SECTION 1 Pain

CH AP T E R 11 of increased blood pressure, heart rate, pupil diameter, and plasma

cortisol levels. In addition, local muscle contraction (e.g., limb flex-
ion, abdominal wall rigidity) is often present.

CHAPTER 11
Pain: Pathophysiology 䡵 PERIPHERAL MECHANISMS

and Management The primary afferent nociceptor

A peripheral nerve consists of the axons of three different types of
neurons: primary sensory afferents, motor neurons, and sympa-
James P. Rathmell thetic postganglionic neurons (Fig. 11-1). The cell bodies of pri-
mary sensory afferents are located in the dorsal root ganglia in the
Howard L. Fields vertebral foramina. The primary afferent axon has two branches:

Pain: Pathophysiology and Management

one projects centrally into the spinal cord and the other projects
The task of medicine is to preserve and restore health and to relieve peripherally to innervate tissues. Primary afferents are classified by
suffering. Understanding pain is essential to both of these goals. their diameter, degree of myelination, and conduction velocity. The
Because pain is universally understood as a signal of disease, it is the largest-diameter afferent fibers, A-beta (Aβ), respond maximally
most common symptom that brings a patient to a physician’s atten- to light touch and/or moving stimuli; they are present primarily in
tion. The function of the pain sensory system is to protect the body nerves that innervate the skin. In normal individuals, the activity of
and maintain homeostasis. It does this by detecting, localizing, and these fibers does not produce pain. There are two other classes of
identifying potential or actual tissue-damaging processes. Because primary afferents: the small-diameter myelinated A-delta (Aδ) and
different diseases produce characteristic patterns of tissue damage, the unmyelinated (C fiber) axons (Fig. 11-1). These fibers are pres-
the quality, time course, and location of a patient’s pain complaint ent in nerves to the skin and to deep somatic and visceral structures.
provide important diagnostic clues. It is the physician’s responsibil- Some tissues, such as the cornea, are innervated only by Aδ and C
ity to provide rapid and effective pain relief. fiber afferents. Most Aδ and C fiber afferents respond maximally
only to intense (painful) stimuli and produce the subjective experi-
THE PAIN SENSORY SYSTEM ence of pain when they are electrically stimulated; this defines them
Pain is an unpleasant sensation localized to a part of the body. It as primary afferent nociceptors (pain receptors). The ability to detect
is often described in terms of a penetrating or tissue-destructive painful stimuli is completely abolished when conduction in Aδ and
process (e.g., stabbing, burning, twisting, tearing, squeezing) and/ C fiber axons is blocked.
or of a bodily or emotional reaction (e.g., terrifying, nauseating, Individual primary afferent nociceptors can respond to several
sickening). Furthermore, any pain of moderate or higher intensity different types of noxious stimuli. For example, most nociceptors
is accompanied by anxiety and the urge to escape or terminate the respond to heat; intense cold; intense mechanical stimuli, such as
feeling. These properties illustrate the duality of pain: it is both a pinch; changes in pH, particularly an acidic environment; and
sensation and emotion. When it is acute, pain is characteristically application of chemical irritants including adenosine triphosphate
associated with behavioral arousal and a stress response consisting (ATP), serotonin, bradykinin, and histamine.

Dorsal root
ganglion

Peripheral nerve
Spinal
cord

Aβ
Aδ
C
Sympathetic
Sympathetic preganglionic
postganglionic

Figure 11-1 Components of a typical cutaneous nerve. There are two bodies in the sympathetic ganglion. Primary afferents include those with
distinct functional categories of axons: primary afferents with cell bodies large-diameter myelinated (Aβ), small-diameter myelinated (Aδ), and unmy-
in the dorsal root ganglion, and sympathetic postganglionic fibers with cell elinated (C) axons. All sympathetic postganglionic fibers are unmyelinated.

93
 Sensitization A Primary activation
When intense, repeated, or prolonged stimuli are applied to dam-
aged or inflamed tissues, the threshold for activating primary affer-
ent nociceptors is lowered, and the frequency of firing is higher for
all stimulus intensities. Inflammatory mediators such as bradyki-
nin, nerve-growth factor, some prostaglandins, and leukotrienes K+
contribute to this process, which is called sensitization. Sensitization
occurs at the level of the peripheral nerve terminal (peripheral sen-
PG
sitization) as well as at the level of the dorsal horn of the spinal cord
(central sensitization). Peripheral sensitization occurs in damaged BK
or inflamed tissues, when inflammatory mediators activate intracel- H+
PART 2

lular 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
Cardinal Manifestations and Presentation of Diseases

