (SS). B. Pain-modulation network. Inputs from frontal

cortex and hypothalamus activate cells in the midbrain that control spinal paintransmission cells via cells in the medulla.

FIGURE 13-5 Functional magnetic resonance imaging (fMRI) demonstrates

placebo-enhanced brain activity in anatomic regions correlating with the

opioidergic descending pain control system. Top panel: Frontal fMRI image shows

placebo-enhanced brain activity in the dorsal lateral prefrontal cortex (DLPFC).

Bottom panel: Sagittal fMRI images show placebo-enhanced responses in the

rostral anterior cingulate cortex (rACC), the rostral ventral medullae (RVM), the

periaqueductal gray (PAG) area, and the hypothalamus. The placebo-enhanced

activity in all areas was reduced by naloxone, demonstrating the link between the

descending opioidergic system and the placebo analgesic response. (F Eippert

et al: Activation of the opioidergic descending pain control system underlies placebo

analgesia. Neuron 63(4):533-543, 2009.)

94PART 2 Cardinal Manifestations and Presentation of Diseases

systemically administered opioids such as morphine. Along with the

opioid receptor, the component nuclei of this pain-modulating circuit

contain endogenous opioid peptides such as the enkephalins and

β-endorphin.

The most reliable way to activate this endogenous opioid-mediated

modulating system is by suggestion of pain relief or by intense emotion

directed away from the pain-causing injury (e.g., during severe threat

or an athletic competition). In fact, pain-relieving endogenous opioids

are released following surgical procedures and in patients given a placebo for pain relief.

Pain-modulating circuits can enhance as well as suppress pain.

Both pain-inhibiting and pain-facilitating neurons in the medulla

project to and control spinal pain-transmission neurons. Because paintransmission neurons can be activated by modulatory neurons, it is

theoretically possible to generate a pain signal with no peripheral noxious stimulus. In fact, human functional imaging studies have demonstrated increased activity in this circuit during migraine headaches. A

central circuit that facilitates pain could account for the finding that

pain can be induced by suggestion or enhanced by expectation and

provides a framework for understanding how psychological factors can

contribute to chronic pain.

■ NEUROPATHIC PAIN

Lesions of the peripheral or central nociceptive pathways typically

result in a loss or impairment of pain sensation. Paradoxically, damage

to or dysfunction of these pathways can also produce pain. For example, damage to peripheral nerves, as occurs in diabetic neuropathy, or

to primary afferents, as in herpes zoster infection, can result in pain

that is referred to the body region innervated by the damaged nerves.

Pain may also be produced by damage to the central nervous system

(CNS), for example, in some patients following trauma or vascular

injury to the spinal cord, brainstem, or thalamic areas that contain

central nociceptive pathways. Such pains are termed neuropathic and

are often severe and resistant to standard treatments for pain.

Neuropathic pain typically has an unusual burning, tingling, or electric shock-like quality and may occur spontaneously, without any stimulus, or be triggered by very light touch. These features are rare in other

types of pain. On examination, a sensory deficit is characteristically

co-extensive with the area of the patient’s pain. Hyperpathia, a greatly

exaggerated pain response to innocuous or mild nociceptive stimuli,

especially when applied repeatedly, is also characteristic of neuropathic

pain; patients often complain that the very lightest moving stimulus

evokes exquisite pain (allodynia). In this regard, it is of clinical interest

that a topical preparation of 5% lidocaine in patch form is effective for

patients with postherpetic neuralgia who have prominent allodynia.

A variety of mechanisms contribute to neuropathic pain. As with

sensitized primary afferent nociceptors, damaged primary afferents,

including nociceptors, become highly sensitive to mechanical stimulation and may generate impulses in the absence of stimulation.

Increased sensitivity and spontaneous activity are due, in part, to an

increased density of sodium channels in the damaged nerve fiber.

Damaged primary afferents may also develop sensitivity to norepinephrine. Interestingly, spinal cord pain-transmission neurons cut off

from their normal input may also become spontaneously active. Thus,

both central and peripheral nervous system hyperactivity contribute to

neuropathic pain.

Sympathetically Maintained Pain Patients with peripheral

nerve injury occasionally develop spontaneous pain in or beyond the

region innervated by the nerve. This pain is often described as having

a burning quality. The pain typically begins after a delay of hours to

days or even weeks and is accompanied by swelling of the extremity, periarticular bone loss, and arthritic changes in the distal joints.

Early in the course of the condition, the pain may be relieved by a

local anesthetic block of the sympathetic innervation to the affected

extremity. Damaged primary afferent nociceptors acquire adrenergic

sensitivity and can be activated by stimulation of the sympathetic outflow. This constellation of spontaneous pain and signs of sympathetic

dysfunction following injury has been termed complex regional pain

syndrome (CRPS). When this occurs after an identifiable nerve injury,

it is termed CRPS type II (also known as posttraumatic neuralgia or,

if severe, causalgia). When a similar clinical picture appears without

obvious nerve injury, it is termed CRPS type I (also known as reflex

sympathetic dystrophy). CRPS can be produced by a variety of injuries,

including fractures of bone, soft tissue trauma, myocardial infarction,

and stroke. CRPS type I typically resolves with symptomatic treatment;

however, when it persists, detailed examination often reveals evidence

of peripheral nerve injury. Although the pathophysiology of CRPS

is poorly understood, the pain and the signs of inflammation, when

acute, can be rapidly relieved by blocking the sympathetic nervous

system. This implies that sympathetic activity can activate undamaged nociceptors when inflammation is present. Signs of sympathetic

hyperactivity should be sought in patients with posttraumatic pain and

inflammation and no other obvious explanation.

TREATMENT

Acute Pain

The ideal treatment for any pain is to remove the cause; thus, while

treatment can be initiated immediately, efforts to establish the

underlying etiology should always proceed as treatment begins.

Sometimes, treating the underlying condition does not immediately

relieve pain. Furthermore, some conditions are so painful that rapid

and effective analgesia is essential (e.g., the postoperative state,

burns, trauma, cancer, or sickle cell crisis). Analgesic medications

are a first line of treatment in these cases, and all practitioners

should be familiar with their use.

ASPIRIN, ACETAMINOPHEN, AND NONSTEROIDAL

ANTI-INFLAMMATORY AGENTS (NSAIDS)

These drugs are considered together because they are used for

similar problems and may have a similar mechanism of action

(Table 13-1). All these compounds inhibit cyclooxygenase (COX),

and except for acetaminophen, all have anti-inflammatory actions,

especially at higher dosages. They are particularly effective for mild

to moderate headache and for pain of musculoskeletal origin.

Because they are effective for these common types of pain and

are available without prescription, COX inhibitors are by far the

most commonly used analgesics. They are absorbed well from the

gastrointestinal tract and, with occasional use, have only minimal side effects. With chronic use, gastric irritation is a common

side effect of aspirin and NSAIDs and is the problem that most

frequently limits the dose that can be given. Gastric irritation is

most severe with aspirin, which may cause erosion and ulceration

of the gastric mucosa leading to bleeding or perforation. Because

aspirin irreversibly acetylates platelet COX and thereby interferes

with coagulation of the blood, gastrointestinal bleeding is a particular risk. Older age and history of gastrointestinal disease increase

the risks of aspirin and NSAIDs. In addition to the well-known

gastrointestinal toxicity of NSAIDs, nephrotoxicity is a significant

problem for patients using these drugs on a chronic basis. Patients

at risk for renal insufficiency, particularly those with significant

contraction of their intravascular volume as occurs with chronic

diuretic use or acute hypovolemia, should avoid NSAIDs. NSAIDs

can also increase blood pressure in some individuals. Long-term

treatment with NSAIDs requires regular blood pressure monitoring

and treatment if necessary. Although toxic to the liver when taken

in high doses, acetaminophen rarely produces gastric irritation and

does not interfere with platelet function.

The introduction of parenteral forms of NSAIDs, ketorolac and

diclofenac, extends the usefulness of this class of compounds in

the management of acute severe pain. Both agents are sufficiently

potent and rapid in onset to supplant opioids as first-line treatment

for many patients with acute severe headache and musculoskeletal

pain.

There are two major classes of COX: COX-1 is constitutively

expressed, and COX-2 is induced in the inflammatory state.

95Pain: Pathophysiology and Management CHAPTER 13

GENERIC NAME PO DOSE, mg INTERVAL COMMENTS

Anticonvulsants and Antiarrythmicsa

Carbamazepine 200–300 q6h Rare aplastic anemia, GI irritation, hepatoitoxicity

Oxcarbamazepine 300 bid Similar to carbamazepine

Gabapentinb 600–1200 q8h Dizziness, GI irritation; useful in trigeminal neuralgia

Pregabalin 150–600 bid Similar to gabapentin; dry mouth, edema

a

Antidepressants, anticonvulsants, and antiarrhythmics have not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of pain. b

Gabapentin in

doses up to 1800 mg/d is FDA approved for postherpetic neuralgia.

Abbreviations: 5-HT, serotonin; NE, norepinephrine; NSAID, nonsteroidal anti-inflammatory agent.

GENERIC NAME

UPTAKE BLOCKADE SEDATIVE

POTENCY

ANTICHOLINERGIC

POTENCY

ORTHOSTATIC

HYPOTENSION

CARDIAC

ARRHYTHMIA

AVERAGE DOSE,

mg/d

RANGE,

5-HT NE mg/d

Antidepressantsa

Doxepin ++ + High Moderate Moderate Less 200 75–400

Amitriptyline ++++ ++ High Highest Moderate Yes 150 25–300

Imipramine ++++ ++ Moderate Moderate High Yes 200 75–400

Nortriptyline +++ ++ Moderate Moderate Low Yes 100 40–150

Desipramine +++ ++++ Low Low Low Yes 150 50–300

Venlafaxine +++ ++ Low None None No 150 75–400

Duloxetine +++ +++ Low None None No 40 30–60

TABLE 13-1 Drugs for Relief of Pain

GENERIC NAME DOSE, mg INTERVAL COMMENTS

Nonnarcotic Analgesics: Usual Doses and Intervals

Acetylsalicylic acid 650 PO q4h Enteric-coated preparations available

Acetaminophen 650 PO q4h Side effects uncommon

Ibuprofen 400 PO q4–6h Available without prescription

Naproxen 250–500 PO q12h Naproxen is the common NSAID that poses the least cardiovascular risk,

but it has a somewhat higher incidence of gastrointestinal bleeding

Fenoprofen 200 PO q4–6h Contraindicated in renal disease

Indomethacin 25–50 PO q8h Gastrointestinal side effects common

Ketorolac 15–60 IM/IV q4–6h Available for parenteral use

Celecoxib 100–200 PO q12–24h Useful for arthritis

Valdecoxib 10–20 PO q12–24h Removed from U.S. market in 2005

GENERIC NAME PARENTERAL DOSE, mg PO DOSE, mg COMMENTS

Narcotic Analgesics: Usual Doses and Intervals

Codeine 30–60 q4h 30–60 q4h Nausea common

Oxycodone — 5–10 q4–6h Usually available with acetaminophen or aspirin

Oxycodone extended-release — 10-40 q12h Oral extended-release tablet; high potential for misuse

Morphine 5 q4h 30 q4h

Morphine sustained release — 15–60 bid to tid Oral slow-release preparation

Hydromorphone 1–2 q4h 2–4 q4h Shorter acting than morphine sulfate

Levorphanol 2 q6–8h 4 q6–8h Longer acting than morphine sulfate; absorbed well PO

Methadone 5–10 q6–8h 5–20 q6–8h Due to long half-life, respiratory depression and sedation may persist after

analgesic effect subsides; therapy should not be initiated with >40 mg/d,

and dose escalation should be made no more frequently than every 3 days

Meperidine 50–100 q3–4h 300 q4h Poorly absorbed PO; normeperidine is a toxic metabolite; routine use of

this agent is not recommended

Butorphanol — 1–2 q4h Intranasal spray

Fentanyl 25–100 μg/h — 72-h transdermal patch

Buprenorphine 5–20 μg/h 7-day transdermal patch

Buprenorphine 0.3 q6–8h Parenteral administration

Tramadol — 50–100 q4–6h Mixed opioid/adrenergic action

COX-2-selective drugs have similar analgesic potency and produce less gastric irritation than the nonselective COX inhibitors.

