Pain: Pathophysiology and Management: Introduction

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

relieve suffering. Understanding pain is essential to both 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 tissue-damaging processes. Since different diseases
produce characteristic patterns of tissue damage, the quality, time
course, and location of a patient's pain complaint and the location of
tenderness provide important diagnostic clues and are used to
evaluate the response to treatment. Once this information is obtained,
it is the obligation of the physician to provide rapid and effective pain
relief.

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 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.

Aspirin, Acetaminophen, and Nonsteroidal AntiInflammatory Agents (NSAIDs)

These drugs are considered together because they are used for
similar problems and may have a similar mechanism of action (Table
12-1). 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.
Since 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 platelets and thereby interferes with
coagulation of the blood, gastrointestinal bleeding is a particular risk.
Increased age and history of gastrointestinal disease increase the risks
of aspirin and NSAIDs. In addition to NSAIDs' well-known
gastrointestinal toxicity, nephrotoxicity is a significant problem for
patients using them on a chronic basis, and patients at risk for renal
insufficiency should be monitored closely. NSAIDs also cause an
increase in blood pressure in a significant number of individuals.
Long-term treatment with NSAIDs requires regular blood pressure

monitoring and treatment if necessary. Although toxic to the liver

when taken in a high dose, acetaminophen rarely produces gastric
irritation and does not interfere with platelet function.
The introduction of a parenteral form of NSAID, ketorolac,
extends the usefulness of this class of compounds in the management
of acute severe pain. Ketorolac is sufficiently potent and rapid in
onset to supplant opioids for many patients with acute severe
headache and musculoskeletal pain.

Fever and Hyperthermia: Introduction

Body temperature is controlled by the hypothalamus. Neurons in
both the preoptic anterior hypothalamus and the posterior
hypothalamus receive two kinds of signals: one from peripheral
nerves that transmit information from warmth/cold receptors in the
skin and the other from the temperature of the blood bathing the
region. These two types of signals are integrated by the
thermoregulatory center of the hypothalamus to maintain normal
temperature. In a neutral temperature environment, the metabolic rate
of humans produces more heat than is necessary to maintain the core
body temperature at 37C.
A normal body temperature is ordinarily maintained, despite
environmental variations, because the hypothalamic thermoregulatory
center balances the excess heat production derived from metabolic
activity in muscle and the liver with heat dissipation from the skin
and lungs. According to studies of healthy individuals 1840 years of
age, the mean oral temperature is 36.8 0.4C (98.2 0.7F), with
low levels at 6 A.M. and higher levels at 46 P.M. The maximum
normal oral temperature is 37.2C (98.9F) at 6 A.M. and 37.7C
(99.9F) at 4 P.M.; these values define the 99th percentile for healthy
individuals. In light of these studies, an A.M. temperature of >37.2C
(>98.9F) or a P.M. temperature of >37.7C (>99.9F) would define
a fever. The normal daily temperature variation is typically 0.5C
(0.9F). However, in some individuals recovering from a febrile
illness, this daily variation can be as great as 1.0C. During a febrile
illness, the diurnal variation is usually maintained but at higher,

febrile levels. The daily temperature variation appears to be fixed in

early childhood; in contrast, elderly individuals can exhibit a reduced
ability to develop fever, with only a modest fever even in severe
infections.
Rectal temperatures are generally 0.4C (0.7F) higher than oral
readings. The lower oral readings are probably attributable to mouth
breathing, which is a factor in patients with respiratory infections and
rapid breathing. Lower-esophageal temperatures closely reflect core
temperature. Tympanic membrane (TM) thermometers measure
radiant heat from the tympanic membrane and nearby ear canal and
display that absolute value (unadjusted mode) or a value
automatically calculated from the absolute reading on the basis of
nomograms relating the radiant temperature measured to actual core
temperatures obtained in clinical studies (adjusted mode). These
measurements, although convenient, may be more variable than
directly determined oral or rectal values. Studies in adults show that
readings are lower with unadjusted-mode than with adjusted-mode
TM thermometers and that unadjusted-mode TM values are 0.8C
(1.6F) lower than rectal temperatures.
In women who menstruate, the A.M. temperature is generally
lower in the 2 weeks before ovulation; it then rises by ~0.6C (1F)
with ovulation and remains at that level until menses occur. Body
temperature can be elevated in the postprandial state. Pregnancy and
endocrinologic dysfunction also affect body temperature.

Pathophysiologic Basis of Peptic Ulcer Disease

PUD encompasses both gastric and duodenal ulcers. Ulcers are
defined as breaks in the mucosal surface >5 mm in size, with depth to
the submucosa. Duodenal ulcers (DUs) and gastric ulcers (GUs);
share many common features in terms of pathogenesis, diagnosis, and
treatment, but several factors distinguish them from one another.
Epidemiology
Duodenal Ulcers
DUs are estimated to occur in 615% of the Western population.
The incidence of DUs declined steadily from 1960 to 1980 and has
remained stable since then. The death rates, need for surgery, and
physician visits have decreased by >50% over the past 30 years. The
reason for the reduction in the frequency of DUs is likely related to
the decreasing frequency of Helicobacter pylori. Before the
discovery of H. pylori, the natural history of DUs was typified by
frequent recurrences after initial therapy. Eradication of H. pylori has
greatly reduced these recurrence rates.
Gastric Ulcers
GUs tend to occur later in life than duodenal lesions, with a peak
incidence reported in the sixth decade. More than half of GUs occur
in males and are less common than DUs, perhaps due to the higher
likelihood of GUs being silent and presenting only after a