horn of the spinal cord. Following injury and resultant sensitiza-

tion, normally innocuous stimuli can produce pain. Sensitization B Secondary activation
is a clinically important process that contributes to tenderness,
soreness, and hyperalgesia (increased pain intensity in response to
the same noxious stimulus; e.g. moderate pressure causes severe
pain). A striking example of sensitization is sunburned skin, in
which severe pain can be produced by a gentle slap on the back or
a warm shower.
Sensitization is of particular importance for pain and tenderness
Mast cell
in deep tissues. Viscera are normally relatively insensitive to nox-
ious mechanical and thermal stimuli, although hollow viscera do SP SP
H
generate 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 BK
5HT
become exquisitely sensitive to mechanical stimulation.
Platelet
A large proportion of Aδ and C fiber afferents innervating vis-
cera 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
Figure 11-2 Events leading to activation, sensitization, and spread
sensitive to mechanical stimuli. Such afferents have been termed
of sensitization of primary afferent nociceptor terminals. A. Direct
silent nociceptors, and their characteristic properties may explain
activation by intense pressure and consequent cell damage. Cell damage
how, under pathologic conditions, the relatively insensitive deep
induces lower pH (H+) and leads to release of potassium (K+) and to synthe-
structures can become the source of severe and debilitating pain
sis of prostaglandins (PG) and bradykinin (BK). Prostaglandins increase the
and tenderness. Low pH, prostaglandins, leukotrienes, and other
sensitivity of the terminal to bradykinin and other pain-producing substances.
inflammatory mediators such as bradykinin play a significant role
B. Secondary activation. Impulses generated in the stimulated terminal prop-
in sensitization.
agate not only to the spinal cord but also into other terminal branches where
Nociceptor-induced inflammation they induce the release of peptides, including substance P (SP). Substance
P causes vasodilation and neurogenic edema with further accumulation of
Primary afferent nociceptors also have a neuroeffector function.
bradykinin (BK). Substance P also causes the release of histamine (H) from
Most nociceptors contain polypeptide mediators that are released
mast cells and serotonin (5HT) from platelets.
from their peripheral terminals when they are activated (Fig. 11-2).
An example is substance P, an 11-amino-acid peptide. Substance P
is released from primary afferent nociceptors and has multiple bio-
logic activities. It is a potent vasodilator, degranulates mast cells, is
a chemoattractant for leukocytes, and increases the production and matter (Fig. 11-3). The terminals of primary afferent axons contact
release of inflammatory mediators. Interestingly, depletion of sub- spinal neurons that transmit the pain signal to brain sites involved
stance P from joints reduces the severity of experimental arthritis. in pain perception. When primary afferents are activated by nox-
Primary afferent nociceptors are not simply passive messengers of ious stimuli, they release neurotransmitters from their terminals
threats to tissue injury but also play an active role in tissue protec- that excite the spinal cord neurons. The major neurotransmitter
tion through these neuroeffector functions. released is glutamate, which rapidly excites dorsal horn neurons.
Primary afferent nociceptor terminals also release peptides, includ-
䡵 CENTRAL MECHANISMS ing substance P and calcitonin gene-related peptide, which produce
a slower and longer-lasting excitation of the dorsal horn neurons.
The spinal cord and referred pain The axon of each primary afferent contacts many spinal neurons,
The axons of primary afferent nociceptors enter the spinal cord via and each spinal neuron receives convergent inputs from many
the dorsal root. They terminate in the dorsal horn of the spinal gray primary afferents.

94
 Skin
A F B
C

SS
Thalamus
Hypothalamus

CHAPTER 11
Midbrain

Viscus Spinothalamic
Anterolateral
tract
tract axon
Medulla
Figure 11-3 The convergence-projection hypothesis of referred pain.
Injury
According to this hypothesis, visceral afferent nociceptors converge on the

Pain: Pathophysiology and Management

same pain-projection 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
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 Figure 11-4 Pain transmission and modulatory pathways.
from the viscera and deep musculoskeletal structures also receive A. Transmission system for nociceptive messages. Noxious stimuli activate
input from the skin. The convergence patterns are determined by the the sensitive peripheral ending of the primary afferent nociceptor by the
spinal segment of the dorsal root ganglion that supplies the afferent process of transduction. The message is then transmitted over the periph-
innervation of a structure. For example, the afferents that supply the eral nerve to the spinal cord, where it synapses with cells of origin of the
central diaphragm are derived from the third and fourth cervical major ascending pain pathway, the spinothalamic tract. The message is
dorsal root ganglia. Primary afferents with cell bodies in these same relayed in the thalamus to the anterior cingulate (C), frontal insular (F), and
ganglia supply the skin of the shoulder and lower neck. Thus, sen- somatosensory cortex (SS). B. Pain-modulation network. Inputs from frontal
sory inputs from both the shoulder skin and the central diaphragm cortex and hypothalamus activate cells in the midbrain that control spinal
converge on pain-transmission neurons in the third and fourth pain-transmission cells via cells in the medulla.
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 mis- of pain produces suffering and exerts potent control of behavior.
localized by the patient to a place that roughly corresponds with the Because of this dimension, fear is a constant companion of pain.
region of skin innervated by the same spinal segment. Thus, inflam- As a consequence, injury or surgical lesions to areas of the frontal
mation near the central diaphragm is usually reported as shoulder cortex activated by painful stimuli diminish the emotional impact
discomfort. This spatial displacement of pain sensation from the site of pain while largely preserving the individual’s ability to recognize
of the injury that produces it is known as referred pain. noxious stimuli as painful.

