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.