complication develops. Autopsy studies suggest a similar incidence

of DUs and GUs.
Pathology
Duodenal Ulcers
DUs occur most often in the first portion of duodenum (>95%),
with ~90% located within 3 cm of the pylorus. They are usually 1 cm
in diameter but can occasionally reach 36 cm (giant ulcer). Ulcers
are sharply demarcated, with depth at times reaching the muscularis
propria. The base of the ulcer often consists of a zone of eosinophilic
necrosis with surrounding fibrosis. Malignant DUs are extremely
rare.
Gastric Ulcers
In contrast to DUs, GUs can represent a malignancy. Benign
GUs are most often found distal to the junction between the antrum
and the acid secretory mucosa. Benign GUs are quite rare in the
gastric fundus and are histologically similar to DUs. Benign GUs
associated with H. pylori are also associated with antral gastritis. In
contrast, NSAID-related GUs are not accompanied by chronic active
gastritis but may instead have evidence of a chemical gastropathy,
typified by foveolar hyperplasia, edema of the lamina propria and
epithelial regeneration in the absence of H. pylori. Extension of
smooth-muscle fibers into the upper portions of the mucosa, where
they are not typically found may also occur.

Pathophysiology
Duodenal Ulcers
H. pylori and NSAID-induced injury account for the majority of
DUs. Many acid secretory abnormalities have been described in DU
patients. Of these, average basal and nocturnal gastric acid secretion
appears to be increased in DU patients as compared to controls;
however, the level of overlap between DU patients and control
subjects is substantial. The reason for this altered secretory process is
unclear, but H. pylori infection may contribute. Accelerated gastric
emptying of liquids has been noted in some DU patients, but its role
in DU formation, if any, is unclear. Bicarbonate secretion is
significantly decreased in the duodenal bulb of patients with an active
DU as compared to control subjects. H. pylori infection may also
play a role in this process (see below).
Gastric Ulcers
As in DUs, the majority of GUs can be attributed to either H.
pylori or NSAID-induced mucosal damage. GUs that occur in the
prepyloric area or those in the body associated with a DU or a
duodenal scar are similar in pathogenesis to DUs. Gastric acid output
(basal and stimulated) tends to be normal or decreased in GU
patients. When GUs develop in the presence of minimal acid levels,
impairment of mucosal defense factors may be present.
Abnormalities in resting and stimulated pyloric sphincter
pressure with a concomitant increase in duodenal gastric reflux have

been implicated in some GU patients. Although bile acids,

lysolecithin, and pancreatic enzymes may injure gastric mucosa, a
definite role for these in GU pathogenesis has not been established.
Delayed gastric emptying of solids has been described in GU patients
but has not been reported consistently.
H. pylori and Acid Peptic Disorders
Gastric infection with the bacterium H. pylori accounts for the
majority of PUD. This organism also plays a role in the development
of gastric mucosal-associated lymphoid tissue (MALT) lymphoma
and gastric adenocarcinoma. Although the entire genome of H. pylori
has been sequenced, it is still not clear how this organism, which
resides in the stomach, causes ulceration in the duodenum, or whether
its eradication will lead to a decrease in gastric cancer.
The Bacterium
The bacterium, initially named Campylobacter pyloridis, is a
gram-negative microaerophilic rod found most commonly in the
deeper portions of the mucous gel coating the gastric mucosa or
between the mucous layer and the gastric epithelium. It may attach to
gastric epithelium but under normal circumstances does not appear to
invade cells. It is strategically designed to live within the aggressive
environment of the stomach. It is S-shaped (~0.5 x 3 m in size) and
contains multiple sheathed flagella. Initially, H. pylori resides in the
antrum but, over time, migrates toward the more proximal segments
of the stomach. The organism is capable of transforming into a
coccoid form, which represents a dormant state that may facilitate

survival in adverse conditions. The genome of H. pylori (1.65 million

base pairs) encodes ~1500 proteins. Among this multitude of proteins
there are factors that are essential determinants of H. pylorimediated
pathogenesis and colonization, such as the outer membrane protein
(Hop proteins), urease, and the vacuolating cytotoxin (Vac A).
Moreover, the majority of H. pylori strains contain a genomic
fragment that encodes the cag pathogenicity island (cag-PAI). Several
of the genes that make up cag-PAI encode components of a type IV
secretion island that translocates Cag A into host cells. Once in the
cell, Cag A activates a series of cellular events important in cell
growth and cytokine production. The first step in infection by H.
pylori is dependent on the bacteria's motility and its ability to produce
urease. Urease produces ammonia from urea, an essential step in
alkalinizing the surrounding pH. Additional bacterial factors include
catalase, lipase, adhesins, platelet-activating factor, and pic B
(induces cytokines). Multiple strains of H. pylori exist and are
characterized by their ability to express several of these factors (Cag
A, Vac A, etc.). It is possible that the different diseases related to H.
pylori infection can be attributed to different strains of the organism
with distinct pathogenic features.