The use of COX-2-selective drugs does not appear to lower the

risk of nephrotoxicity compared to nonselective NSAIDs. On the

other hand, COX-2-selective drugs offer a significant benefit in

the management of acute postoperative pain because they do not

affect blood coagulation. Nonselective COX inhibitors (especially

aspirin) are usually contraindicated postoperatively because they

impair platelet-mediated blood clotting and are thus associated

with increased bleeding at the operative site. COX-2 inhibitors,

including celecoxib (Celebrex), are associated with increased cardiovascular risk, including cardiovascular death, myocardial infarction, stroke, heart failure, or a thromboembolic event. It appears

that this is a class effect of NSAIDs, excluding aspirin. These drugs

96PART 2 Cardinal Manifestations and Presentation of Diseases

are contraindicated in patients in the immediate period after coronary artery bypass surgery and should be used with caution in

elderly patients and those with a history of or significant risk factors

for cardiovascular disease.

OPIOID ANALGESICS

Opioids are the most potent pain-relieving drugs currently available. Of all analgesics, they have the broadest range of efficacy

and provide the most reliable and effective treatment for rapid

pain relief. Although side effects are common, most are reversible:

nausea, vomiting, pruritus, sedation, and constipation are the most

frequent and bothersome side effects. Respiratory depression is

uncommon at standard analgesic doses but can be life-threatening.

Opioid-related side effects can be reversed rapidly with the narcotic antagonist naloxone. Many physicians, nurses, and patients

have a certain trepidation about using opioids that is based on a

fear of initiating addiction in their patients. In fact, there is a very

small chance of patients becoming addicted to narcotics as a result

of their appropriate medical use. For chronic pain, particularly

chronic noncancer pain, the risk of addiction in patients taking

opioids on a chronic basis remains small, but the risk does appear to

increase with dose escalation. The physician should not hesitate to

use opioid analgesics in patients with acute severe pain. Table 13-1

lists the most commonly used opioid analgesics.

Opioids produce analgesia by actions in the CNS. They activate pain-inhibitory neurons and directly inhibit pain-transmission

neurons. Most of the commercially available opioid analgesics

act at the same opioid receptor (μ-receptor), differing mainly in

potency, speed of onset, duration of action, and optimal route

of administration. Some side effects are due to accumulation of

nonopioid metabolites that are unique to individual drugs. One

striking example of this is normeperidine, a metabolite of meperidine. At higher doses of meperidine, typically >1 g/d, accumulation

of normeperidine can produce hyperexcitability and seizures that

are not reversible with naloxone. Normeperidine accumulation is

increased in patients with renal failure.

The most rapid pain relief is obtained by intravenous administration of opioids; relief with oral administration is significantly

slower. Because of the potential for respiratory depression, patients

with any form of respiratory compromise must be kept under close

observation following opioid administration; an oxygen-saturation

monitor may be useful, but only in a setting where the monitor is

under constant surveillance. Opioid-induced respiratory depression is primarily manifest as a reduction in respiratory rate and

is typically accompanied by sedation. A fall in oxygen saturation

represents a critical level of respiratory depression and the need

for immediate intervention to prevent life-threatening hypoxemia.

Newer monitoring devices that incorporate capnography or pharyngeal air flow can detect apnea at the point of onset and should

be used in hospitalized patients. Ventilatory assistance should be

maintained until the opioid-induced respiratory depression has

resolved. The opioid antagonist naloxone should be readily available whenever opioids are used at high doses or in patients with

compromised pulmonary function. Opioid effects are dose-related,

and there is great variability among patients in the doses that relieve

pain and produce side effects. Synergistic respiratory depression is

common when opioids are administered with other CNS depressants. Co-administration of benzodiazepines is particularly likely to

produce respiratory depression and should be avoided, especially in

outpatient pain management. Because of this variability in patient

response, initiation of therapy requires titration to optimal dose and

interval. The most important principle is to provide adequate pain

relief. This requires determining whether the drug has adequately

relieved the pain and timely reassessment to determine the optimal

interval for dosing. The most common error made by physicians in

managing severe pain with opioids is to prescribe an inadequate dose.

Because many patients are reluctant to complain, this practice leads to

needless suffering. In the absence of sedation at the expected time of

peak effect, a physician should not hesitate to repeat the initial dose

to achieve satisfactory pain relief.

A now standard approach to the problem of achieving adequate

pain relief is the use of patient-controlled analgesia (PCA). PCA

uses a microprocessor-controlled infusion device that can deliver

a baseline continuous dose of an opioid drug as well as preprogrammed additional doses whenever the patient pushes a button.

The patient can then titrate the dose to the optimal level. This

approach is used most extensively for the management of postoperative pain, but there is no reason why it should not be used for any

hospitalized patient with persistent severe pain. PCA is also used for

short-term home care of patients with intractable pain, such as that

caused by metastatic cancer.

It is important to understand that the PCA device delivers small,

repeated doses to maintain pain relief; in patients with severe pain,

the pain must first be brought under control with a loading dose

before transitioning to the PCA device. The bolus dose of the drug

(typically 1 mg of morphine, 0.2 mg of hydromorphone, or 10 μg

of fentanyl) can then be delivered repeatedly as needed. To prevent

overdosing, PCA devices are programmed with a lockout period

after each demand dose is delivered (typically starting at 10 min)

and a limit on the total dose delivered per hour. Although some

have advocated the use of a simultaneous continuous or basal

infusion of the PCA drug, this may increase the risk of respiratory

depression and has not been shown to increase the overall efficacy

of the technique.

The availability of new routes of administration has extended the

usefulness of opioid analgesics. Most important is the availability

of spinal administration. Opioids can be infused through a spinal

catheter placed either intrathecally or epidurally. By applying opioids directly to the spinal or epidural space adjacent to the spinal

cord, regional analgesia can be obtained using relatively low total

doses. Indeed, the dose required to produce effective analgesia

when using morphine intrathecally (0.1–0.3 mg) is a fraction of that

required to produce similar analgesia when administered intravenously (5–10 mg). In this way, side effects such as sedation, nausea,

and respiratory depression can be minimized. This approach has

been used extensively during labor and delivery and for postoperative pain relief following surgical procedures. Continuous intrathecal delivery via implanted spinal drug-delivery systems is now

commonly used, particularly for the treatment of cancer-related

pain that would require sedating doses for adequate pain control if

given systemically. Opioids can also be given intranasally (butorphanol), rectally, and transdermally (fentanyl and buprenorphine), or

through the oral mucosa (fentanyl), thus avoiding the discomfort

of frequent injections in patients who cannot be given oral medication. The fentanyl and buprenorphine transdermal patches have

the advantage of providing fairly steady plasma levels, which may

improve patient comfort.

Recent additions to the armamentarium for treating opioidinduced side effects are the peripherally acting opioid antagonists

alvimopan (Entereg) and methylnaltrexone (Rellistor). Alvimopan

is available as an orally administered agent that is restricted to the

intestinal lumen by limited absorption; methylnaltrexone is available in a subcutaneously administered form that has virtually no

penetration into the CNS. Both agents act by binding to peripheral

μ-receptors, thereby inhibiting or reversing the effects of opioids

at these peripheral sites. The action of both agents is restricted to

receptor sites outside of the CNS; thus, these drugs can reverse the

adverse effects of opioid analgesics that are mediated through their

peripheral receptors without reversing their CNS-mediated analgesic effects. Alvimopan has proven effective in lowering the duration

of persistent ileus following abdominal surgery in patients receiving

opioid analgesics for postoperative pain control. Methylnaltrexone

has proven effective for relief of opioid-induced constipation in

patients taking opioid analgesics on a chronic basis.

97Pain: Pathophysiology and Management CHAPTER 13

Opioid and COX Inhibitor Combinations When used in combination, opioids and COX inhibitors have additive effects. Because a

lower dose of each can be used to achieve the same degree of pain

relief and their side effects are nonadditive, such combinations are

used to lower the severity of dose-related side effects. However,

fixed-ratio combinations of an opioid with acetaminophen carry

an important risk. Dose escalation as a result of increased severity

of pain or decreased opioid effect as a result of tolerance may lead

to ingestion of levels of acetaminophen that are toxic to the liver.

Although acetaminophen-related hepatotoxicity is uncommon, it

remains a significant cause for liver failure. Thus, many practitioners have moved away from the use of opioid-acetaminophen combination analgesics to avoid the risk of excessive acetaminophen

exposure as the dose of the analgesic is escalated.

CHRONIC PAIN

Managing patients with chronic pain is intellectually and emotionally

challenging. Sensitization of the nervous system can occur without an

obvious precipitating cause, e.g., fibromyalgia, or chronic headache. In

many patients, chronic pain becomes a distinct disease unto itself. The

pain-generating mechanism is often difficult or impossible to determine with certainty; such patients are demanding of the physician’s

time and often appear emotionally distraught. The traditional medical

approach of seeking an obscure organic pathology is often unhelpful.

On the other hand, psychological evaluation and behaviorally based

treatment paradigms are frequently helpful, particularly in the setting

of a multidisciplinary pain-management center. Unfortunately, this

approach, while effective, remains largely underused in current medical practice.

There are several factors that can cause, perpetuate, or exacerbate

chronic pain. First, of course, the patient may simply have a disease that

is characteristically painful for which there is presently no cure. Arthritis,

cancer, chronic daily headaches, fibromyalgia, and diabetic neuropathy

are examples of this. Second, there may be secondary perpetuating

factors that are initiated by disease and persist after that disease has

resolved. Examples include damaged sensory nerves, sympathetic

efferent activity, and painful reflex muscle contraction (spasm). Finally,

a variety of psychological conditions can exacerbate or even cause pain.

There are certain areas to which special attention should be paid in

a patient’s medical history. Because depression is the most common

emotional disturbance in patients with chronic pain, patients should be

questioned about their mood, appetite, sleep patterns, and daily activity. A simple standardized questionnaire, such as the Beck Depression

Inventory, can be a useful screening device. It is important to remember that major depression is a common, treatable, and potentially fatal

illness.

Other clues that a significant emotional disturbance is contributing

to a patient’s chronic pain complaint include pain that occurs in multiple, unrelated sites; a pattern of recurrent, but separate, pain problems

beginning in childhood or adolescence; pain beginning at a time of

emotional trauma, such as the loss of a parent or spouse; a history of

physical or sexual abuse; and past or present substance abuse.

