Pharmacology of Analgesics: Clinical Considerations

Anita Aminoshariae, DMD, MS; Géza T. Terézhalmy, DDS, MA

Continuing Education Units: 3 hours

Online Course: www.dentalcare.com/en-US/dental-education/continuing-education/ce442/ce442.aspx

Disclaimer: Participants must always be aware of the hazards of using limited knowledge in integrating new techniques or
procedures into their practice. Only sound evidence-based dentistry should be used in patient therapy.

Participants in this course will be introduced to evidence-based information related to the basic mechanisms
of pain, the pharmacology of analgesics, and the rationale for the selection of an analgesic for the treatment
of acute odontogenic pain.

Conflict of Interest Disclosure Statement

• Dr. Aminoshariae reports no conflicts of interest associated with this work.
• Dr. Terézhalmy has done consulting work for Procter & Gamble and is a member of the dentalcare.com
Advisory Board.

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ADA CERP is a service of the American Dental Association to assist dental professionals in identifying
quality providers of continuing dental education. ADA CERP does not approve or endorse individual courses
or instructors, nor does it imply acceptance of credit hours by boards of dentistry.

Concerns or complaints about a CE provider may be directed to the

provider or to ADA CERP at: http://www.ada.org/cerp

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by the Academy of General Dentistry. The formal continuing education programs of this
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of dentistry or AGD endorsement. The current term of approval extends from 8/1/2013 to
7/31/2017. Provider ID# 211886

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 Overview
Participants in this course will be introduced to evidence-based information related to the basic mechanisms
of pain, the pharmacology of analgesics, and the rationale for the selection of an analgesic for the treatment
of acute odontogenic pain.

Learning Objectives
Upon completion of this course, the dental professional should be able to:
• Discuss the physiology of pain
• Discuss the pharmacology of analgesics
• Given a patient with pain, prescribe the most appropriate analgesic
• Discuss potential adverse drug events associated with the use of analgesics

Course Contents mean hospital charge per emergency visits was

• Introduction
• Physiology of Pain
Stimulatory Regulation of Nociceptive Pain
Inhibitory Regulation of Nociceptive Pain
Role of the Higher Central Nervous System
in Nociceptive Pain
• Pharmacology of Analgesic Agents
Aniline Analgesics
Nonsteroidal Anti-inflammatory Agents
Opioid-receptor Agonists
• Therapeutic Considerations
Mild Odontogenic Pain
 Acetaminophen-related Prescribing
Precautions
Moderate Odontogenic Pain
 NSAID-related Prescribing Precautions
Severe Odontogenic Pain
 Opioid-receptor Agonist-related Prescribing
Precautions
• Conclusion
• Course Test Preview
• References
• About the Authors
Introduction
The most common complaint causing a person
to seek the services of an oral healthcare
provider is pain. Pain is a sensory and emotional
experience associated with actual or potential
tissue damage and underlies most quality of life
issues.1,2 It is estimated that in the United States
approximately 12% of the population suffers from
odontalgia.1 It is also a matter of record that in
2006 the primary diagnostic codes for 403,149
emergency department visits to U.S. hospitals
were for pulpal and periapical diseases.3 The
average age of patients was 32.9 years, the
$480, and total charges for all emergency visits
were $163,692,957.
Pain is the consequence of a complex series
of neuronal4-6, inflammatory7, immunologic8,9,
vascular10,11, and morphologic responses11,12
to tissue injury. Since tissue damage,
associated with trauma and inflammation, is the
quintessential stimulus for odontogenic pain,
the primary obligation and ultimate responsibility
of every oral healthcare provider is to exercise
a degree of skill, care, and judgment that will
promote optimal healing of diseased tissues and
relieve pain. This requires an understanding
of the complexity of pain, an appreciation for
the factors that determine its expression in the
clinical setting, the initiation of disease-modifying
procedures, and the implementation of sound
pharmacological strategies.
Physiology of Pain
Stimulatory Regulation of Nociceptive Pain
Nociception is the sensory detection, transduction,
and neural transmission of noxious stimuli, which
affect “high-threshold” primary afferent sensory
neurons called nociceptors located in superficial
soma (skin, mucosa), deep soma (muscles,
bone) and viscera (organs).13 Nociceptors require
intense, actually or potentially tissue damaging
stimuli to depolarize their terminals. Intense
mechanical stimuli activate mechanoreceptors.
Some thermal nociceptors may be activated by
cold, while others respond to heat. However,
chemical activators (e.g., protons, ATP,
bradykinin), which directly excite primary afferent
sensory neurons, are the most important stimuli.14