Ascending pathways for pain 䡵 PAIN MODULATION

A majority of spinal neurons contacted by primary afferent noci- The pain produced by injuries of similar magnitude is remarkably
ceptors send their axons to the contralateral thalamus. These variable in different situations and in different individuals. For
axons form the contralateral spinothalamic tract, which lies in the example, athletes have been known to sustain serious fractures
anterolateral white matter of the spinal cord, the lateral edge of the with only minor pain, and Beecher’s classic World War II survey
medulla, and the lateral pons and midbrain. The spinothalamic revealed that many soldiers in battle were unbothered by injuries
pathway is crucial for pain sensation in humans. Interruption of that would have produced agonizing pain in civilian patients.
this pathway produces permanent deficits in pain and temperature Furthermore, even the suggestion that a treatment will relieve pain
discrimination. can have a significant analgesic effect (the placebo effect). On the
Spinothalamic tract axons ascend to several regions of the thala- other hand, many patients find even minor injuries (such as veni-
mus. There is tremendous divergence of the pain signal from these puncture) frightening and unbearable, and the expectation of pain
thalamic sites to broad areas of the cerebral cortex that subserve can induce pain even without a noxious stimulus. The suggestion
different aspects of the pain experience (Fig. 11-4). One of the that pain will worsen following administration of an inert substance
thalamic projections is to the somatosensory cortex. This projec- can increase its perceived intensity (the nocebo effect).
tion mediates the purely sensory aspects of pain, i.e., its location, The powerful effect of expectation and other psychological vari-
intensity, and quality. Other thalamic neurons project to cortical ables on the perceived intensity of pain is explained by brain circuits
regions that are linked to emotional responses, such as the cingulate that modulate the activity of the pain-transmission pathways. One
gyrus and other areas of the frontal lobes, including the insular cor- of these circuits has links to the hypothalamus, midbrain, and
tex. These pathways to the frontal cortex subserve the affective or medulla, and it selectively controls spinal pain-transmission neurons
unpleasant emotional dimension of pain. This affective dimension through a descending pathway (Fig. 11-4).

95
 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
pain-transmission neurons can be activated by modulatory neu-
rons, 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 understand-
ing how psychological factors can contribute to chronic pain.
PART 2

䡵 NEUROPATHIC PAIN
Lesions of the peripheral or central nociceptive pathways typically
result in a loss or impairment of pain sensation. Paradoxically, dam-
age to or dysfunction of these pathways can also produce pain. For
example, damage to peripheral nerves, as occurs in diabetic neu-
ropathy, or to primary afferents, as in herpes zoster, can result in
Cardinal Manifestations and Presentation of Diseases

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
cerebrovascular injury to spinal cord, brainstem, or thalamic areas
that contain central nociceptive pathways. Such neuropathic pains
are often severe and are typically resistant to standard treatments
for pain.
Neuropathic pain typically has an unusual burning, tingling,
or electric shock–like quality and may be triggered by very light
touch. These features are rare in other types of pain. On examina-
tion, a sensory deficit is characteristically present in the area of the
patient’s pain. Hyperpathia, a greatly exaggerated pain sensation
to innocuous or mild nociceptive stimuli, 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
Figure 11-5 Functional magnetic resonance imaging (fMRI) demon- sensitized primary afferent nociceptors, damaged primary affer-
strates placebo-enhanced brain activity in anatomic regions correlating ents, including nociceptors, become highly sensitive to mechanical
with the opioidergic descending pain control system. Top panel, Frontal stimulation and may generate impulses in the absence of stimula-
fMRI image shows placebo-enhanced brain activity in the dorsal lateral tion. Increased sensitivity and spontaneous activity are due, in
prefrontal cortex (DLPFC). Bottom panel, Sagittal fMRI images show placebo- part, to an increased concentration of sodium channels. Damaged
enhanced responses in the rostral anterior cingulate cortex (rACC), the rostral primary afferents may also develop sensitivity to norepinephrine.
ventral medullae (RVM), the periaqueductal gray (PAG) area, and the hypothal- Interestingly, spinal cord pain-transmission neurons cut off from
amus. The placebo-enhanced activity in all areas was reduced by naloxone, their normal input may also become spontaneously active. Thus,
demonstrating the link between the descending opioidergic system and the both CNS and peripheral nervous system hyperactivity contribute
placebo analgesic response. (Adapted with permission from Eippert et al.) to neuropathic pain.

Human brain–imaging studies have implicated this pain- Sympathetically maintained pain
modulating circuit in the pain-relieving effect of attention, sug- Patients with peripheral nerve injury occasionally develop spon-
gestion, and opioid analgesic medications (Fig. 11-5). Furthermore, taneous pain in the region innervated by the nerve. This pain is
each of the component structures of the pathway contains opioid often described as having a burning quality. The pain typically
receptors and is sensitive to the direct application of opioid drugs. begins after a delay of hours to days or even weeks and is accom-
In animals, lesions of this descending modulatory system reduce the panied by swelling of the extremity, periarticular bone loss, and
analgesic effect of systemically administered opioids such as mor- arthritic changes in the distal joints. The pain may be relieved
phine. Along with the opioid receptor, the component nuclei of this by a local anesthetic block of the sympathetic innervation to the
pain-modulating circuit contain endogenous opioid peptides such affected extremity. Damaged primary afferent nociceptors acquire
as the enkephalins and β-endorphin. adrenergic sensitivity and can be activated by stimulation of the
The most reliable way to activate this endogenous opioid- sympathetic outflow. This constellation of spontaneous pain and
mediated modulating system is by suggestion of pain relief or by signs of sympathetic dysfunction following injury has been termed
intense emotion directed away from the pain-causing injury (e.g., complex regional pain syndrome (CRPS). When this occurs after
during severe threat or an athletic competition). In fact, pain-relieving an identifiable nerve injury, it is termed CRPS type II (also known
endogenous opioids are released following surgical procedures and as posttraumatic neuralgia or, if severe, causalgia). When a similar
in patients given a placebo for pain relief. clinical picture appears without obvious nerve injury, it is termed