On examination, special attention should be paid to whether the

patient guards the painful area and whether certain movements or postures are avoided because of pain. Discovering a mechanical component to the pain can be useful both diagnostically and therapeutically.

Painful areas should be examined for deep tenderness, noting whether

this is localized to muscle, ligamentous structures, or joints. Chronic

myofascial pain is very common, and in these patients, deep palpation

may reveal highly localized trigger points that are firm bands or knots

in muscle. Relief of the pain following injection of local anesthetic into

these trigger points supports the diagnosis. A neuropathic component

to the pain is indicated by evidence of nerve damage, such as sensory

impairment, exquisitely sensitive skin (allodynia), weakness, and muscle atrophy, or loss of deep tendon reflexes. Evidence suggesting sympathetic nervous system involvement includes the presence of diffuse

swelling, changes in skin color and temperature, and hypersensitive

skin and joint tenderness compared with the normal side. Relief of

the pain with a sympathetic block supports the diagnosis, but once the

condition becomes chronic, the response to sympathetic blockade is

of variable magnitude and duration; the role for repeated sympathetic

blocks in the overall management of CRPS is unclear.

A guiding principle in evaluating patients with chronic pain is to

assess both emotional and somatic causal and perpetuating factors

before initiating therapy. Addressing these issues together, rather than

waiting to address emotional issues after somatic causes of pain have

been ruled out, improves compliance in part because it assures patients

that a psychological evaluation does not mean that the physician is

questioning the validity of their complaint. Even when a somatic cause

for a patient’s pain can be found, it is still wise to look for other factors.

For example, a cancer patient with painful bony metastases may have

additional pain due to nerve damage and may also be depressed. Optimal therapy requires that each of these factors be assessed and treated.

TREATMENT

Chronic Pain

Once the evaluation process has been completed and the likely

causative and exacerbating factors identified, an explicit treatment

plan should be developed. An important part of this process is to

identify specific and realistic functional goals for therapy, such as

getting a good night’s sleep, being able to go shopping, or returning to work. A multidisciplinary approach that uses medications,

counseling, physical therapy, nerve blocks, and even surgery may

be required to improve the patient’s quality of life. There are also

some newer, minimally invasive procedures that can be helpful for

some patients with intractable pain. These include image-guided

interventions such as epidural injection of glucocorticoids for acute

radicular pain and radiofrequency treatment of the facet joints for

chronic facet-related back and neck pain. For patients with severe

and persistent pain that is unresponsive to more conservative

treatment, placement of electrodes on peripheral nerves or within

the spinal canal on nerve roots or in the space overlying the dorsal

columns of the spinal cord (spinal cord stimulation) or implantation of intrathecal drug-delivery systems has shown significant

benefit. The criteria for predicting which patients will respond to

these procedures continue to evolve. They are generally reserved for

patients who have not responded to conventional pharmacologic

approaches. Referral to a multidisciplinary pain clinic for a full

evaluation should precede any invasive procedure. Such referrals

are clearly not necessary for all chronic pain patients. For some,

pharmacologic management alone can provide adequate relief.

ANTIDEPRESSANT MEDICATIONS

The tricyclic antidepressants (TCAs), particularly nortriptyline and

desipramine (Table 13-1), are useful for the management of chronic

pain. Although developed for the treatment of depression, the TCAs

have a spectrum of dose-related biologic activities that include

analgesia in a variety of chronic clinical conditions. Although the

mechanism is unknown, the analgesic effect of TCAs has a more

rapid onset and occurs at a lower dose than is typically required

for the treatment of depression. Furthermore, patients with chronic

pain who are not depressed obtain pain relief with antidepressants.

There is evidence that TCAs potentiate opioid analgesia, so they

may be useful adjuncts for the treatment of severe persistent pain

such as occurs with malignant tumors. Table 13-2 lists some of the

painful conditions that respond to TCAs. TCAs are of particular

value in the management of neuropathic pain such as occurs in

diabetic neuropathy and postherpetic neuralgia, for which there are

few other therapeutic options.

The TCAs that have been shown to relieve pain have significant

side effects (Table 13-1; Chap. 452). Some of these side effects,

98PART 2 Cardinal Manifestations and Presentation of Diseases

such as orthostatic hypotension, drowsiness, cardiac conduction

delay, memory impairment, constipation, and urinary retention, are

particularly problematic in elderly patients, and several are additive

to the side effects of opioid analgesics. The selective serotonin

reuptake inhibitors such as fluoxetine (Prozac) have fewer and less

serious side effects than TCAs, but they are much less effective for

relieving pain. It is of interest that venlafaxine (Effexor) and duloxetine (Cymbalta), which are nontricyclic antidepressants that block

both serotonin and norepinephrine reuptake, appear to retain most

of the pain-relieving effect of TCAs with a side effect profile more

like that of the selective serotonin reuptake inhibitors. These drugs

may be particularly useful in patients who cannot tolerate the side

effects of TCAs.

ANTICONVULSANTS AND ANTIARRHYTHMICS

These drugs are useful primarily for patients with neuropathic

pain. Phenytoin (Dilantin) and carbamazepine (Tegretol) were first

shown to relieve the pain of trigeminal neuralgia (Chap. 441). This

pain has a characteristic brief, shooting, electric shock-like quality.

In fact, anticonvulsants seem to be particularly helpful for pains that

have such a lancinating quality. Newer anticonvulsants, the calcium

channel alpha-2-delta subunit ligands gabapentin (Neurontin) and

pregabalin (Lyrica), are effective for a broad range of neuropathic

pains. Furthermore, because of their favorable side effect profile,

these newer anticonvulsants are often used as first-line agents.

CANNABINOIDS

These agents are widely used for their analgesic properties, although

published evidence suggests that any effects are likely to be modest,

with small increases in pain threshold reported and variable reductions in clinical pain intensity. Cannabis more consistently reduces

the unpleasantness of the pain experience and, in cancer-related

pain, can lessen the nausea and vomiting associated with chemotherapy use. Marijuana and related compounds are discussed in

Chap. 455.

CHRONIC OPIOID MEDICATION

The long-term use of opioids is accepted for patients with pain

due to malignant disease. Although opioid use for chronic pain

of nonmalignant origin is controversial, it is clear that, for many

patients, opioids are the only option that produces meaningful pain

relief. This is understandable because opioids are the most potent

and have the broadest range of efficacy of any analgesic medications. Although addiction is rare in patients who first use opioids

for pain relief, some degree of tolerance and physical dependence

is likely with long-term use. Furthermore, studies suggest that

long-term opioid therapy may worsen pain in some individuals,

termed opioid-induced hyperalgesia. Therefore, before embarking

on opioid therapy, other options should be explored, and the limitations and risks of opioids should be explained to the patient. It is

also important to point out that some opioid analgesic medications

have mixed agonist-antagonist properties (e.g., butorphanol and

buprenorphine). From a practical standpoint, this means that they

may worsen pain by inducing an abstinence syndrome in patients

who are actively being treated with other opioids and are physically

dependent.

With long-term outpatient use of orally administered opioids,

it may be desirable to use long-acting compounds such as levorphanol, methadone, extended-release morphine or oxycodone, or

transdermal fentanyl (Table 13-1). The pharmacokinetic profiles

of these drug preparations enable the maintenance of sustained

analgesic blood levels, potentially minimizing side effects such

as sedation that are associated with high peak plasma levels, and

reducing the likelihood of rebound pain associated with a rapid fall

in plasma opioid concentration. Extended-release opioid formulations are approved primarily for patients who are already taking

other opioids and should not be used as first-line opioids for pain.

Although long-acting opioid preparations may provide superior

pain relief in patients with a continuous pattern of ongoing pain,

others suffer from intermittent severe episodic pain and experience

superior pain control and fewer side effects with the periodic use of

short-acting opioid analgesics. Constipation is a virtually universal

side effect of opioid use and should be treated expectantly. As noted

earlier in the discussion of acute pain treatment, a recent advance

for patients is the development of peripherally acting opioid antagonists that can reverse the constipation associated with opioid use

without interfering with analgesia.

Soon after the introduction of an extended-release oxycodone

formulation (OxyContin) in the late 1990s, a dramatic rise in

emergency department visits and deaths associated with oxycodone

ingestion appeared. This appears to be due primarily to individuals

using a prescription opioid nonmedically. Drug-induced deaths

have rapidly risen and are now the second leading cause of death

in Americans, just behind motor vehicle fatalities. In 2011, the

Office of National Drug Control Policy established a multifaceted

approach to address prescription drug abuse, including prescription drug monitoring programs (PDMPs) that allow practitioners

to determine if patients are receiving prescriptions from multiple

providers and use of law enforcement to eliminate improper prescribing practices. In 2016, the Centers for Disease Control and

Prevention (CDC) released the CDC Guideline for Prescribing

Opioids for Chronic Pain, with recommendations for primary care

clinicians who are prescribing opioids for chronic noncancer pain.

A modified approach to opioid prescribing was published in 2019

by the Health and Human Services Task Force on chronic pain best

medical practices. These guidelines address (1) when to initiate

or continue opioids for chronic pain; (2) opioid selection, dosage,

duration, follow-up, and discontinuation; and (3) assessing risk and

addressing harms of opioid use. The recent increase in scrutiny

leaves many practitioners hesitant to prescribe opioid analgesics,

other than for brief periods to control pain associated with illness

or injury. For now, the choice to begin chronic opioid therapy

for a given patient is left to the individual practitioner. Pragmatic

guidelines for properly selecting and monitoring patients receiving

chronic opioid therapy are shown in Table 13-3; a checklist for

primary care clinicians prescribing opioids for noncancer pain is

shown in Table 13-4.

TREATMENT OF NEUROPATHIC PAIN

It is important to individualize treatment for patients with neuropathic pain. Several general principles should guide therapy: the

first is to move quickly to provide relief, and the second is to minimize drug side effects. For example, in patients with postherpetic

neuralgia and significant cutaneous hypersensitivity, topical lidocaine (Lidoderm patches) can provide immediate relief without side

effects. The anticonvulsants gabapentin or pregabalin (see above) or

antidepressants (nortriptyline, desipramine, duloxetine, or venlafaxine) can be used as first-line drugs for patients with neuropathic

pain. Systemically administered antiarrhythmic drugs such as lidocaine and mexiletine are less likely to be effective. Although intravenous infusion of lidocaine can provide analgesia for patients with

different types of neuropathic pain, the relief is usually transient,

TABLE 13-2 Painful Conditions That Respond to Tricyclic

Antidepressants

Postherpetic neuralgiaa

Diabetic neuropathya

Fibromyalgiaa

Tension headachea

Migraine headachea

Rheumatoid arthritisa,b

Chronic low back painb

Cancer

Central poststroke pain

a

Controlled trials demonstrate analgesia. b

Controlled studies indicate benefit but not

analgesia.

 

88PART 1 The Profession of Medicine

declining life-sustaining interventions, possibly including refusal of

nutrition and hydration.

■ CARE DURING THE LAST HOURS

Most laypersons have limited experiences with the actual dying process

and death. They frequently do not know what to expect of the final

hours and afterward. The family and other caregivers must be prepared, especially if the plan is for the patient to die at home.