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Other chemicals, known as sensitizing agents
(e.g., prostaglandin E2), increase the sensitivity of
nociceptors to chemical activators.15
Protons, from low extracellular pH associated with
ischemia and inflammation, activate acid sensitive
ions channels (ASICs) and transient receptor
potential vanilloid ion channels (TRPV1, TRPV2),
which may also be activated by noxious heat.
High extracellular ATP levels associated with cell
injury activate P2X ligand-gated channels and
P2Y Gs-protein-coupled receptors. Bradykinins,
associated with tissue damage and inflammation,
activate Gs-protein-coupled bradykinin B1 and
B2 receptors.16 B1 receptors are expressed in
response to bacterial lipopolysaccharides and
inflammatory cytokines.17,18 B2 receptors are
expressed constitutionally in neurons and their
activation promotes the synthesis of prostaglandin
E2 (PGE2), the prototypical sensitizing agent.
Activation of peripheral sensory terminals by
noxious stimuli leads to intracellular sodium and
calcium ion influx and neuronal depolarization
(Figure 1). The generator potential or membrane
depolarization induced by nociceptive signals
leads to action potential production if the threshold
for activation of voltage-sensitive sodium channels
is reached. There are six types of voltage-gated
sodium channels, of which four are expressed
uniquely in primary afferent sensory fibers and two
of these only respond to high-threshold peripheral
stimuli.
Figure 1. Activation of peripheral sensory terminals.
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In the trigeminal-spinal complex, incoming action
potentials activate pre-synaptic voltage-sensitive
calcium channels, which lead to calcium influx,
synaptic release of glutamate, and subsequent
action potential generation in secondary neurons
(Figure 2). Secondary afferent neurons travel in
the lateral areas of the spinal cord and project
to the thalamus where they synapse with tertiary
afferent neurons. Tertiary afferent neurons
project to various regions of the brain including
the somatosensory cortex, responsible for the
localization of pain; and the limbic system,
responsible for the emotional aspects of pain.19,20
Afferent sensory neurons can be classified into
three principal categories: group A, B, and C.
Group A is further subdivided into A-alpha (α),
A-beta (β), A-gamma (γ), and A-delta (δ) fibers.
Group A and B fibers are myelinated. Group C
fibers are nonmyelinated. Nociceptive information
is conducted by A-δ and C fibers. Information via
A-δ fibers arrives rapidly; it is perceived as sharp,
bright, well-localized pain, which is not particularly
persistent, but it is immediately associated with
tissue injury (first pain). Information via C fibers
arrives slowly; it is perceived as dull, throbbing,
burning, diffusely localizable pain, which has a
persistent quality (second pain).
Inhibitory Regulation of Nociceptive Pain
Depolarization of primary afferent sensory neurons
of sufficient intensity leads to action potential
production and signal generation in secondary
 Figure 2. Neurotransmission in the trigeminal nucleus.
and, ultimately, tertiary neurons. Synaptic
transmission is regulated by the actions of
both local inhibitory interneurons and efferent
projections from the brainstem. The major
inhibitory neurotransmitters relevant to this
discussion are opioid peptides, norepinephrine,
serotonin (5-HT), and endogenous cannabinoids.
Opioid Peptides
In painful inflammatory conditions opioid
receptors on peripheral sensory fibers are
up-regulated and resident immune cells express
their endogenous opioid peptides.21-23 Opioid
receptor activation on peripheral terminals inhibits
activation of primary afferent neurons. In the
trigeminal ganglion, opioid peptides inhibit the
release of presynaptic vesicles from primary
afferent neurons. In the mid-brain, they increase
descending inhibitory activity to the trigeminal
nucleus and spinal cord; and, in the brain, opioid
peptides alter mood, produce sedation, and
reduce the emotional reaction to pain.
Norepinephrine and Serotonin 5-HT
Norepinephrine is released by descending
projections from the brainstem to the spinal
cord. Activation of α2-adrenergic Gi-protein-
coupled receptors, which are expressed both
presynaptically and postsynaptically, reduces
presynaptic vesicle release and decreases
postsynaptic neuronal excitation. Serotonin is
also released by projections that descend from
the brainstem to the spinal cord. Serotonergic
Gi-protein-coupled receptors, which are
also expressed both presynaptically and
postsynaptically, appear to mediate the inhibitory
actions of serotonin.
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Endogenous Cannabinoids
There are two cannabinoid G-protein-coupled
receptors: CB1 and CB2. CB1 is expressed in
sensory neurons, the spinal cord, and the brain.
CB2 receptors are expressed predominantly in
immune cells; but in pathological pain states, they
may be upregulated in the central nervous system
(CNS) and the trigeminal or dorsal root ganglia.24
Anandamide and 2-arachidonylglycerol, two
endogenous cannabinoids, appear to modulate
pain at peripheral afferent sensory fibers and
in the spinal cord; and in the periaqueductal
grey they appear to modulate efferent inhibitory
projections.25,26
Role of the Higher Central Nervous System in
Nociceptive Pain
The term perception (attention and cognition),
when applied to pain, refers to the awareness
of a noxious sensation, appreciation of negative
emotions, interpretation, and attribution of
meaning to the experience. While patients are
surprisingly uniform in their perception of pain,
they differ greatly in their reaction to it. Attention
and cognition, along with cultural, emotional, and