96
CRPS type I (also known as reflex sympathetic dystrophy). CRPS can
COX-2–selective drugs have similar analgesic potency and pro-
be produced by a variety of injuries, including fractures of bone,
duce less gastric irritation than the nonselective COX inhibitors.
soft tissue trauma, myocardial infarction, and stroke (Chap. 375).
The use of COX-2–selective drugs does not appear to lower
CRPS type I typically resolves with symptomatic treatment; how-
the risk of nephrotoxicity compared to nonselective NSAIDs.
ever, when it persists, detailed examination often reveals evidence
On the other hand, COX-2–selective drugs offer a significant
of peripheral nerve injury. Although the pathophysiology of CRPS
benefit in the management of acute postoperative pain because
is poorly understood, the pain and the signs of inflammation, when
they do not affect blood coagulation. Nonselective COX inhibi-
acute, can be rapidly relieved by blocking the sympathetic nervous
tors are usually contraindicated postoperatively because they
system. This implies that sympathetic activity can activate undam-
impair platelet-mediated blood clotting and are thus associated
aged nociceptors when inflammation is present. Signs of sympa-
with increased bleeding at the operative site. COX-2 inhibitors,

CHAPTER 11
thetic hyperactivity should be sought in patients with posttraumatic
including celecoxib (Celebrex) are associated with increased
pain and inflammation and no other obvious explanation.
cardiovascular risk. It is possible that this is a class effect of
NSAIDs, excluding aspirin. These drugs are contraindicated in
TREATMENT Acute Pain patients in the immediate period after coronary artery bypass
surgery and should be used with caution in patients with a his-
tory of or significant risk factors for cardiovascular disease.
The ideal treatment for any pain is to remove the cause; thus,
while treatment can be initiated immediately, efforts to establish
OPIOID ANALGESICS Opioids are the most potent pain-relieving
the underlying etiology should always proceed as treatment

Pain: Pathophysiology and Management

drugs currently available. Of all analgesics, they have the broad-
begins. Sometimes, treating the underlying condition does not
est range of efficacy and provide the most reliable and effective
immediately relieve pain. Furthermore, some conditions are so
method for rapid pain relief. Although side effects are common,
painful that rapid and effective analgesia is essential (e.g., the
most are reversible: nausea, vomiting, pruritus, and constipation
postoperative state, burns, trauma, cancer, or sickle cell crisis).
are the most frequent and bothersome side effects. Respiratory
Analgesic medications are a first line of treatment in these cases,
depression is uncommon at standard analgesic doses, but can
and all practitioners should be familiar with their use.
be life-threatening. Opioid-related side effects can be reversed
ASPIRIN, ACETAMINOPHEN, AND NONSTEROIDAL ANTI- rapidly with the narcotic antagonist naloxone. The physician
INFLAMMATORY AGENTS (NSAIDS) These drugs are considered should not hesitate to use opioid analgesics in patients with
together because they are used for similar problems and may acute severe pain. Table 11-1 lists the most commonly used
have a similar mechanism of action (Table 11-1). All these opioid analgesics.
compounds inhibit cyclooxygenase (COX), and, except for Opioids produce analgesia by actions in the CNS. They activate
acetaminophen, all have anti-inflammatory actions, especially at pain-inhibitory neurons and directly inhibit pain-transmission
higher dosages. They are particularly effective for mild to mod- neurons. Most of the commercially available opioid analgesics
erate headache and for pain of musculoskeletal origin. act at the same opioid receptor (μ-receptor), differing mainly in
Because they are effective for these common types of pain potency, speed of onset, duration of action, and optimal route
and are available without prescription, COX inhibitors are by of administration. Some side effects are due to accumulation of
far the most commonly used analgesics. They are absorbed well nonopioid metabolites that are unique to individual drugs. One
from the gastrointestinal tract and, with occasional use, have striking example of this is normeperidine, a metabolite of mep-
only minimal side effects. With chronic use, gastric irritation is eridine. Normeperidine produces hyperexcitability and seizures
a common side effect of aspirin and NSAIDs and is the problem that are not reversible with naloxone. Normeperidine accumula-
that most frequently limits the dose that can be given. Gastric tion is increased in patients with renal failure.
irritation is most severe with aspirin, which may cause erosion The most rapid relief with opioids is obtained by intravenous
and ulceration of the gastric mucosa leading to bleeding or per- administration; relief with oral administration is significantly
foration. Because aspirin irreversibly acetylates platelet cycloox- slower. Common side effects include nausea, vomiting, consti-
ygenase and thereby interferes with coagulation of the blood, pation, and sedation. The most serious side effect is respiratory
gastrointestinal bleeding is a particular risk. Older age and his- depression. Patients with any form of respiratory compromise
tory of gastrointestinal disease increase the risks of aspirin and must be kept under close observation following opioid admin-
NSAIDs. In addition to the well-known gastrointestinal toxicity istration; an oxygen-saturation monitor may be useful. Opioid-
of NSAIDs, nephrotoxicity is a significant problem for patients induced respiratory depression is typically accompanied by
using these drugs on a chronic basis. Patients at risk for renal significant sedation and a reduction in respiratory rate. A fall
insufficiency, particularly those with significant contraction of in oxygen saturation represents a critical level of respiratory
their intravascular volume as occurs with chronic diuretic use depression and the need for immediate intervention to prevent
or acute hypovolemia, should be monitored closely. NSAIDs life-threatening hypoxemia. Ventilatory assistance should be
can also increase blood pressure in some individuals. Long- maintained until the opioid-induced respiratory depression
term treatment with NSAIDs requires regular blood pressure has resolved. The opioid antagonist naloxone should be readily
monitoring and treatment if necessary. Although toxic to the available whenever opioids are used at high doses or in patients
liver when taken in high doses, acetaminophen rarely produces with compromised pulmonary function. Opioid effects are dose-
gastric irritation and does not interfere with platelet function. related, and there is great variability among patients in the doses
The introduction of a parenteral form of NSAID, ketorolac, that relieve pain and produce side effects. Because of this, initia-
extends the usefulness of this class of compounds in the manage- tion of therapy requires titration to optimal dose and interval.
ment of acute severe pain. Ketorolac is sufficiently potent and The most important principle is to provide adequate pain relief.
rapid in onset to supplant opioids for many patients with acute This requires determining whether the drug has adequately
severe headache and musculoskeletal pain. relieved the pain and frequent reassessment to determine the
There are two major classes of COX: COX-1 is constitutively optimal interval for dosing. The most common error made by
expressed, and COX-2 is induced in the inflammatory state. physicians in managing severe pain with opioids is to prescribe