Patients in the last days of life typically experience extreme weakness

and fatigue and become bedbound; this can lead to pressure sores. The

issue of turning patients who are near the end of life, however, must be

balanced against the potential discomfort that movement may cause.

Patients stop eating and drinking with drying of mucosal membranes

and dysphagia. Careful attention to oral swabbing, lubricants for lips,

and use of artificial tears can provide a form of care to substitute for

attempts at feeding the patient. With loss of the gag reflex and dysphagia, patients may also experience accumulation of oral secretions,

producing noises during respiration sometimes called “the death

rattle.” Scopolamine can reduce the secretions. Patients also experience changes in respiration with periods of apnea or Cheyne-Stokes

breathing. Decreased intravascular volume and cardiac output cause

tachycardia, hypotension, peripheral coolness, and livedo reticularis

(skin mottling). Patients can have urinary and, less frequently, fecal

incontinence. Changes in consciousness and neurologic function generally lead to two different paths to death.

Each of these terminal changes can cause patients and families distress, requiring reassurance and targeted interventions (Table 12-9).

Informing families that these changes might occur and providing them

with an information sheet can help preempt problems and minimize

distress. Understanding that patients stop eating because they are

dying, not dying because they have stopped eating, can reduce family

and caregiver anxiety. Similarly, informing the family and caregivers

that the “death rattle” may occur and that it is not indicative of suffocation, choking, or pain can reduce their worry from the breathing

sounds.

Families and caregivers may also feel guilty about stopping treatments, fearing that they are “killing” the patient. This may lead

to demands for interventions, such as feeding tubes, that may be

ineffective. In such cases, the physician should remind the family and

caregivers about the inevitability of events and the palliative goals.

TABLE 12-9 Managing Changes in the Patient’s Condition during the Final Days and Hours

CHANGES IN

THE PATIENT’S

CONDITION

POTENTIAL

COMPLICATION

FAMILY’S POSSIBLE

REACTION AND

CONCERN ADVICE AND INTERVENTION

Profound

fatigue

Bedbound with

development of

pressure ulcers that

are prone to infection,

malodor, and pain, and

joint pain

Patient is lazy and

giving up.

Reassure family and caregivers that terminal fatigue will not respond to interventions and should not

be resisted.

Use an air mattress if necessary.

Anorexia None Patient is giving up;

patient will suffer

from hunger and will

starve to death.

Reassure family and caregivers that the patient is not eating because he or she is dying; not eating

at the end of life does not cause suffering or death.

Forced feeding, whether oral, parenteral, or enteral, does not reduce symptoms or prolong life.

Dehydration Dry mucosal

membranes (see below)

Patient will suffer

from thirst and die of

dehydration.

Reassure family and caregivers that dehydration at the end of life does not cause suffering because

patients lose consciousness before any symptom distress.

Intravenous hydration can worsen symptoms of dyspnea by pulmonary edema and peripheral edema

as well as prolong the dying process.

Dysphagia Inability to swallow oral

medications needed for

palliative care

Do not force oral intake.

Discontinue unnecessary medications that may have been continued, including antibiotics,

diuretics, antidepressants, and laxatives.

If swallowing pills is difficult, convert essential medications (analgesics, antiemetics, anxiolytics,

and psychotropics) to oral solutions, buccal, sublingual, or rectal administration.

“Death

rattle”—noisy

breathing

Patient is choking

and suffocating.

Reassure the family and caregivers that this is caused by secretions in the oropharynx and the

patient is not choking.

Reduce secretions with scopolamine (0.2–0.4 mg SC q4h or 1–3 patches q3d).

Reposition patient to permit drainage of secretions.

Do not suction. Suction can cause patient and family discomfort and is usually ineffective.

Apnea,

Cheyne-Stokes

respirations,

dyspnea

Patient is

suffocating.

Reassure family and caregivers that unconscious patients do not experience suffocation or air

hunger.

Apneic episodes are frequently a premorbid change.

Opioids or anxiolytics may be used for dyspnea.

Oxygen is unlikely to relieve dyspneic symptoms and may prolong the dying process.

Urinary or fecal

incontinence

Skin breakdown if days

until death

Potential transmission

of infectious agents to

caregivers

Patient is dirty,

malodorous, and

physically repellent.

Remind family and caregivers to use universal precautions.

Frequent changes of bedclothes and bedding.

Use diapers, urinary catheter, or rectal tube if diarrhea or high urine output.

Agitation or

delirium

Day/night reversal

Hurt self or caregivers

Patient is in horrible

pain and going to

have a horrible

death.

Reassure family and caregivers that agitation and delirium do not necessarily connote physical pain.

Depending on the prognosis and goals of treatment, consider evaluating for causes of delirium and

modifying medications.

Manage symptoms with haloperidol, chlorpromazine, diazepam, or midazolam.

Dry mucosal

membranes

Cracked lips, mouth

sores, and candidiasis

can also cause pain.

Odor

Patient may be

malodorous,

physically repellent.

Use baking soda mouthwash or saliva preparation q15–30 min.

Use topical nystatin for candidiasis.

Coat lips and nasal mucosa with petroleum jelly q60–90 min.

Use ophthalmic lubricants q4h or artificial tears q30 min.

Palliative and End-of-Life Care

89CHAPTER 12

Interventions may prolong the dying process and cause discomfort.

Physicians also should emphasize that withholding treatments is both

legal and ethical and that the family members are not the cause of the

patient’s death. This reassurance may have to be provided multiple

times.

Hearing and touch are said to be the last senses to stop functioning.

Whether this is the case or not, families and caregivers can be encouraged to communicate with the dying patient. Encouraging them to

talk directly to the patient, even if he or she is unconscious, and hold

the patient’s hand or demonstrate affection in other ways can be an

effective way to channel their urge “to do something” for the patient.

When the plan is for the patient to die at home, the physician must

inform the family and caregivers how to determine that the patient has

died. The cardinal signs are cessation of cardiac function and respiration; the pupils become fixed; the body becomes cool; muscles relax;

and incontinence may occur. Remind the family and caregivers that the

eyes may remain open even after the patient has died.

The physician should establish a plan for who the family or caregivers will contact when the patient is dying or has died. Without a

plan, family members may panic and call 911, unleashing a cascade

of unwanted events, from arrival of emergency personnel and resuscitation to hospital admission. The family and caregivers should be

instructed to contact the hospice (if one is involved), the covering physician, or the on-call member of the palliative care team. They should

also be told that the medical examiner need not be called unless the

state requires it for all deaths. Unless foul play is suspected, the health

care team need not contact the medical examiner either.

Just after the patient dies, even the best-prepared family may experience shock and loss and be emotionally distraught. They need time

to assimilate the event and be comforted. Health care providers are

likely to find it meaningful to write a bereavement card or letter to

the family. The purpose is to communicate about the patient, perhaps

emphasizing the patient’s virtues and the honor it was to care for the

patient, and to express concern for the family’s hardship. Some physicians attend the funerals of their patients. Although this is beyond any

medical obligation, the presence of the physician can be a source of

support to the grieving family and provides an opportunity for closure

for the physician.

Death of a spouse is a strong predictor of poor health, and even mortality, for the surviving spouse. It may be important to alert the spouse’s

physician about the death so that he or she is aware of symptoms that

might require professional attention.

■ FURTHER READING

Emanuel E et al: Attitudes and practices of euthanasia and physicianassisted suicide in the United States, Canada, and Europe. JAMA

316:79, 2016.

Kelley AS, Meier DE: Palliative care—A shifting paradigm. N Engl J

Med 363:781, 2010.

Kelley AS et al: Hospice enrollment saves money for Medicare and

improves care quality across a number of different lengths-of-stay.

Health Aff 32:552, 2012.

Kelley AS et al: Palliative care for the seriously ill. N Engl J Med

373:747, 2015.

Mack JW et al: Associations between end-of-life discussion characteristics and care received near death: A prospective cohort study. J Clin

Oncol 30:4387, 2012.

Murray SA et al: Illness trajectories and palliative care. BMJ 330:1007,

2005.

Neuman P et al: Medicare per capita spending by age and service: New

data highlights oldest beneficiaries. Health Aff (Millwood) 34:335,

2015.

Nicholas LH et al: Regional variation in the association between

advance directives and end-of-life Medicare expenditures. JAMA

306:1447, 2011.

Ornstein KA et al: Evaluation of racial disparities in hospice use and

end-of-life treatment intensity in the REGARDS cohort. JAMA Netw

Open 3(8):e2014639, 2020.

Quinn KL et al: Association of receipt of palliative care interventions

with health care use, quality of life, and symptom burden among

adults with chronic noncancer illness: A systematic review and

meta-analysis. JAMA 324:1439, 2020.

Teno JM et al: Change in end-of-life care for medicare beneficiaries:

Site of death, place of care, and health transitions in 2000, 2005, and

2009. JAMA 309:470, 2013.

Teno JM et al: Site of death, place of care, and health care transitions

among US Medicare beneficiaries, 2000-2015. JAMA 320:264, 2018.

Van Den Beuken-VanEverdingen MH et al: Update on prevalence

of pain in patients with cancer: Systematic review and meta-analysis.

J Pain Symptom Manage 51:1070, 2016.

WEBSITES

American Academy of Hospice and Palliative Medicine: www.

aahpm.org

Center to Advance Palliative Care: http://www.capc.org

Education in Palliative and End of Life Care (EPEC): http://

www.epec.net

Family Caregiver Alliance: http://www.caregiver.org

National Hospice and Palliative Care Organization (including

state-specific advance directives): http://www.nhpco.org

Nccn: The National Comprehensive Cancer Network palliative care

guidelines: http://www.nccn.org

Our Care Wishes Advance Care Planning Tool: https://www.

ourcarewishes.org

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Section 1 Pain

Cardinal Manifestations and Presentation of Diseases PART 2

13 Pain: Pathophysiology

and Management

James P. Rathmell, Howard L. Fields

The province of medicine is to preserve and restore health and to

relieve suffering. Understanding pain is essential to both of these goals.

Because pain is universally understood as a signal of disease, it is the

most common symptom that brings a patient to a physician’s attention.

The function of the pain sensory system is to protect the body and

maintain homeostasis. It does this by detecting, localizing, and identifying potential or actual tissue-damaging processes. Because different

diseases produce characteristic patterns of tissue damage, the quality,

time course, and location of a patient’s pain lend important diagnostic

clues. It is the physician’s responsibility to assess each patient promptly

for any remediable cause underlying the pain and to provide rapid and

effective pain relief whenever possible.

THE PAIN SENSORY SYSTEM

Pain is an unpleasant sensation localized to a part of the body. It is

often described in terms of a penetrating or tissue-destructive process (e.g., stabbing, burning, twisting, tearing, squeezing) and/or of a

bodily or emotional reaction (e.g., terrifying, nauseating, sickening).

Furthermore, any pain of moderate or higher intensity is accompanied

by anxiety and the urge to escape or terminate the feeling. These properties illustrate the duality of pain: it is both sensation and emotion.

When it is acute, pain is characteristically associated with behavioral

arousal and a stress response consisting of increased blood pressure,

heart rate, pupil diameter, and plasma cortisol levels. In addition, local

muscle contraction (e.g., limb flexion, abdominal wall rigidity) is often

present.