motivational differences, will alter or modulate the
intensity of a patient’s response to noxious stimuli.
Attention
Attention is largely under conscious control. The
patient experiencing pain has a choice: attend
to the noxious sensations or attend to signals
that can exclude pain perception from conscious
awareness. Manipulation of attention for pain
control has been used with varying degrees of
success. For example, most hypnotic procedures
involve the redirection of attention away from
pain; breathing exercises use attentional control
to suppress the pain of natural childbirth; and
music used during dental procedures requires
that the patient concentrate on the music.
Cognition
Cognitive processes include memory,
discrimination, and judgment; the matching of
present circumstances against expectations;
and the attribution of meaning to the experience.
Nociceptive afferent activity may affect cognition
differently from patient-to-patient and, at different
times, even within the same patient if the thought
processes associated with the experience are
different. Patients in pain also tend to behave
in ways congruent with their cultural heritage.
Clearly, the expression or display of pain is
modulated by its social consequences.
Pharmacology of Analgesic Agents
Analgesics are specific inhibitors of pain pathways.
They activate specific receptors in primary afferent
sensory neurons and the CNS. Since odontogenic
pain predictably is associated with tissue trauma
and inflammation, pharmacological treatment with
a disease-modifying analgesic, i.e., an agent that
not just suppresses the symptom of pain but also
reduces inflammation, should be considered as the
drug of choice.
Aniline Analgesics
Acetaminophen has analgesic and antipyretic
properties, but it has no clinically significant
anti-inflammatory activity. Its antipyretic activity
appears to be related to N-arachidonoyl-
phenolamine (AM404), a metabolite of
acetaminophen and a member of a group
of bioactive N-acylamines that includes the
endogenous cannabinoid 2-arachidonylglycerol,
which inhibits cyclooxygenase activity in the
CNS.27-29 The likely mechanism of its analgesic
effect is also related to the activity of AM404.
It appears to inhibit the cellular uptake of
anandamide leading to increased cannabinoid
receptor activity.25,26
The absorption of acetaminophen following oral
administration is rapid and complete. Onset of
analgesia is about 30 minutes. Its plasma protein
binding is low (<25%), consequently, it is readily
distributed throughout the body. Acetaminophen
is metabolized primarily by hepatic conjugation;
but about 10-15% is metabolized by the
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CYP450 isoenzyme 2E1 forming a highly reactive
metabolite, which if not detoxified by glutathione
conjugation is responsible for acetaminophen’s
hepatotoxic potential.30 Inactive metabolites of
acetaminophen are eliminated in the kidney.
Nonsteroidal Anti-inflammatory Agents
Nonsteroidal anti-inflammatory drugs (NSAIDs)
inhibit the activity of cyclooxygenase isoenzymes
COX-1 and COX-2; and, consequently, the
synthesis of prostaglandins.31 COX-1 is expressed
constitutively in virtually all healthy tissues,
including platelets, and it is associated primarily
with homeostatic or “housekeeping” mechanisms.
COX-2 is expressed primarily in the brain, kidneys,
female reproductive systems, and bone; and it
can be induced by inflammatory cytokines in other
tissues. COX-2 is not found in platelets. Inhibition
of COX-2 is primarily responsible for the anti-
inflammatory effect of NSAIDs.
Prostaglandin PGE2 affects vascular tone and
permeability, modulates inflammation, and
influences pain perception.14,17,18 By reducing
peripheral prostaglandin synthesis, NSAIDs
decrease the recruitment of leukocytes and the
synthesis of leukocyte-derived mediators of
inflammation, and increase the activation threshold
of primary afferent sensory neurons by chemical
activators. In the trigeminal nucleus or dorsal horn
of the spinal cord, PGE2 acts as a pain-producing
substance. NSAIDs, which cross the blood-brain
barrier, also prevent the synthesis of PGE2 in the
CNS. Consequently, NSAIDs are considered
disease modifying analgesics.
Acetylsalicylic acid (aspirin) is effective in the
treatment of most types of mild-to-moderate pain.
However, a single dose of aspirin can irreversibly
inhibit platelet function, interfere with hemostasis
and cause prolonged bleeding; and precipitate
asthma-like symptoms in susceptible patients. High
doses and chronic use of aspirin can cause GI
ulceration. Furthermore, aspirin increases the risk of
Reye’s syndrome in children and adolescents during
viral syndromes. Because of the availability of more
effective and less toxic alternatives, now aspirin (in
low dose) is used primarily for cardio-protection and
stroke prevention.
Ibuprofen is the gold standard against which
new analgesics are evaluated. Naproxen (and
naproxen sodium), like ibuprofen, has analgesic,
anti-inflammatory and antipyretic activity. Other
available oral formulations of NSAIDs offer no
apparent advantage over ibuprofen or naproxen.
Ketorolac is available in both oral and parenteral
formulations. The use of the oral formulation is
restricted to those patients who have received the
drug parenterally during the perioperative period.32
Celecoxib, the only available selective COX-2
inhibitor in the U.S., offers no advantage over
nonselective NSAIDs in treating odontogenic pain.31
NSAIDs are rapidly absorbed from the stomach
and the upper small intestine. They reach
appreciable plasma concentrations in 30 to 60
minutes and peak values at about 2 to 3 hours.
NSAIDs are distributed throughout the body and
cross the placenta. Depending on the agent and
dosing, their duration of action is between 4 to 12