97
 TABLE 11-1 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 q 4–6 h Available without prescription
Naproxen 250–500 PO q 12 h Delayed effects may be due to long half-life
Fenoprofen 200 PO q 4–6 h Contraindicated in renal disease
PART 2

Indomethacin 25–50 PO q8h Gastrointestinal side effects common

Ketorolac 15–60 IM/IV q 4–6 h Available for parenteral use
Celecoxib 100–200 PO q 12–24 h Useful for arthritis
Valdecoxib 10–20 PO q12–24 h Removed from U.S. market in 2005
Generic Name Parenteral Dose, mg PO Dose, mg Comments
Cardinal Manifestations and Presentation of Diseases

Narcotic analgesics: usual doses and intervals

Codeine 30–60 q 4 h 30–60 q 4 h Nausea common
Oxycodone — 5–10 q 4–6 h Usually available with acetaminophen or aspirin
Morphine 5q4h 30 q 4 h
Morphine sustained release — 15–60 bid to tid Oral slow-release preparation
Hydromorphone 1–2 q 4 h 2–4 q 4 h Shorter acting than morphine sulfate
Levorphanol 2 q 6–8 h 4 q 6–8 h Longer acting than morphine sulfate; absorbed well PO
Methadone 5-10 q 6–8 h 5-20 q 6–8 h Delayed sedation due to long half-life; therapy should not be
initiated with greater than 40 mg/day and dose escalation should
be made no more frequently than every 3 days
Meperidine 50–100 q 3–4 h 300 q 4 h Poorly absorbed PO; normeperidine a toxic metabolite; routine
use of this agent is not recommended
Butorphanol — 1–2 q 4 h Intranasal spray
Fentanyl 25–100 µg/h — 72-h transdermal patch
Tramadol — 50–100 q 4–6 h Mixed opioid/adrenergic action
Uptake Blockade
Sedative Anticholinergic Orthostatic Cardiac Ave. Dose,
Generic Name 5-HT NE Potency Potency Hypotension Arrhythmia mg/d Range, mg/d
a
Antidepressants
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
Generic Name PO Dose, mg Interval Generic Name PO Dose, mg Interval
a
Anticonvulsants and antiarrhythmics
Phenytoin 300 daily/qhs Clonazepam 1 q6h
Carbamazepine 200–300 q6h Gabapentinb 600–1200 q8h
Oxcarbazepine 300 bid Pregabalin 150–600 bid
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.
Note: 5-HT, serotonin; NE, norepinephrine.

98
an inadequate dose. Because many patients are reluctant to act by binding to peripheral μ-receptors, thereby inhibiting or
complain, this practice leads to needless suffering. In the absence reversing the effects of opioids at these peripheral sites. The
of sedation at the expected time of peak effect, a physician action of both agents is restricted to receptor sites outside of the
should not hesitate to repeat the initial dose to achieve satisfac- CNS; thus, these drugs can reverse the adverse effects of opioid
tory pain relief. analgesics that are mediated through their peripheral recep-
An innovative approach to the problem of achieving adequate tors without reversing their analgesic effects. Both agents are
pain relief is the use of patient-controlled analgesia (PCA). effective for persistent ileus following abdominal surgery to the
PCA uses a microprocessor-controlled infusion device that can extent that opioid analgesics used for postoperative pain control
deliver a baseline continuous dose of an opioid drug as well as contribute to this serious problem. Likewise, both agents have
preprogrammed additional doses whenever the patient pushes been tested for their effectiveness in treating opioid-induced

CHAPTER 11
a button. The patient can then titrate the dose to the optimal bowel dysfunction (constipation) in patients taking opioid anal-
level. This approach is used most extensively for the manage- gesics on a chronic basis. Although contradictory, the weight of
ment of postoperative pain, but there is no reason why it should evidence indicates that alvimopan can reduce the incidence and
not be used for any hospitalized patient with persistent severe duration of ileus following major abdominal surgery and meth-
pain. PCA is also used for short-term home care of patients with ylnaltrexone can produce rapid reversal of constipation in many
intractable pain, such as that caused by metastatic cancer. patients receiving opioids on a chronic basis.
It is important to understand that the PCA device deliv-
Opioid and COX Inhibitor Combinations When used in com-
ers small, repeated doses to maintain pain relief; in patients
bination, opioids and COX inhibitors have additive effects.