■ PERIPHERAL MECHANISMS

The Primary Afferent Nociceptor A peripheral nerve consists

of the axons of three different types of neurons: primary sensory

afferents, motor neurons, and sympathetic postganglionic neurons

(Fig. 13-1). The cell bodies of primary sensory afferents are located

in the dorsal root ganglia within the

vertebral foramina. The primary afferent

axon has two branches: one projects centrally into the spinal cord and the other

projects peripherally to innervate tissues.

Primary afferents are classified by their

diameter, degree of myelination, and

conduction velocity. The largest diameter afferent fibers, A-beta (Aβ), respond

maximally to light touch and/or moving

stimuli; they are present primarily in

nerves that innervate the skin. In normal

individuals, the activity of these fibers

does not produce pain. There are two

other classes of primary afferent nerve

fibers: the small diameter myelinated

A-delta (Aδ) and the unmyelinated (C)

axons (Fig. 13-1). These fibers are present in nerves to the skin and to deep

somatic and visceral structures. Some

tissues, such as the cornea, are innervated only by Aδ and C fiber afferents.

Most Aδ and C fiber afferents respond maximally to intense (painful)

stimuli and produce the subjective experience of pain when they

are activated; this defines them as primary afferent nociceptors (pain

receptors). The ability to detect painful stimuli is completely abolished

when conduction in Aδ and C fiber axons is blocked.

Individual primary afferent nociceptors can respond to several different types of noxious stimuli. For example, most nociceptors respond

to heat; intense cold; intense mechanical distortion, such as a pinch;

changes in pH, particularly an acidic environment; and application of

chemical irritants including adenosine triphosphate (ATP), serotonin,

bradykinin (BK), and histamine. The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the vanilloid receptor, mediates perception of some noxious stimuli, especially

heat sensations, by nociceptive neurons; it is activated by heat, acidic

pH, endogenous mediators, and capsaicin, a component of hot chili

peppers.

Sensitization When intense, repeated, or prolonged stimuli are

applied to damaged or inflamed tissues, the threshold for activating

primary afferent nociceptors is lowered, and the frequency of firing

is higher for all stimulus intensities. Inflammatory mediators such as

BK, nerve-growth factor, some prostaglandins (PGs), and leukotrienes

contribute to this process, which is called sensitization. Sensitization

occurs at the level of the peripheral nerve terminal (peripheral sensitization) as well as at the level of the dorsal horn of the spinal cord

(central sensitization). Peripheral sensitization occurs in damaged or

inflamed tissues, when inflammatory mediators activate intracellular signal transduction in nociceptors, prompting an increase in the

production, transport, and membrane insertion of chemically gated

and voltage-gated ion channels. These changes increase the excitability of nociceptor terminals and lower their threshold for activation

by mechanical, thermal, and chemical stimuli. Central sensitization

occurs when activity, generated by nociceptors during inflammation,

enhances the excitability of nerve cells in the dorsal horn of the spinal

cord. Following injury and resultant sensitization, normally innocuous

stimuli can produce pain (termed allodynia). Sensitization is a clinically important process that contributes to tenderness, soreness, and

hyperalgesia (increased pain intensity in response to the same noxious

stimulus; e.g., pinprick causes severe pain). A striking example of sensitization is sunburned skin, in which severe pain can be produced by

a gentle slap or a warm shower.

Sensitization is of particular importance for pain and tenderness

in deep tissues. Viscera are normally relatively insensitive to noxious

mechanical and thermal stimuli, although hollow viscera do generate

Peripheral nerve

Dorsal root

ganglion

Spinal

cord

Sympathetic

postganglionic

Aβ

Aδ

C

Sympathetic

preganglionic

FIGURE 13-1 Components of a typical cutaneous nerve. There are two distinct functional categories of axons: primary

afferents with cell bodies in the dorsal root ganglion and sympathetic postganglionic fibers with cell bodies in the

sympathetic ganglion. Primary afferents include those with large-diameter myelinated (Aβ), small-diameter myelinated

(Aδ), and unmyelinated (C) axons. All sympathetic postganglionic fibers are unmyelinated.

92PART 2 Cardinal Manifestations and Presentation of Diseases

significant discomfort when distended. In contrast, when affected by

a disease process with an inflammatory component, deep structures

such as joints or hollow viscera characteristically become exquisitely

sensitive to mechanical stimulation.

A large proportion of Aδ and C fiber afferents innervating viscera

are completely insensitive in normal noninjured, noninflamed tissue.

That is, they cannot be activated by known mechanical or thermal

stimuli and are not spontaneously active. However, in the presence of

inflammatory mediators, these afferents become sensitive to mechanical stimuli. Such afferents have been termed silent nociceptors, and

their characteristic properties may explain how, under pathologic

conditions, the relatively insensitive deep structures can become the

source of severe and debilitating pain and tenderness. Low pH, PGs,

leukotrienes, and other inflammatory mediators such as BK play a

significant role in sensitization.

Nociceptor-Induced Inflammation Primary afferent nociceptors are not simply passive messengers of threats to tissue injury but also

play an active role in tissue protection through a neuroeffector function. Most nociceptors contain polypeptide mediators, including substance P, calcitonin gene related peptide (CGRP), and cholecystokinin,

that are released from their peripheral terminals when they are activated (Fig. 13-2). Substance P is an 11-amino-acid peptide that is

released in peripheral tissues from primary afferent nociceptors and

has multiple biologic activities. It is a potent vasodilator, causes mast

cell degranulation, is a chemoattractant for leukocytes, and increases

the production and release of inflammatory mediators. Interestingly,

depletion of substance P from joints reduces the severity of experimental arthritis.

■ CENTRAL MECHANISMS

The Spinal Cord and Referred Pain The axons of primary

afferent nociceptors enter the spinal cord via the dorsal root. They

terminate in the dorsal horn of the spinal gray matter (Fig. 13-3).

The terminals of primary afferent axons contact spinal neurons that

transmit the pain signal to brain sites involved in pain perception.

When primary afferents are activated by noxious stimuli, they release

neurotransmitters from their terminals that excite the spinal cord neurons. The major neurotransmitter released is glutamate, which rapidly

excites the second-order dorsal horn neurons. Primary afferent nociceptor terminals also release substance P and CGRP, which produce a

slower and longer-lasting excitation of the dorsal horn neurons. The

axon of each primary afferent contacts many spinal neurons, and each

spinal neuron receives convergent inputs from many primary afferents.

The convergence of sensory inputs to a single spinal pain-transmission

neuron is of great importance because it underlies the phenomenon of

referred pain. All spinal neurons that receive input from the viscera

and deep musculoskeletal structures also receive input from the skin.

The convergence patterns are determined by the spinal segment of the

dorsal root ganglion that supplies the afferent innervation of a structure. For example, the afferents that supply the central diaphragm are

derived from the third and fourth cervical dorsal root ganglia. Primary

afferents with cell bodies in these same ganglia supply the skin of the

shoulder and lower neck. Thus, sensory inputs from both the shoulder

skin and the central diaphragm converge on pain-transmission neurons in the third and fourth cervical spinal segments. Because of this

convergence and the fact that the spinal neurons are most often activated

by inputs from the skin, activity evoked in spinal neurons by input from

deep structures is often mislocalized by the patient to a bodily location

that roughly corresponds with the region of skin innervated by the same

spinal segment. Thus, inflammation near the central diaphragm is

often reported as shoulder discomfort. This spatial displacement of

pain sensation from the site of the injury that produces it is known as

referred pain.

Ascending Pathways for Pain A majority of spinal neurons

contacted by primary afferent nociceptors send their axons to the contralateral thalamus. These axons form the contralateral spinothalamic

tract, which lies in the anterolateral white matter of the spinal cord,

the lateral edge of the medulla, and the lateral pons and midbrain.

The spinothalamic pathway is crucial for pain sensation in humans.

Interruption of this pathway produces permanent deficits in pain and

temperature discrimination.

Spinothalamic tract axons ascend to several regions of the thalamus.

There is tremendous divergence of the pain signal from these thalamic

sites to several distinct areas of the cerebral cortex that subserve different aspects of the pain experience (Fig. 13-4). One of the thalamic

projections is to the somatosensory cortex. This projection mediates

the sensory discriminative aspects of pain, i.e., its location, intensity,

and quality. Other thalamic neurons project to cortical regions that

are linked to emotional responses, such as the cingulate and insular

cortex. These pathways to the frontal cortex subserve the affective or

unpleasant emotional dimension of pain. This affective dimension of

pain produces suffering and exerts potent control of behavior. Because

of this dimension, fear is a constant companion of pain. As a consequence, injury or surgical lesions to areas of the frontal cortex activated

by painful stimuli can diminish the emotional impact of pain while

Primary activation

Secondary activation

A

B

Platelet

Mast cell

SP H

5HT

SP

BK

PG

K+

BK

H+

FIGURE 13-2 Events leading to activation, sensitization, and spread of sensitization

of primary afferent nociceptor terminals. A. Direct activation by intense pressure

and consequent cell damage. Cell damage induces lower pH (H+

) and leads to

release of potassium (K+

) and to synthesis of prostaglandins (PGs) and bradykinin

(BK). PGs increase the sensitivity of the terminal to BK and other pain-producing

substances. B. Secondary activation. Impulses generated in the stimulated terminal

propagate not only to the spinal cord but also into other terminal branches where

they induce the release of peptides, including substance P (SP). Substance P causes

vasodilation and neurogenic edema with further accumulation of BK. Substance P

also causes the release of histamine (H) from mast cells and serotonin (5HT) from

platelets.

 

Palliative and End-of-Life Care

85CHAPTER 12

caregivers should be identified through local sources or nationally

through groups such as the National Family Caregivers Association

(www.nfcacares.org), the American Cancer Society (www.cancer.org),

and the Alzheimer’s Association (www.alz.org).

■ EXISTENTIAL NEEDS AND THEIR MANAGEMENT

Frequency Religion and spirituality are often important to dying

patients. Nearly 70% of patients report becoming more religious or

spiritual when they became terminally ill, and many find comfort in

religious or spiritual practices such as prayer. However, ~20% of terminally ill patients become less religious, frequently feeling cheated or

betrayed by becoming terminally ill. For other patients, the need is for

existential meaning and purpose that is distinct from, and may even be

antithetical to, religion or spirituality. When asked, patients and family

caregivers frequently report wanting their professional caregivers to be

more attentive to religion and spirituality.

Assessment Health care providers are often hesitant about involving themselves in the religious, spiritual, and existential experiences

of their patients because it may seem private or not relevant to the

current illness. But physicians and other members of the care team

should be able at least to detect spiritual and existential needs. Screening questions have been developed for a physician’s spiritual history

taking. Spiritual distress can amplify other types of suffering and

even masquerade as intractable physical pain, anxiety, or depression.

The screening questions in the comprehensive assessment are usually

sufficient. Deeper evaluation and intervention are rarely appropriate

for the physician unless no other member of a care team is available

or suitable. Pastoral care providers may be helpful, whether from the

medical institution or from the patient’s own community.

Interventions Precisely how religious practices, spirituality, and

existential explorations can be facilitated and improve end-of-life care

is not well established. What is clear is that for physicians, one main

intervention is to inquire about the role and importance of spirituality and religion in a patient’s life. This will help a patient feel heard

and help physicians identify specific needs. In one study, only 36%

of respondents indicated that a clergy member would be comforting.