hours. NSAIDs are metabolized in the liver by
first-order kinetics; however, after larger doses,
the enzymes become saturated, which leads
to zero-order kinetics and increased half-lives.
Metabolites are excreted primarily by the kidneys.
Opioid-receptor Agonists
There are three types of opioid receptors: mu
(μ), delta (δ), and kappa (K). Opioid-receptor
agonists produce analgesia by acting primarily at
μ-receptors found in the brain, brainstem, spinal
cord, and primary afferent sensory neurons.21-23
Presynaptic μ-receptor activation inhibits calcium
influx into sensory neurons, which decreases
neurotransmitter release. Postsynaptic μ-receptor
activation increases K+ conductance, which
decreases postsynaptic response to excitatory
neurotransmission.
Morphine is the archetypical opioid analgesic.
It is a naturally occurring strong, full μ-receptor
agonist, i.e., it fully activates the μ-receptor
displaying maximum efficacy. However, after oral
administration, morphine is rapidly metabolized
by hepatic glucuronidation and its bioavailability
is low. Oxycodone is a semi-synthetic strong full
μ-receptor agonist. After oral administration its
bioavailability is high. Oxycodone is metabolized
by glucuronidation to noroxycodone and by
the CYP450 isoenzyme 2D6 to oxymorphone.
However, it is oxycodone, and not its metabolites,
that is primarily responsible for analgesia.
Codeine is a naturally occurring weak, full
μ-receptor agonist, i.e., its efficacy is less than that
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produced by a strong full agonist even when all
the available receptors are activated Its analgesic
action is largely dependent on its hepatic
demethylation to morphine, which is responsible
for its analgesic activity. Demethylation by the
CYP450 isoenzyme 2D6 is subject to genetic
polymorphism. Up to 10% of patients are poor
metabolizers and do not experience analgesia
in response to treatment with codeine. Another
10% of the patients rapidly convert codeine to
high levels of morphine, leading to severe toxicity
(including death), even with therapeutic doses.
Hydrocodone is a synthetic weak full μ-receptor
agonist. It is similar in structure to codeine, but
hydrocodone is a more effective analgesic. Its
bioavailability after oral administration is high.
Hydrocodone is demethylated by the CYP450
isoenzyme 2D6 into hydromorphone. Because
hydromorphone has a much stronger affinity
for the μ-receptor than hydrocodone, it has
been proposed that hydrocodone is a prodrug.
Patients who are CYP450 isoenzyme 2D6
deficient and those on CYP450 isoenzyme 2D6
inhibitors may not achieve adequate analgesia.
Tramadol is a weak, centrally acting μ-receptor
agonist/norepinephrine and serotonin reuptake
inhibitor.33 A weak, centrally acting μ-receptor
agonist is less effective than a strong full
μ-receptor agonist and its activity appears to be
limited to the CNS. After oral administration,
tramadol is readily absorbed from the
gastrointestinal tract. It reaches appreciable
plasma concentrations in 60 minutes and
peak values at about 2 hours. Tramadol’s
bioavailability is high and it is readily distributed
from the vascular compartment to all tissues.
Tramadol is extensively metabolized in the liver.33
The unchanged fraction of the drug and its
metabolites are excreted in the kidneys.33
Tapentadol is a weak, centrally acting μ-receptor
agonist/norepinephrine reuptake inhibitor.34 It
is rapidly absorbed after oral administration,
although the bioavailability of the drug is low,
due to extensive first-pass metabolism.34,35
Tapentadol is readily distributed from the vascular
compartment (plasma protein binding ≈20%)
to all tissues. The primary metabolic pathway
of tapentadol is hepatic glucuronidation.34,35
Tapentadol and its metabolites are rapidly and
completely excreted in the kidneys.34,35
Therapeutic Considerations
Satisfactory relief of odontogenic pain can be
attained through an approach that incorporates
disease-modifying procedures, i.e., primary dental
care, in conjunction with intraoperative local
anesthesia and the postoperative administration
of disease-modifying analgesics. Consequently,
NSAIDs are the first line of treatment for superficial
somatic odontogenic pain, e.g., postsurgical pain
from an incision (skin, mucosa). Deep somatic
odontogenic pain, e.g., pain following injury or
extensive surgical procedures (muscle, bone),
is best treated with combination analgesics, i.e.,
NSAIDs with acetaminophen or NSAIDs and/or
acetaminophen with an opioid.
Adjuvant drugs may enhance the efficacy of
analgesics or have analgesic activity of their own.36
Caffeine in doses greater than 100 mg enhances
the analgesic effect of commonly used analgesics,
i.e., NSAIDs and acetaminophen. Hydroxyzine (an
antihistamine) in doses of 25 to 50 mg enhances
the analgesic effect of opioids in postoperative pain,
and significantly reduces the incidence of opioid-
induced nausea and vomiting. Corticosteroids,
through their anti-inflammatory and phospholipase-
inhibitory effects, can enhance analgesia in patients
with pain of inflammatory origin.
The placebo effect of analgesics and its magnitude
can be modulated by psychological factors such
as conditioning and expectancy.37 Investigators
have found that the placebo response can be
blocked pharmacologically by naloxone, an opioid-
receptor antagonist, and psychologically by hidden
injections.37 Consequently, the placebo effect
can be harnessed to the patient’s advantage.
The clinician’s words (attitude) relative to the
therapeutic agent affect the patient’s expectations
and associated neurobiological changes can result
in enhanced analgesia and, ultimately, can lead
to a reduction in drug intake with maintenance of
clinical effect.37
The optimal dose of an analgesic that will provide