Pain: Pathophysiology and Management

with severe pain, the pain must first be brought under control
Because a lower dose of each can be used to achieve the same
with a loading dose before transitioning to the PCA device.
degree of pain relief and their side effects are nonadditive, such
The bolus dose of the drug (typically 1 mg morphine, 0.2 mg
combinations are used to lower the severity of dose-related side
of hydromorphone, or 10 μg fentanyl) can then be delivered
effects. However, fixed-ratio combinations of an opioid with
repeatedly as needed. To prevent overdosing, PCA devices are
acetaminophen carry a special risk. Dose escalation as a result of
programmed with a lockout period after each demand dose is
increased severity of pain or decreased opioid effect as a result
delivered (5–10 min) and a limit on the total dose delivered per
of tolerance may lead to levels of acetaminophen that are toxic
hour. While some have advocated the use of a simultaneous
to the liver. Although acetaminophen-related hepatotoxicity is
continuous or basal infusion of the PCA drug, this increases
uncommon, it remains a leading cause for liver failure. Thus,
the risk of respiratory depression and has not been shown to
many practitioners have moved away from the use of opioid-
increase the overall efficacy of the technique.
acetaminophen combination analgesics to avoid the risk of
Many physicians, nurses, and patients have a certain trepida-
excessive acetaminophen exposure as the dose of the analgesic
tion about using opioids that is based on an exaggerated fear of
is escalated.
addiction. In fact, there is a vanishingly small chance of patients
becoming addicted to narcotics as a result of their appropriate
medical use. CHRONIC PAIN
The availability of new routes of administration has extended
Managing patients with chronic pain is intellectually and emotion-
the usefulness of opioid analgesics. Most important is the avail-
ally challenging. The patient’s problem is often difficult or impos-
ability of spinal administration. Opioids can be infused through
sible to diagnose with certainty; such patients are demanding of the
a spinal catheter placed either intrathecally or epidurally. By
physician’s time and often appear emotionally distraught. The tra-
applying opioids directly to the spinal or epidural space adjacent
ditional medical approach of seeking an obscure organic pathology
to the spinal cord, regional analgesia can be obtained using
is usually unhelpful. On the other hand, psychological evaluation
relatively low total doses. Indeed, the dose required to produce
and behaviorally based treatment paradigms are frequently helpful,
effective localized analgesia when using morphine intrathecally
particularly in the setting of a multidisciplinary pain-management
(0.1–0.3 mg) is a fraction of that required to produce similar
center. Unfortunately, this approach, while effective, remains
analgesia when administered intravenously (5–10 mg). In this
largely underused in current medical practice.
way, side effects such as sedation, nausea, and respiratory
There are several factors that can cause, perpetuate, or exacer-
depression can be minimized. This approach has been used
bate chronic pain. First, of course, the patient may simply have a
extensively in obstetric procedures and for postoperative pain
disease that is characteristically painful for which there is presently
relief following surgical procedures on the lower extremities.
no cure. Arthritis, cancer, chronic daily headaches, fibromyalgia,
Continuous intrathecal delivery via implanted spinal drug-
and diabetic neuropathy are examples of this. Second, there may
delivery systems is now commonly used, particularly for the
be secondary perpetuating factors that are initiated by disease and
treatment of cancer-related pain that would require sedating
persist after that disease has resolved. Examples include damaged
doses for adequate pain control if given systemically. Opioids
sensory nerves, sympathetic efferent activity, and painful reflex
can also be given intranasally (butorphanol), rectally, and trans-
muscle contraction. Finally, a variety of psychological conditions
dermally (fentanyl), thus avoiding the discomfort of frequent
can exacerbate or even cause pain.
injections in patients who cannot be given oral medication. The
There are certain areas to which special attention should be paid
fentanyl transdermal patch has the advantage of providing fairly
in a patient’s medical history. Because depression is the most com-
steady plasma levels, which maximizes patient comfort.
mon emotional disturbance in patients with chronic pain, patients
Recent additions to the armamentarium for treating opioid-
should be questioned about their mood, appetite, sleep patterns,
induced side effects are the peripherally acting opioid antago-
and daily activity. A simple standardized questionnaire, such as the
nists alvimopan (Entereg) and methylnaltrexone (Rellistor).
Beck Depression Inventory, can be a useful screening device. It is
Alvimopan is available as an orally administered agent that is
important to remember that major depression is a common, treat-
restricted to the intestinal lumen by limited absorption; meth-
able, and potentially fatal illness.
ylnaltrexone is available in a subcutaneously administered form
Other clues that a significant emotional disturbance is contribut-
that has virtually no penetration into the CNS. Both agents
ing to a patient’s chronic pain complaint include pain that occurs