Nevertheless, the increase in religious and spiritual interest among a

substantial fraction of dying patients suggests inquiring of individual

patients how this need can be addressed. Some evidence supports specific methods of addressing existential needs in patients, ranging from

establishing a supportive group environment for terminal patients to

individual treatments emphasizing a patient’s dignity and sources of

meaning.

MANAGING THE LAST STAGES

■ PALLIATIVE CARE SERVICES: HOW AND WHERE

Determining the best approach to providing palliative care to patients

will depend on patient preferences, the availability of caregivers and

specialized services in close proximity, institutional resources, and

reimbursement. Hospice is a leading, but not the only, model of palliative care services. In the United States, slightly more than a third—

35.7%—of hospice care is provided in private residential homes with

14.5% of hospice care in nursing homes. In the United States, Medicare

pays for hospice services under Part A, the hospital insurance part

of reimbursement. Two physicians must certify that the patient has a

prognosis of ≤6 months if the disease runs its usual course. Prognoses

are probabilistic by their nature; patients are not required to die within

6 months but rather to have a condition from which half the individuals with it would not be alive within 6 months. Patients sign a hospice

enrollment form that states their intent to forgo curative services

related to their terminal illness but can still receive medical services

for other comorbid conditions. Patients also can withdraw enrollment

and reenroll later; the hospice Medicare benefit can be revoked later

to secure traditional Medicare benefits. Payments to the hospice are

per diem (or capitated), not fee-for-service. Payments are intended

to cover physician services for the medical direction of the care team;

regular home care visits by registered nurses and licensed practical

nurses; home health aide and homemaker services; chaplain services;

social work services; bereavement counseling; and medical equipment,

supplies, and medications. No specific therapy is excluded, and the goal

is for each therapy to be considered for its symptomatic (as opposed to

disease-modifying) effect. Additional clinical care, including services

of the primary physician, is covered by Medicare Part B even while the

hospice Medicare benefit is in place.

The Affordable Care Act directs the secretary of Health and Human

Services to gather data on Medicare hospice reimbursement with the

goal of reforming payment rates to account for resource use over an

entire episode of care. The legislation also requires additional evaluations and reviews of eligibility for hospice care by hospice physicians

or nurses. The Center for Medicare and Medicaid Innovation (CMMI)

sponsors and carries out demonstration projects to test models and

evaluate the potential of new methods. In 2016, CMMI started a 5-year

test of concurrent hospice and palliative care services with curative

treatment for terminally ill patients who have a life expectancy of

≤6 months. A 4-year test initiated in 2021 will examine the inclusion of

hospice in Medicare Advantage covering 8% of the market and include

important health plans.

By 2018, the average length of enrollment in a hospice for Medicare

beneficiaries was 90 days. However, the median length of stay was

just 18 days, suggesting most patients are in hospice for a short time.

Such short stays create barriers to establishing high-quality palliative

services in patients’ homes and also place financial strains on hospice

providers since the initial assessments are resource intensive. Physicians should initiate early referrals to the hospice to allow more time

for patients to receive palliative care.

In the United States, hospice care has been the main method for

securing palliative services for terminally ill patients. However, leading

physicians have increasingly emphasized the need to introduce palliative care much earlier in patients’ illness, and efforts are being made

to develop palliative care services that can be provided before the last

6 months of life and across a variety of settings. Studies of terminally

ill patients indicate that those who received in-home palliative care

delivered by an interdisciplinary team compared to usual care were

more satisfied, more likely to die at home, and had fewer visits to the

emergency room and lower per-day costs. More companies and home

health agencies are now offering nonhospice palliative care services

in patients’ homes in an effort to increase quality of life and forestall

emergency room visits and hospitalizations. Similarly, palliative care

services are increasingly available via consultation, rather than being

available only in hospital, day care, outpatient, and nursing home

settings. Palliative care consultations for nonhospice patients can be

billed as for other consultations under Medicare Part B. It is argued

that using palliative care earlier in patients’ illness allows patients and

family members to become more acculturated to avoiding life-sustaining treatments, facilitating a smoother transition to hospice care closer

to death.

■ WITHDRAWING AND WITHHOLDING

LIFE-SUSTAINING TREATMENT

Legal Aspects For centuries, it has been deemed ethical to withhold or withdraw life-sustaining interventions. The current legal consensus in the United States and most wealthy countries is that patients

have a moral as well as legal right to refuse medical interventions.

American courts also have held that incompetent patients have a right

to refuse medical interventions. For patients who are incompetent and

terminally ill and who have not completed an advance care directive,

next of kin can exercise that right, although this may be restricted in

some states, depending on how clear and convincing the evidence

is of the patient’s preferences. Courts have limited families’ ability to

terminate life-sustaining treatments in patients who are conscious and

incompetent but not terminally ill. In theory, patients’ right to refuse

medical therapy can be limited by four countervailing interests: (1)

preservation of life, (2) prevention of suicide, (3) protection of third

parties such as children, and (4) preservation of the integrity of the

86PART 1 The Profession of Medicine

medical profession. In practice, these interests almost never override

the right of competent patients and incompetent patients who have left

explicit wishes or advance care directives.

For incompetent patients who either appointed a proxy without

specific indications of their wishes or never completed an advance

care directive, three criteria have been suggested to guide the decision

to terminate medical interventions. First, some commentators suggest

that ordinary care should be administered but extraordinary care could

be terminated. Because the ordinary/extraordinary distinction is too

vague, courts and commentators widely agree that it should not be used

to justify decisions about stopping treatment. Second, many courts

have advocated the use of the substituted-judgment criterion, which

holds that the proxy decision-makers should try to imagine what the

incompetent patient would do if he or she were competent. However,

multiple studies indicate that many proxies, even close family members, cannot accurately predict what the patient would have wanted.

Therefore, substituted judgment becomes more of a guessing game

than a way of fulfilling the patient’s wishes. Finally, the best-interests

criterion holds that proxies should evaluate treatments by balancing

their benefits and risks and select those treatments where the benefits

maximally outweigh the burdens of treatment. Clinicians have a clear

and crucial role in this by carefully and dispassionately explaining the

known benefits and burdens of specific treatments. Yet even when that

information is as clear as possible, different individuals can have very

different views of what is in the patient’s best interests, and families

may have disagreements or even overt conflicts. This criterion has

been criticized because there is no single way to determine the balance

between benefits and burdens; it depends on a patient’s personal values. For instance, for some people, being alive even if mentally incapacitated is a benefit, whereas for others, it may be the worst possible

existence. As a matter of practice, physicians rely on family members to

make decisions that they feel are best and object only if those decisions

seem to demand treatments that the physicians consider not beneficial.

Practices Withholding and withdrawing acutely life-sustaining

medical interventions from terminally ill patients are now standard

practice. More than 90% of American patients die without cardiopulmonary resuscitation (CPR), and just as many forgo other potentially

life-sustaining interventions. For instance, in ICUs in the period of

1987–1988, CPR was performed 49% of the time, but it was performed

only 10% of the time in 1992–1993 and on just 1.8% of admissions

from 2001 to 2008. On average, 3.8 interventions, such as vasopressors

and transfusions, were stopped for each dying ICU patient. However,

up to 19% of decedents in hospitals received interventions such as

extubation, ventilation, and surgery in the 48 h preceding death. There

is wide variation in practices among hospitals and ICUs, suggesting

an important element of physician preferences rather than consistent

adherence to professional society recommendations.

Mechanical ventilation may be the most challenging intervention

to withdraw. The two approaches are terminal extubation, which is

the removal of the endotracheal tube, and terminal weaning, which

is the gradual reduction of the fraction of inspired oxygen (FIO2

) or

ventilator rate. One-third of ICU physicians prefer to use the terminal

weaning technique, and 13% extubate; the majority of physicians utilize

both techniques. The American Thoracic Society’s 2008 clinical policy

guidelines note that there is no single correct process of ventilator

withdrawal and that physicians use and should be proficient in both

methods but that the chosen approach should carefully balance benefits and burdens as well as patient and caregiver preferences. Some

recommend terminal weaning because patients do not develop upper

airway obstruction and the distress caused by secretions or stridor;

however, terminal weaning can prolong the dying process and not

allow a patient’s family to be with the patient unencumbered by an

endotracheal tube. To ensure comfort for conscious or semiconscious

patients before withdrawal of the ventilator, neuromuscular blocking

agents should be terminated and sedatives and analgesics administered.

Removing the neuromuscular blocking agents permits patients to show

discomfort, facilitating the titration of sedatives and analgesics; it also

permits interactions between patients and their families. A common

practice is to inject a bolus of midazolam (2–4 mg) or lorazepam

(2–4 mg) before withdrawal, followed by a bolus of 5–10 mg of morphine and continuous infusion of morphine (50% of the bolus dose per

hour) during weaning. In patients who have significant upper airway

secretions, IV scopolamine at a rate of 100 μg/h can be administered.

Additional boluses of morphine or increases in the infusion rate should

be administered for respiratory distress or signs of pain. Higher doses

will be needed for patients already receiving sedatives and opioids.

The median time to death after stopping of the ventilator is 1 h.

However, up to 10% of patients unexpectedly survive for 1 day or more

after mechanical ventilation is stopped. Women and older patients

tend to survive longer after extubation. Families need to be reassured

about both the continuations of treatments for common symptoms,

such as dyspnea and agitation, after withdrawal of ventilatory support

and the uncertainty of length of survival after withdrawal of ventilatory

support.

■ FUTILE CARE

Beginning in the late 1980s, some commentators argued that physicians could terminate futile treatments demanded by the families of

terminally ill patients. Although no objective definition or standard

of futility exists, several categories have been proposed. Physiologic

futility means that an intervention will have no physiologic effect.

Some have defined qualitative futility as applying to procedures that

“fail to end a patient’s total dependence on intensive medical care.”

Quantitative futility occurs “when physicians conclude (through personal experience, experiences shared with colleagues, or consideration

of reported empiric data) that in the last 100 cases, a medical treatment

has been useless.” The term conceals subjective value judgments about

when a treatment is “not beneficial.” Deciding whether a treatment that

obtains an additional 6 weeks of life or a 1% survival advantage confers benefit depends on patients’ preferences and goals. Furthermore,

physicians’ predictions of when treatments are futile deviate markedly

from the quantitative definition. When residents thought CPR was

quantitatively futile, more than one in five patients had a >10% chance

of survival to hospital discharge. Most studies that purport to guide

determinations of futility are based on insufficient data and therefore

cannot provide statistical confidence for clinical decision-making.

Quantitative futility rarely applies in ICU settings.

Many commentators reject using futility as a criterion for withdrawing care, preferring instead to consider futility situations as ones that

represent conflict that calls for careful negotiation between families

and health care providers. The American Medical Association and

other professional societies have developed process-based approaches

to resolving cases clinicians feel are futile. These process-based measures mainly suggest involving consultants and/or ethics committees

when there are seemingly irresolvable differences. Some hospitals have

enacted “unilateral do-not-resuscitate” policies to allow clinicians to

provide a do-not-resuscitate order in cases in which consensus cannot

be reached with families and medical opinion is that resuscitation

would be futile if attempted. This type of a policy is not a replacement

for careful and patient communication and negotiation but recognizes

that agreement cannot always be reached.