adequate pain relief must be established by titration
and the drug should be administered on schedule.
“By-the-clock” administration of analgesics is much
more effective than waiting for pain to return before
giving the next dose and may actually reduce the
total dosage required for the management of a
painful episode. The dosage interval is predicated
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on the elimination half-life of the drug. Metabolism
and adverse drug effects can vary widely among
individuals and some patients may respond better
to one NSAID or combination opioid analgesics
than to another.
Currently available analgesic formulations are not
optimal, further emphasizing the importance of
individualized approach to pain control. At times,
clinicians may have to prescribe more than one
type of analgesic concurrently to achieve maximal
results. For example, the co-administration of
ibuprofen with acetaminophen in full doses; or
ibuprofen and/or acetaminophen in full doses
with an opioid will result in enhanced analgesia.
The concurrent administration of drugs with
different mechanisms of action is good medicine;
the concurrent administration of drugs with
similar mechanisms of action has no rational
pharmacological basis.
Mild Odontogenic Pain
In patients with mild odontogenic pain, an over-
the-counter NSAID is the drug of choice (Table 1).
Ibuprofen, 200 mg, is more effective than aspirin,
650 mg; or acetaminophen, 650 mg; or naproxen
200 to 220 mg.38-42 Ibuprofen, 400 mg, is more
effective than ibuprofen, 200 mg; and it is
equianalgesic to naproxen, 400 to 440 mg.38-
A full dose of ibuprofen, and presumably
42
naproxen, in combination with a full dose of
acetaminophen is more effective than either of
the two components alone.43 A meta-analysis has
also shown that this combination can also reduce
postoperative opioid requirements.44
Acetaminophen, in doses between 650 to 1000
mg, has been shown to be safe and effective
for treating pain after mandibular third-molar
extractions.45 However, acetaminophen has
no clinically significant anti-inflammatory effect
and ibuprofen, 200 mg, is more effective than
acetaminophen, 1000 mg.38 Therefore, with
notable exceptions, acetaminophen should
be considered an alternative analgesic when
NSAIDs are contraindicated (see NSAID-related
prescription precautions).
Acetaminophen-related Prescribing Precautions
In healthy people, therapeutic doses of
acetaminophen have virtually no adverse effects.
In general, the occasional use of acetaminophen
 Table 1. Over-the-counter analgesics for mild odontogenic pain
during pregnancy is also considered safe.46 It
is also the preferred analgesic in patients with
liver disease because of the absence of platelet
impairment associated with NSAIDs.30 However,
hepatotoxicity may occur with overdose and in
patients with liver disease, alcohol and malnutrition
(even with therapeutic doses of acetaminophen)
may enhance this toxicity. It is also of note that
the long-term use of acetaminophen may increase
the anticoagulant effect of warfarin.
At therapeutic doses, the half-life of acetaminophen
may be prolonged in patients with chronic liver
disease; but CYP450 isoenzyme 2E1 activity is not
increased, glutathione stores are not depleted to
critical levels, and there is no evidence of increased
risk of hepatotoxicity.30 The minimum hepatotoxic
single dose in healthy adults is between 15 to 20
extra-strength (500 mg) doses; for children it is 150
mg/kg.48 Nausea, vomiting, anorexia, diarrhea,
and abdominal pain occur during the first 24 hours.
Clinical evidence of hepatic damage may be noted
in 2 to 6 days. When the drug’s half-life exceeds
12 hours, hepatic coma and death are likely.
Moderate Odontogenic Pain
In patients with moderate odontogenic pain, full
doses of ibuprofen or naproxen are the drugs
of choice (Table 2).38,41,49,50 Ibuprofen, 400 mg, is
more effective than codeine with aspirin, 60/650
mg; or codeine with acetaminophen, 60/600 mg.38
Ibuprofen, 400 mg, is equianalgesic to naproxen,
400 to 440 mg, and naproxen 500 to 550 mg; but
ibuprofen, 600 to 800 mg, is more effective.38 Full
doses of ibuprofen, and presumably naproxen, in
combination with a full dose of acetaminophen is
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more effective than either of the two components
alone.43
Meta-analysis has shown that full doses
of ibuprofen, and presumably naproxen, in
combination with a full dose of acetaminophen
can also reduce postoperative opioid
requirements.44 However, if moderate pain is
not controlled adequately with full doses of a
NSAID/acetaminophen combination, a weak full
μ-receptor agonist, e.g., codeine or hydrocodone
(Table 3), with “add-on” doses of ibuprofen
or acetaminophen to augment fixed-dose
formulations may be considered.
Meta-analysis has also shown that NSAIDs have
a pre-emptive effect and reduce postoperative
analgesic requirements.51 This pre-emptive effect
has been shown in association with periodontal
surgical procedures, reducing both postoperative
surgical pain and the need for postoperative
use of opioids.52 Another study suggests that
there may be a window-period, and timely
administration, i.e., within an hour of the surgical
procedure, will provide a similar benefit.53 It
has also been reported that the preoperative
administration of ibuprofen, 1 hour before the
administration of local anesthesia, is an effective
method for achieving deep anesthesia during
RCT of teeth with irreversible pulpitis.54
NSAID-related Prescribing Precautions
There are no “absolutely” safe biologically active
therapeutic agents, i.e., drugs seldom exert their
beneficial effects without also causing adverse
drug events (ADEs). It is axiomatic that NSAIDs
 Table 2. Nonsteroidal anti-inflammatory agents for moderate odontogenic pain