99
 in multiple, unrelated sites; a pattern of recurrent, but separate, pain
problems beginning in childhood or adolescence; pain beginning at TABLE 11-2 Painful Conditions That Respond to
a time of emotional trauma, such as the loss of a parent or spouse; Tricyclic Antidepressants
a history of physical or sexual abuse; and past or present substance
abuse. Postherpetic neuralgiaa
On examination, special attention should be paid to whether the Diabetic neuropathya
patient guards the painful area and whether certain movements or Tension headachea
postures are avoided because of pain. Discovering a mechanical Migraine headachea
component to the pain can be useful both diagnostically and thera-
Rheumatoid arthritisa,b
peutically. Painful areas should be examined for deep tenderness,
noting whether this is localized to muscle, ligamentous structures, Chronic low back painb
or joints. Chronic myofascial pain is very common, and, in these Cancer
PART 2

patients, deep palpation may reveal highly localized trigger points Central post-stroke pain
that are firm bands or knots in muscle. Relief of the pain following
a
injection of local anesthetic into these trigger points supports the Controlled trials demonstrate analgesia.
b
Controlled studies indicate benefit but not analgesia.
diagnosis. A neuropathic component to the pain is indicated by
evidence of nerve damage, such as sensory impairment, exquisitely
sensitive skin, weakness, and muscle atrophy, or loss of deep tendon
Cardinal Manifestations and Presentation of Diseases

reflexes. Evidence suggesting sympathetic nervous system involve-

ment includes the presence of diffuse swelling, changes in skin
color and temperature, and hypersensitive skin and joint tenderness ANTIDEPRESSANT MEDICATIONS The tricyclic antidepressants
compared with the normal side. Relief of the pain with a sympathetic (TCAs), particularly nortriptyline and desipramine (Table 11-1)
block is diagnostic. are useful for the management of chronic pain. Although devel-
A guiding principle in evaluating patients with chronic pain is to oped for the treatment of depression, the TCAs have a spectrum
assess both emotional and organic factors before initiating therapy. of dose-related biologic activities that include analgesia in a
Addressing these issues together, rather than waiting to address variety of chronic clinical conditions. Although the mechanism
emotional issues after organic causes of pain have been ruled out, is unknown, the analgesic effect of TCAs has a more rapid onset
improves compliance in part because it assures patients that a and occurs at a lower dose than is typically required for the treat-
psychological evaluation does not mean that the physician is ques- ment of depression. Furthermore, patients with chronic pain
tioning the validity of their complaint. Even when an organic cause who are not depressed obtain pain relief with antidepressants.
for a patient’s pain can be found, it is still wise to look for other There is evidence that TCAs potentiate opioid analgesia, so they
factors. For example, a cancer patient with painful bony metastases may be useful adjuncts for the treatment of severe persistent
may have additional pain due to nerve damage and may also be pain such as occurs with malignant tumors. Table 11-2 lists
depressed. Optimal therapy requires that each of these factors be some of the painful conditions that respond to TCAs. TCAs are
looked for and treated. 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 sig-
TREATMENT Chronic Pain nificant side effects (Table 11-1; Chap. 390). Some of these side
effects, such as orthostatic hypotension, drowsiness, cardiac-
Once the evaluation process has been completed and the likely
conduction delay, memory impairment, constipation, and uri-
causative and exacerbating factors identified, an explicit treat-
nary retention, are particularly problematic in elderly patients,
ment plan should be developed. An important part of this
and several are additive to the side effects of opioid analgesics.
process is to identify specific and realistic functional goals for
The selective serotonin reuptake inhibitors such as fluoxetine
therapy, such as getting a good night’s sleep, being able to go
(Prozac) have fewer and less serious side effects than TCAs, but
shopping, or returning to work. A multidisciplinary approach
they are much less effective for relieving pain. It is of interest
that uses medications, counseling, physical therapy, nerve
that venlafaxine (Effexor) and duloxetine (Cymbalta), which
blocks, and even surgery may be required to improve the
are nontricyclic antidepressants that block both serotonin and
patient’s quality of life. There are also some newer, relatively
norepinephrine reuptake, appear to retain most of the pain-
invasive procedures that can be helpful for some patients with
relieving effect of TCAs with a side-effect profile more like that
intractable pain. These include image-guided interventions such
of the selective serotonin reuptake inhibitors. These drugs may
as epidural injection of glucocorticoids for acute radicular pain,
be particularly useful in patients who cannot tolerate the side
radiofrequency treatment of the facet joints for chronic facet-
effects of TCAs.
related pain, percutaneous intradiscal treatments for both axial
and radicular pain, and placement of implanted intraspinal elec- ANTICONVULSANTS AND ANTIARRHYTHMICS These drugs are
trodes and implantation of intrathecal drug-delivery systems for useful primarily for patients with neuropathic pain. Phenytoin
severe and persistent pain that is unresponsive to more conser- (Dilantin) and carbamazepine (Tegretol) were first shown to
vative treatments. There are no set criteria for predicting which relieve the pain of trigeminal neuralgia. This pain has a charac-
patients will respond to these procedures. They are generally teristic brief, shooting, electric shock–like quality. In fact, anti-
reserved for patients who have not responded to conventional convulsants seem to be particularly helpful for pains that have
pharmacologic approaches. Referral to a multidisciplinary pain such a lancinating quality. Newer anticonvulsants, gabapentin
clinic for a full evaluation should precede any invasive proce- (Neurontin) and pregabalin (Lyrica), are effective for a broad
dures. Such referrals are clearly not necessary for all chronic range of neuropathic pains. Furthermore, because of their favor-
pain patients. For some, pharmacologic management alone can able side-effect profile, these newer anticonvulsants are often
provide adequate relief. used as first-line agents.