In 1999, Texas enacted the so-called Futile Care Act. Other states,

such as Virginia, Maryland, and California, have also enacted such

laws that provide physicians a “safe harbor” from liability if they

refuse a patient’s or family’s request for life-sustaining interventions.

For instance, in Texas, when a disagreement about terminating

interventions between the medical team and the family has not been

resolved by an ethics consultation, the physician is tasked with trying

to facilitate transfer of the patient to an institution willing to provide

treatment. If this fails after 10 days, the hospital and physician may unilaterally withdraw treatments determined to be futile. The family may

appeal to a state court. Early data suggest that the law increases futility

consultations for the ethics committee and that, although most families

concur with withdrawal, ~10–15% of families refuse to withdraw treatment. As of 2007, there had been 974 ethics committee consultations

on medical futility cases and 65 in which committees ruled against

families and gave notice that treatment would be terminated. In 2007,

Palliative and End-of-Life Care

87CHAPTER 12

a survey of Texas hospitals showed that 30% of hospitals had used the

futility law in 213 adult cases and 42 pediatric cases. Treatment was

withdrawn for 27 of those patients, and the remainder were transferred

to other facilities or died while awaiting transfer.

■ EUTHANASIA AND PHYSICIAN-ASSISTED SUICIDE

Euthanasia and PAS are defined in Table 12-8. Terminating lifesustaining care and providing opioid medications to manage symptoms

such as pain or dyspnea have long been considered ethical by the medical profession and legal by courts and should not be conflated with

euthanasia or PAS.

Legal Aspects Euthanasia and PAS are legal in the Netherlands,

Belgium, Luxembourg, Colombia, Canada, Spain, Western Australia,

and New Zealand. Euthanasia was legalized in the Northern Territory

of Australia in 1996, but that legislation was repealed 9 months

later in 1997. Under certain conditions, a layperson in Switzerland or

Germany can legally elect assisted suicide. In the United States, PAS is

legal in Washington, D.C., and 10 states: Oregon, Washington State,

Montana, Vermont, California, Colorado, Hawaii, Maine, New Jersey,

and New Mexico. No state in the United States has legalized euthanasia.

In the United States, multiple criteria must be met for PAS: the patient

must have a terminal condition of <6 months and must be determined

eligible through a process that includes a 15-day waiting period. In

2009, the state supreme court of Montana ruled that state law permits

PAS for terminally ill patients. Many other countries, such as Portugal,

are actively debating the legalization of euthanasia and/or PAS.

Practices Fewer than 10–20% of terminally ill patients actually

consider euthanasia and/or PAS for themselves. Use of euthanasia and

PAS is increasing but remains relatively rare. In all countries, even the

Netherlands and Belgium where these practices have been tolerated

and legal for many years, <5% of death occur by euthanasia or PAS. As

of the most recent data, 4.7% of all deaths were by euthanasia or PAS

in the Netherlands (2015) and 4.6% in Belgium (2013). Just 0.50% of all

deaths in Oregon in 2019 (188 of 37,397 deaths) and 0.36% of all deaths

in Washington State in 2018 (203 of 56,913 deaths) were reported to be

by PAS, although these may be underestimates since the cause of some

deaths of patients who received medications could not be verified.

In Belgium, the Netherlands, Oregon, and Washington, >70% of

patients utilizing these interventions are dying of cancer; <10% of

deaths by euthanasia or PAS involve patients with AIDS or amyotrophic

TABLE 12-8 Definitions of Physician-Assisted Suicide and Euthanasia

TERM DEFINITION LEGAL STATUS

Voluntary active

euthanasia

Intentionally administering

medications or other

interventions to cause the

patient’s death with the patient’s

informed consent

Netherlands, Belgium,

Luxembourg, Canada,

Colombia, Spain,

Western Australia, New

Zealand

Involuntary

active

euthanasia

Intentionally administering

medications or other

interventions to cause the

patient’s death when the patient

was competent to consent but

did not—e.g., the patient may not

have been asked

Nowhere

Passive

euthanasia

Withholding or withdrawing lifesustaining medical treatments

from a patient to let him or her

die (terminating life-sustaining

treatments)

Everywhere

Physicianassisted suicide

A physician provides medications

or other interventions to a patient

with the understanding that the

patient can use them to commit

suicide

Netherlands, Belgium,

Luxembourg, Canada,

Colombia, Germany,

Switzerland, Oregon,

Washington, Montana,

Vermont, California,

Colorado, District of

Columbia, Hawaii, Maine,

New Jersey, New Mexico

lateral sclerosis. While the numbers are small, in the Netherlands, the

numbers of euthanasia or PAS cases in patients with psychiatric disorders, dementia, and the accumulation of health issues are increasing.

Pain is not the primary motivator for patients’ requests for or interest in euthanasia and/or PAS. Among the first patients to receive PAS

in Oregon, only 1 of the 15 patients had inadequate pain control, compared with 15 of the 43 patients in a control group who experienced

inadequate pain relief. About 33% of patients in Oregon seeking PAS

currently cite pain or fear of pain as their main reason for doing so.

Conversely, depression and hopelessness are strongly associated with

patient interest in euthanasia and PAS. Concerns about loss of dignity

or autonomy or being a burden on family members appear to be more

important factors motivating a desire for euthanasia or PAS. Losing

autonomy (87% Oregon [OR], 85% Washington [WA]), not being able

to enjoy activities (90% OR, 84% WA), and fear of losing dignity (72%

OR, 69% WA) are the most-cited end-of-life concerns in both states.

A high percentage of patients seeking PAS note being a burden on

family (59% OR, 51% WA). A study from the Netherlands showed that

depressed terminally ill cancer patients were four times more likely

to request euthanasia and confirmed that uncontrolled pain was not

associated with greater interest in euthanasia.

Euthanasia and PAS are no guarantee of a painless, quick death.

Data from the Netherlands indicate that in as many as 20% of euthanasia and PAS cases technical and other problems arose, including

patients waking from coma, not becoming comatose, regurgitating

medications, and experiencing a prolonged time to death. Data from

Oregon between 1998 and 2017 and Washington between 2009 and

2017 indicate that of patients who received PAS prescriptions, 81%

died at home and prescribers were present in 9.7% of cases. The time

between drug intake and coma ranged from 1 min to 11 h, and the time

from drug intake to death ranged from 1 min to 104 h. The median

time from ingestion to coma was 5 min and from ingestion to death

was 25 min. In Oregon between 1998 and 2015, 53% of patients had no

complications, 44% of patients had no data on complications, and 2.4%

of patients had regurgitation after taking the prescribed medicine as

the only complication. In addition, six patients awakened. In Washington

State between 2014 and 2015, 1.4% of patients had regurgitation, one

patient had a seizure, and the reported range of time to death extended

to 30 h. In the Netherlands, problems were significantly more common

in PAS, sometimes requiring the physician to intervene and provide

euthanasia.

Regardless of whether they practice in a setting where euthanasia

is legal or not, many physicians over the course of their careers will

receive a patient request for euthanasia or PAS. In the United States,

18% of physicians have received a request for PAS and 11% have

received a request for euthanasia. Three percent complied with a

request for PAS, while 5% complied with a request for euthanasia. In

the Netherlands, where the practices are legal, 77% of physicians have

received a request for PAS or euthanasia and 60% have performed these

interventions.

Competency in dealing with such a request is crucial. Although

challenging, the request can also provide a chance to address intense

suffering. After receiving a request for euthanasia and/or PAS, health

care providers should carefully clarify the request with empathic, openended questions to help elucidate the underlying cause for the request,

such as, “What makes you want to consider this option?” Endorsing

either moral opposition or moral support for the act tends to be counterproductive, giving an impression of being judgmental or of endorsing the idea that the patient’s life is worthless. Health care providers

must reassure the patient of continued care and commitment. The

patient should be educated about alternative, less laden options, such

as symptom management and withdrawing any unwanted treatments,

and the reality of euthanasia and/or PAS, since the patient may have

misconceptions about their effectiveness as well as the legal implications of the choice. Depression, hopelessness, and other symptoms of

psychological distress, as well as physical suffering and economic burdens, are likely factors motivating the request, and such factors should

be assessed and treated aggressively. After these interventions and

clarification of options, most patients proceed with another approach,

 

Palliative and End-of-Life Care

83CHAPTER 12

fluoxetine is 10 mg once a day. In most cases, once-a-day dosing is

possible. The choice of which SSRI to use should be driven by (1) the

patient’s past success or failure with the specific medication and (2) the

most favorable side effect profile for that specific agent. For instance,

for a patient in whom fatigue is a major symptom, a more activating

SSRI (fluoxetine) would be appropriate. For a patient in whom anxiety

and sleeplessness are major symptoms, a more sedating SSRI (paroxetine) would be appropriate. Importantly, it can take up to 4 weeks for

these drugs to have an effect.

Atypical antidepressants are recommended only in select circumstances, usually with the assistance of a specialty consultation.

Trazodone can be an effective antidepressant but is sedating and can

cause orthostatic hypotension and, occasionally, priapism. Therefore,

it should be used before bed and only when a sedating effect is desired

and is often used for patients with insomnia at a dose starting at 25 mg.

Bupropion can also be used. In addition to its antidepressant effects,

bupropion is energizing, making it useful for depressed patients who

experience fatigue. However, it can cause seizures, preventing its use

for patients with a risk of CNS neoplasms or terminal delirium. Finally,

alprazolam, a benzodiazepine, starting at 0.25–1.0 mg tid, can be effective in seriously ill patients who have a combination of anxiety and

depression. Although it is potent and works quickly, it has many drug

interactions and may cause delirium, especially among very ill patients,

because of its strong binding to the benzodiazepine–γ-aminobutyric

acid (GABA) receptor complex.

Unless used as adjuvants for the treatment of pain, tricyclic antidepressants are not recommended. While they can be effective, their

therapeutic window and serious side effects typically limit their utility.

Similarly, monoamine oxidase (MAO) inhibitors are not recommended because of their side effects and dangerous drug interactions.

Delirium (See Chap. 27) • FREQUENCY In the weeks or months

before death, delirium is uncommon, although it may be significantly

underdiagnosed. However, delirium becomes relatively common in the

days and hours immediately before death. Up to 85% of patients dying

from cancer may experience terminal delirium.

ETIOLOGY Delirium is a global cerebral dysfunction characterized by

alterations in cognition and consciousness. It is frequently preceded

by anxiety, changes in sleep patterns (especially reversal of day and

night), and decreased attention. In contrast to dementia, delirium has

an acute onset, is characterized by fluctuating consciousness and inattention, and is reversible, although reversibility may be more theoretical than real for patients near death. Delirium may occur in a patient

with dementia; indeed, patients with dementia are more vulnerable to

delirium.

Causes of delirium include metabolic encephalopathy arising from

liver or renal failure, hypoxemia, or infection; electrolyte imbalances

such as hypercalcemia; paraneoplastic syndromes; dehydration; and

primary brain tumors, brain metastases, or leptomeningeal spread of

tumor. Among dying patients, delirium is commonly caused by side

effects of treatments, including radiation for brain metastases and

medications, such as opioids, glucocorticoids, anticholinergic drugs,

antihistamines, antiemetics, benzodiazepines, and chemotherapeutic

agents. The etiology may be multifactorial; e.g., dehydration may exacerbate opioid-induced delirium.