Table 3. Weak full μ-receptor agonists for moderate odontogenic pain

like other therapeutic agents, even after the
administration of a single dose, may produce
ADEs. However, there is also supporting evidence
that NSAID-related ADEs are more likely to be
associated with prolonged use, high doses, the
presence of comorbidities, and polypharmacy.
Intolerance
Intolerance to NSAIDs is most likely to occur in
individuals with a history of asthma, nasal polyps,
and chronic urticaria.55 A history of rhinorrhea,
urticaria, angioedema, or bronchospasm occurring
within 3 hours after exposure is an acceptable
method of determining intolerance. Even a
single dose of these agents can precipitate
asthma in susceptible patients.56 Intolerance is
not an immune phenomenon; rather it is related
to the ability of NSAIDs to inhibit the enzyme
cyclooxygenase and the consequent shunting of
arachidonic acid down the lipoxygenase pathway,
which results in increased levels of leukotrienes.57
Gastropathy
Therapeutic doses of NSAIDs may cause nausea
and vomiting; and have been associated with
abdominal pain, diarrhea, and dyspepsia.55
They can exacerbate the symptoms of peptic
ulcer disease; and with chronic use, ulceration,

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perforation, and bleeding can occur.58 The
prolonged use of high doses of NSAIDs, the
concomitant use of anticoagulants, aspirin,
and corticosteroids, excessive alcohol intake,
and advanced age increase the risk of these
complications.58 Mucosal injury is primarily related
to blockade of gastro-protective prostaglandin
synthesis. Ibuprofen, in general, appears
to have the lowest risk of NSAID-associated
gastrointestinal toxicity.41
Antithrombotic Effect
NSAIDs impair platelet adhesion to tissue
components and platelet aggregation primarily
through the inhibition of thromboxane A2 (TXA2)
synthesis.55 In contrast to aspirin, platelet
inhibition is reversible and short-lived with
therapeutic doses of NSAIDs. Platelet function
returns to normal when most of the drug has
been eliminated from the body. However, in the
presence of bleeding diatheses, either hereditary,
acquired, or drug induced, the antiplatelet effect of
these agents may contribute to serious bleeding.
NSAIDs in combination with anticoagulants can
increase the International Normalized Ration
(INR) by as much as 15%.59
Hepatic Toxicity
Adverse hepatic reactions have been reported
in association with NSAIDs, but they appear
to be idiosyncratic and often dose-related.55,60
Predisposing factors for toxic reactions include
advanced age, decreased renal function, and
collagen vascular diseases. Hepatotoxicity, like
most adverse drug reactions, occurs within 6-12
weeks of initiation of long-term therapy.61 Patients
with cirrhosis of the liver also have impaired
hemostasis and the administration of NSAIDs may
further increase the risk of bleeding.
Renal Toxicity
NSAIDs decrease the synthesis of renal
prostaglandins; consequently, decrease renal
blood flow, cause fluid retention and increase
blood pressure, and may precipitate renal failure
in susceptible patients.55 Risk factors include
old age, chronic renal insufficiency, congestive
heart failure, hepatic cirrhosis, and the concurrent
use of β-adrenergic receptor antagonists and
angiotensin-converting enzyme inhibitors.62
Nephrotic syndrome, acute interstitial nephritis,
and an increased incidence of end-stage renal
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disease have been reported in patients treated
chronically with NSAIDs.63 NSAIDs should be
avoided in persons with preexisting renal disease.
Cardiovascular Toxicity
Selective COX-2 inhibitors are associated
with a small but absolute cardiovascular risk.41
COX-2 inhibition leads to less prostacyclin
(PGI2) and more TXA2 synthesis. PGI2 is a
vasodilator and blocks platelet aggregation;
TXA2 is vasoconstrictive and promotes platelet
aggregation. COX-2 inhibition allows TXA2 to
function unopposed. Although NSAIDs block
both COX-1 and COX-2, the FDA considers
cardiovascular risk a class effect. The risk
appears to be related to dose and duration
of treatment. In general, NSAIDs should be
used with caution in patients with a history of
hypertension, ischemic heart disease, stroke, or
congestive heart failure.64
Central Nervous System Effects
Rarely, NSAIDs may cause tinnitus, dizziness,
anxiety, drowsiness, confusion, disorientation,
depression, and severe headaches. These
adverse effects are seen more commonly in older
persons. Tinnitus is reversible and appears to be
a signs of high blood levels of NSAIDs.55 Aseptic
meningitis has been reported in persons with
systemic lupus erythematosus who were taking
ibuprofen or naproxen.65,66
Effects on Pregnancy and Lactation
NSAIDs at the time of conception may increase
the risk of miscarriage.55,67 During pregnancy,
low dose intermittent administration of NSAIDs,
in general, is considered to be safe. However,
NSAIDs should not be prescribed during the third
trimester of pregnancy.68,69 Potential maternal
effects include prolonged gestation and labor,
and increased peripartum bleeding. Potential
fetal effects include premature closure of ductus
arteriosus; pulmonary hypertension; renal
dysfunction; reduced amniotic fluid volume; and
increased cutaneous and intracranial bleeding. In
breastfeeding women, ibuprofen and naproxen
are considered safe.
Effects on Children
The primary concern when children are taking