100
CHRONIC OPIOID MEDICATION The long-term use of opioids such as lidocaine and mexiletene are less likely to be effective;
is accepted for patients with pain due to malignant disease. although intravenous infusion of lidocaine predictably provides
Although opioid use for chronic pain of nonmalignant origin analgesia in those with many forms of neuropathic pain, the
is controversial, it is clear that for many such patients, opioid relief is usually transient, typically lasting just hours after the
analgesics are the best available option. This is understandable cessation of the infusion. The oral lidocaine congener mexi-
because opioids are the most potent and have the broadest range letene is poorly tolerated, producing frequent gastrointestinal
of efficacy of any analgesic medications. Although addiction is adverse effects. There is no consensus on which class of drug
rare in patients who first use opioids for pain relief, some degree should be used as a first-line treatment for any chronically painful
of tolerance and physical dependence is likely with long-term condition. However, because relatively high doses of anticon-
use. Therefore, before embarking on opioid therapy, other vulsants are required for pain relief, sedation is very common.

CHAPTER 11
options should be explored, and the limitations and risks of Sedation is also a problem with TCAs but is much less of a prob-
opioids should be explained to the patient. It is also important lem with serotonin/norepinephrine reuptake inhibitors (SNRIs,
to point out that some opioid analgesic medications have mixed e.g., venlafaxine and duloxetine). Thus, in the elderly or in those
agonist-antagonist properties (e.g., pentazocine and butor- patients whose daily activities require high-level mental activ-
phanol). From a practical standpoint, this means that they may ity, these drugs should be considered the first line. In contrast,
worsen pain by inducing an abstinence syndrome in patients opioid medications should be used as a second- or third-line
who are physically dependent on other opioid analgesics. drug class. While highly effective for many painful conditions,
With long-term outpatient use of orally administered opioids, opioids are sedating, and their effect tends to lessen over time,

Pain: Pathophysiology and Management

it is desirable to use long-acting compounds such as levor- leading to dose escalation and, occasionally, a worsening of pain
phanol, methadone, or sustained-release morphine (Table 11-1). due to physical dependence. Drugs of different classes can be
Transdermal fentanyl is another excellent option. The pharma- used in combination to optimize pain control.
cokinetic profile of these drug preparations enables prolonged It is worth emphasizing that many patients, especially those
pain relief, minimizes side effects such as sedation that are asso- with chronic pain, seek medical attention primarily because
ciated with high peak plasma levels, and reduces the likelihood they are suffering and because only physicians can provide the
of rebound pain associated with a rapid fall in plasma opioid medications required for pain relief. A primary responsibility
concentration. While long-acting opioid preparations may pro- of all physicians is to minimize the physical and emotional dis-
vide superior pain relief in patients with a continuous pattern of comfort of their patients. Familiarity with pain mechanisms and
ongoing pain, others suffer from intermittent severe episodic pain analgesic medications is an important step toward accomplish-
and experience superior pain control and fewer side effects with ing this aim.
the periodic use of short-acting opioid analgesics. Constipation is
a virtually universal side effect of opioid use and should be treated
expectantly. A recent advance for patients with chronic debilitat- FURTHER READINGS
ing conditions is the development of methylnaltrexone, a periph- Costigan M: Neuropathic pain: A maladaptive response of the
erally acting mu opioid antagonist that blocks the constipation nervous system to damage. Annu Rev Neurosci 32:1, 2009
and itching associated with chronic opioid use without interfering
Craig AD: How do you feel? Interoception: The sense of the physi-
with analgesia; the usual dose is 0.15 mg/kg of body weight given
ological condition of the body. Nat Rev Neurosci 8:655, 2002
subcutaneously no more often than once daily.
Dworkin RH: Pharmacologic management of neuropathic pain:
TREATMENT OF NEUROPATHIC PAIN It is important to indi- Evidence-based recommendations. Pain 123:237, 2007
vidualize treatment for patients with neuropathic pain. Several
Eippert F et al: Activation of the opioidergic descending pain con-
general principles should guide therapy: the first is to move
trol system underlies placebo analgesia. Neuron 63:533, 2009
quickly to provide relief, and the second is to minimize drug
side effects. For example, in patients with postherpetic neuralgia Fields HL: Should we be reluctant to prescribe opioids for chronic
and significant cutaneous hypersensitivity, topical lidocaine nonmalignant pain? Pain 129:233, 2007
(Lidoderm patches) can provide immediate relief without side Macintyre PE: Safety and efficacy of patient-controlled analgesia.
effects. Anticonvulsants (gabapentin or pregabalin, see above) Br J Anaesth 87:36, 2001
or antidepressants (nortriptyline, desipramine, duloxetine, or Oaklander AL: Is reflex sympathetic dystrophy/complex regional
venlafaxine) can be used as first-line drugs for patients with neu- pain syndrome type I a small-fiber neuropathy? Ann Neurol
ropathic pain. Systemically administered antiarrhythmic drugs 64:629, 2009

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