ASSESSMENT Delirium should be recognized in any terminally ill

patient exhibiting new onset of disorientation, impaired cognition,

somnolence, fluctuating levels of consciousness, or delusions with or

without agitation. Delirium must be distinguished from acute anxiety,

depression, and dementia. The central distinguishing feature is altered

consciousness, which usually is not noted in anxiety, depression, or

dementia. Although “hyperactive” delirium, characterized by overt

confusion and agitation, is probably more common, patients should

also be assessed for “hypoactive” delirium, which is characterized by

sleep-wake reversal and decreased alertness.

In some cases, use of formal assessment tools such as the MiniMental Status Examination (which does not distinguish delirium from

dementia) and the Delirium Rating Scale (which does distinguish

delirium from dementia) may be helpful in distinguishing delirium

from other processes. The patient’s list of medications must be evaluated carefully. Nonetheless, a reversible etiologic factor for delirium is

found in fewer than half of all terminally ill patients. Given that most

terminally ill patients experiencing delirium are very close to death and

often at home, extensive diagnostic evaluations such as lumbar punctures and neuroradiologic examinations are inappropriate.

INTERVENTIONS One of the most important objectives of terminal

care is to provide terminally ill patients the lucidity to say goodbye to

the people they love. Delirium, especially when in combination with

agitation during the final days, is distressing to family and caregivers. A

strong determinant of bereavement difficulties is witnessing a difficult

death. Thus, terminal delirium should be treated aggressively.

At the first sign of delirium, such as day-night reversal with slight

changes in mentation, the physician should let the family members

know that it is time to be sure that everything they want to say has

been said. The family should be informed that delirium is common

just before death.

If medications are suspected of being a cause of the delirium, unnecessary agents should be discontinued. Other potentially reversible

causes, such as constipation, urinary retention, and metabolic abnormalities, should be treated. Supportive measures aimed at providing a

familiar environment should be instituted, including restricting visits

only to individuals with whom the patient is familiar and eliminating

new experiences; orienting the patient, if possible, by providing a clock

and calendar; and gently correcting the patient’s hallucinations or cognitive mistakes.

Pharmacologic management focuses on the use of neuroleptics and,

in extreme cases, anesthetics (Table 12-7). Haloperidol remains the

first-line therapy. Usually, patients can be controlled with a low dose

(1–3 mg/d), given every 6 h, although some may require as much as

20 mg/d. Haloperidol can be administered PO, SC, or IV. IM injections should not be used, except when this is the only way to address

a patient’s delirium. Olanzapine, an atypical neuroleptic, has shown

significant effectiveness in completely resolving delirium in cancer

patients. It also has other beneficial effects for terminally ill patients,

including antinausea, antianxiety, and weight gain. Olanzapine is

useful for patients with longer anticipated life expectancies because

it is less likely to cause dysphoria and has a lower risk of dystonic

reactions. Additionally, because olanzapine is metabolized through

multiple pathways, it can be used in patients with hepatic and renal

dysfunction. Olanzapine has the disadvantage that it is only available

orally and takes a week to reach steady state. The usual dose is 2.5–5 mg

PO bid. Chlorpromazine (10–25 mg every 4–6 h) can be useful if

sedation is desired and can be administered IV or PR in addition to

PO. Dystonic reactions resulting from dopamine blockade are a side

effect of neuroleptics, although they are reported to be rare when these

drugs are used to treat terminal delirium. If patients develop dystonic

reactions, benztropine should be administered. Neuroleptics may be

TABLE 12-7 Medications for the Management of Delirium

INTERVENTIONS DOSE

Neuroleptics

Haloperidol 0.5–5 mg q2–12h, PO/IV/SC/IM

Thioridazine 10–75 mg q4–8h, PO

Chlorpromazine 12.5–50 mg q4–12h, PO/IV/IM

Atypical neuroleptics

Olanzapine 2.5–5 mg qd or bid, PO

Risperidone 1–3 mg q12h, PO

Anxiolytics

Lorazepam 0.5–2 mg q1–4h, PO/IV/IM

Midazolam 1–5 mg/h continuous infusion, IV/SC

Anesthetics

Propofol 0.3–2.0 mg/h continuous infusion, IV

84PART 1 The Profession of Medicine

combined with lorazepam to reduce agitation when the delirium is the

result of alcohol or sedative withdrawal.

If no response to first-line therapy is observed, a specialty consultation should be obtained with a goal to change to a different medication.

If the patient fails to improve after a second neuroleptic, sedation with

either an anesthetic such as propofol or continuous-infusion midazolam may be necessary. By some estimates, as many as 25% of patients

at the very end of life who experience delirium, especially restless delirium with myoclonus or convulsions, may require sedation.

Physical restraints should be used with great reluctance and only when

patients’ violence is threatening to themselves or others. If restraints are

used, their appropriateness should be frequently reevaluated.

Insomnia • FREQUENCY Sleep disorders, defined as difficulty

initiating sleep or maintaining sleep, sleep difficulty at least 3 nights a

week, or sleep difficulty that causes impairment of daytime functioning, occurs in 19–63% of patients with advanced cancer. Some 30–74%

of patients with other end-stage conditions, including AIDS, heart

disease, COPD, and renal disease, experience insomnia.

ETIOLOGY Patients with cancer may experience changes in sleep efficiency, such as an increase in stage I sleep. Insomnia may also coexist

with both physical illnesses, like thyroid disease, and psychological illnesses, like depression and anxiety. Medications, including antidepressants, psychostimulants, glucocorticoids, and β agonists, are significant

contributors to sleep disorders, as are caffeine and alcohol. Multiple

over-the-counter medications contain caffeine and antihistamines,

which can contribute to sleep disorders.

ASSESSMENT Assessments should include specific questions concerning sleep onset, sleep maintenance, and early-morning wakening, as

these will provide clues to both the causative agents and management

of insomnia. Patients should be asked about previous sleep problems,

screened for depression and anxiety, and asked about symptoms of

thyroid disease. Caffeine and alcohol are prominent causes of sleep

problems, and a careful history of the use of these substances should

be obtained. Both excessive use and withdrawal from alcohol can be

causes of sleep problems.

INTERVENTIONS The mainstays of any intervention include improvement of sleep hygiene (encouragement of regular time for sleep,

decreased nighttime distractions, elimination of caffeine and other

stimulants and alcohol), interventions to treat anxiety and depression,

and treatment for the insomnia itself. For patients with depression who

have insomnia and anxiety, a sedating antidepressant such as mirtazapine can be helpful. In the elderly, trazodone, beginning at 25 mg at

nighttime, is an effective sleep aid at doses lower than those that cause

its antidepressant effect. Zolpidem may have a decreased incidence

of delirium in patients compared with traditional benzodiazepines,

but this has not been clearly established. When benzodiazepines are

prescribed, short-acting ones (such as lorazepam) are favored over longeracting ones (such as diazepam). Patients who receive these medications

should be observed for signs of increased confusion and delirium.

■ SOCIAL NEEDS AND THEIR MANAGEMENT

Financial Burdens • FREQUENCY Dying can impose substantial

economic strains on patients and families, potentially causing distress.

This is known as financial toxicity. In the United States, which has the

least comprehensive health insurance systems among wealthy countries, a quarter of families coping with end-stage cancer report that care

was a major financial burden and a third used up most of their savings. Among Medicare beneficiaries, average out-of-pocket costs were

>$8000. Between 10% and 30% of families are forced to sell assets, use

savings, or take out a mortgage to pay for the patient’s health care costs.

The patient is likely to reduce hours worked and eventually stop

working altogether. In 20% of cases, a family member of the terminally

ill patient also must stop working to provide care. The major underlying causes of economic burden are related to poor physical functioning and care needs, such as the need for housekeeping, nursing, and

personal care. More debilitated patients and poor patients experience

greater economic burdens.

INTERVENTION The economic burden of end-of-life care should

not be ignored as a private matter. It has been associated with a

number of adverse health outcomes, including preferring comfort

care over life-prolonging care, as well as consideration of euthanasia

or physician-assisted suicide (PAS). Economic burdens increase the

psychological distress of the families and caregivers of terminally ill

patients, and poverty is associated with many adverse health outcomes.

Importantly, studies have found that “patients with advanced cancer

who reported having end-of-life conversations with physicians had significantly lower health care costs in their final week of life. Higher costs

were associated with worse quality of death.” Assistance from a social

worker, early on if possible, to ensure access to all available benefits

may be helpful. Many patients, families, and health care providers are

unaware of options for long-term care insurance, respite care, the Family Medical Leave Act (FMLA), and other sources of assistance. Some

of these options (such as respite care) may be part of a formal hospice

program, but others (such as the FMLA) do not require enrollment in

a hospice program.

Relationships • FREQUENCY Settling personal issues and closing

the narrative of lived relationships are universal needs. When asked if

sudden death or death after an illness is preferable, respondents often

initially select the former, but soon change to the latter as they reflect

on the importance of saying goodbye. Bereaved family members who

have not had the chance to say goodbye often have a more difficult

grief process.

INTERVENTIONS Care of seriously ill patients requires efforts to facilitate the types of encounters and time spent with family and friends

that are necessary to meet those needs. Family and close friends may

need to be accommodated in hospitals and other facilities with unrestricted visiting hours, which may include sleeping near the patient,

even in otherwise regimented institutional settings. Physicians and

other health care providers may be able to facilitate and resolve strained

interactions between the patient and other family members. Assistance

for patients and family members who are unsure about how to create

or help preserve memories, whether by providing materials such as a

scrapbook or memory box or by offering them suggestions and informational resources, can be deeply appreciated. Taking photographs and

creating videos can be especially helpful to terminally ill patients who

have younger children or grandchildren.

Family Caregivers • FREQUENCY Caring for seriously ill patients

places a heavy burden on families. Families are frequently required to

provide transportation and homemaking, as well as other services.

Typically, paid professionals, such as home health nurses and hospice

workers, supplement family care; only about a quarter of all caregiving

consists of exclusively paid professional assistance. Over the past 40

years, there has been a significant decline in the United States of deaths

occurring in hospitals, with a simultaneous increase in deaths in other

facilities and at home. Over a third of deaths occur in patients’ homes.

This increase in out-of-hospital deaths increases reliance on families

for end-of-life care. Increasingly, family members are being called upon

to provide physical care (such as moving and bathing patients) and

medical care (such as assessing symptoms and giving medications) in

addition to emotional care and support.

Three-quarters of family caregivers of terminally ill patients are

women—wives, daughters, sisters, and even daughters-in-law. Since

many are widowed, women tend to be able to rely less on family for

caregiving assistance and may need more paid assistance. About 20% of

terminally ill patients report substantial unmet needs for nursing and

personal care. The impact of caregiving on family caregivers is substantial: both bereaved and current caregivers have a higher mortality rate

than that of non-caregiving controls.

INTERVENTIONS It is imperative to inquire about unmet needs and

to try to ensure that those needs are met either through the family or

by paid professional services when possible. Community assistance

through houses of worship or other community groups often can be

mobilized by telephone calls from the medical team to someone the

patient or family identifies. Sources of support specifically for family