NSAIDs is dosage errors resulting in overdose,
which may result in significant morbidity and
even death.55 Educating the caregivers (parents,
guardians, others) about the importance of
correct dosing and dosage intervals, avoiding
the concurrent use of other medications that may
contain NSAIDs (combination cold remedies), and
proper storage of analgesics (as other medications)
in childproof containers can minimize the risk.
Drug-drug Interactions
Drug-drug interactions all seem to have either a
pharmacodynamic or a pharmacokinetic basis.
NSAIDs may decrease the antihypertensive
effects (decreased prostaglandin synthesis)
of β-adrenergic blocking agents, angiotensin-
converting enzyme inhibitors, and diuretics;
increase the toxicity of lithium and methotrexate
(decreased renal excretion); increase the
risk of peptic ulcer disease (additive) with
corticosteroids; and increase the risk of bleeding
(platelet inhibition) and increase the INR
(mechanism unknown) with warfarin sodium.70-74
NSAIDs can also interfere with the anti-platelet
effect of low dose aspirin (81 mg per day) by
blocking the access of aspirin to its active site,
potentially rendering aspirin less effective when
used for cardio-protection and stroke prevention.75
To avoid significant interference, oral healthcare
providers should advise patients regarding the
appropriate concomitant use of NSAIDs and
aspirin, i.e., at least 2 hours should elapse after
aspirin dosing before taking a NSAID and at least
8 hours should elapse after NSAID dosing before
taking an aspirin.76
Severe Odontogenic Pain
In patients with severe odontogenic pain, a
strong full μ-receptor agonist, i.e., oxycodone,
in combination with ibuprofen or acetaminophen
(Table 4), with “add-on” doses of ibuprofen
or acetaminophen to augment fixed-dose
formulations, should be considered. Opioid dose
requirements vary widely from one patient to
another; but the equivalent of oral morphine, 10
mg per 70 kg of body weight, is a reasonable
staring dose.36 The dose equivalent of codeine is
about 60 mg; of hydrocodone it is about 10 mg;
and of oxycodone it is about 5 mg.77
Hydrocodone with ibuprofen, 15/400 mg, is
superior to ibuprofen, 400 mg.78 Oxycodone
with ibuprofen, 5/400 mg, is more effective than
oxycodone with acetaminophen, 5/650 mg; or
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hydrocodone with acetaminophen, 7.5/500 mg.79,80
Oxycodone with acetaminophen, 5/500 mg, is as
effective as codeine with acetaminophen, 60/1000
mg; however, ibuprofen, 600 to 800 mg, is more
effective than either of the above formulations.38
Codeine, hydrocodone, and oxycodone
formulations with acetaminophen are alternative
drugs when NSAIDs are contraindicated.
Tramadol with acetaminophen, 75/650 mg, is
as effective for the management of postsurgical
dental pain as hydrocodone with acetaminophen,
10/650 mg.81 However, tramadol with
acetaminophen, 112/650 mg, is less effective
than ibuprofen, 200 mg.38 Tapentadol, 200 mg, is
less effective for the management of postsurgical
dental pain than ibuprofen, 400 mg.82 Clearly,
neither tramadol nor tapentadol should be
considered preferred analgesics for postsurgical
odontogenic pain. Tapentadol also has a high
potential for abuse.
Opioid-receptor Agonist-related Prescribing
Precautions
As noted before, there are no “absolutely” safe
biologically active therapeutic agents and drugs
seldom exert their beneficial effects without also
causing ADEs. Opioid analgesics like other
therapeutic agents, even after the administration
of a single dose, may produce ADEs. However,
there is also supporting evidence that opioid-
related ADEs are more likely to be associated
with prolonged use, high doses, the presence of
comorbidities, and polypharmacy.
Intolerance
Opioid analgesic-related allergic reactions are
rare. However, μ-receptor agonists are able to
induce histamine release and produce pruritus
and cutaneous blood vessels tend to dilate
around the “blush areas”, such as the face, neck,
and upper thorax. Histamine release can also
lead to peripheral vasodilatation and orthostatic
hypotension. Opioid-receptor agonists appear
to directly activate mast cells and the release
of vasoactive substances does not appear to
have an immunologic basis.83 Antihistamines,
e.g., diphenhydramine, are effective to manage
symptoms.
Gastropathy
Nausea and vomiting, as a result of μ-receptor
activation in the medullary chemoreceptor trigger
 Table 4. Strong full μ-receptor agonists for severe odontogenic pain
zone, are common adverse effect associated
with the initiation of opioid analgesic therapy.
With chronic use, constipation is the most
common adverse effect. Opioid analgesics in the
gastrointestinal tract bind μ-receptors, which leads
to an increase in the tone of the anterior portion
of the stomach and decreases gastric motility.
Constipation is dose related and patients do not
develop tolerance to this effect. The risk may be
minimized by increasing fluid and dietary fiber
intake.84
Respiratory effects
Mu-receptor activation in the brain stem
depresses respiratory chemoreceptor sensitivity
to carbon dioxide.85 Concurrent administration
of oxygen may cause apnea. Carbon dioxide
retention produces intracranial vasodilatation
and may aggravate increased intracranial
pressure. Opioids should be used with great
caution in cases of head injury, the elderly, the
debilitated, and those with pulmonary disease,
particularly severe asthma because of cough
reflex suppression, impairment of ciliary activity,
and aggravation of bronchospasm.
CNS effects
Mu-receptor activation in the brain causes
dizziness, drowsiness, sedation, and cognitive
changes.83,86 Cognitive chances present
primarily in patients who already have cognitive
dysfunction. A paradoxical reaction to the CNS
effects in the elderly is not uncommon. To avoid
both toxic and paradoxical effects, dosages must
be reduced by as much as one-half to one-fourth.
Opioid analgesics also modulate mood and
behavior, causing euphoria in some; and anxiety
and dysphoria in others. Mu-receptor activation
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in the oculomotor nerve causes pupillary
constriction (miosis).85
Tolerance
Repeated use of a constant dose of an opioid-
receptor agonist can lead to tolerance or
decreased therapeutic efficacy.87 Tolerance
appears to be either innate, i.e., genetically
determined; or acquired, which appears to
have a pharmacokinetic or pharmacodynamic
basis.88,89 Tolerance may develop with both acute
and chronic opioid use. To maintain adequate
analgesia, the development of tolerance requires
either an increase in the dosage or frequency of
drug administration. There does not appear to be
any evidence that tolerance leads to dependence.
Dependence
Dependence is a potential hazard of opioid use.
However, patients who take opioids for acute
pain rarely experience euphoria and even more
rarely do they develop psychological dependence
or addiction. Clinically significant physical
dependence is more likely to develop after several
weeks of treatment with relatively large doses of
an opioid.90,91 In these patients abrupt cessation
of treatment results in withdrawal syndrome
characterized by dilated pupils, rapid pulse, goose
flesh, muscle jerks, flu-like symptoms, vomiting,
diarrhea, tremors, yawning, and sleep.88
Overdose
Opioid overdose is a life-threatening condition.
The sine qua non of opioid intoxication is
respiratory depression.92 A respiratory rate of
≤12 breaths per minute in a patient who is not
in physiologic sleep strongly suggests opioid
intoxication, particularly when accompanied by
miosis and stupor.93 Patients with respiratory
rates ≤12 breaths per minute and stupor should
be ventilated with a bag-valve mask; and
administered naloxone, a competitive μ-receptor
antagonist, which reverses all signs of opioid
intoxication.92 Once the respiratory rate improves,
the patient should be observed for 4 to 6 hours.
Pregnant and Nursing Women
The use of opioids in the pregnant or nursing
patient is discouraged because of their general
CNS depressant effects on the fetus and infant.
The short-term use of therapeutic doses of
codeine in combination with acetaminophen is
appropriate for the management of moderate-to-
severe odontogenic pain. However, if the mother
is a rapid metabolizer, she may produce much
more morphine than those with normal metabolic
activity.94 This, in 2 to 3 days, can lead to
symptoms compatible with morphine overdose.94
Drug-drug Interactions
Drug-drug interactions all seem to have either a
pharmacodynamic or a pharmacokinetic basis.
The most serious adverse effect of opioids is
respiratory depression.85 Consequently, the
risk of respiratory depression is increased
(additive) with sedative-hypnotic agents such
as benzodiazepines or barbiturates; tricyclic
antidepressants; and other CNS depressants.
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Conclusion
Analgesic efficacy in a given patient is determined
by the degree of analgesia produced following
dose escalation limited by the development of
adverse effects. Start with a specific drug for
a specific type of pain. Drug metabolism can
differ widely among patients and effects reported
should not be viewed as psychological since they
generally have a pharmacological basis. Know
the pharmacology of the medications prescribed.
Onset, peak, and duration of analgesic action and
maximum safe dosages vary with drugs. When
using fixed-dose opioid formulations, to enhance
analgesia, add a NSAID and/or acetaminophen.
Administer analgesics regularly. “Around-
the-clock” administration of analgesics has
positive pharmacological and psychological
effects on the patient. Side effects such as
sedation, nausea, and vomiting should be
carefully watched for and the dosage adjusted or
symptomatic therapy initiated. Although rare in
oral healthcare settings, watch for development
of tolerance. Increasing dosage and frequency
of administration or switching to an alternate
medication may be necessary to maintain
analgesic effect. Finally, when prescribing an
analgesic: prescribe dose enough, soon enough,
often enough, long enough - prescribe as you
would receive.
Course Test Preview
To receive Continuing Education credit for this course, you must complete the online test. Please go to:
www.dentalcare.com/en-us/dental-education/continuing-education/ce442/ce442-test.aspx

1. Pain is _______________.
a. an unpleasant sensory and emotional experience
b. associated with actual tissue damage
c. associated with potential tissue damage
d. All of the above.

2. Nociception or pain perception is _______________.

a. the sensory detection of noxious events in the CNS
b. transduction of noxious events to the CNS
c. neuronal transmission of noxious events to the CNS
d. All of the above.

3. Which of the following are noxious stimuli that affect “high-threshold” primary afferent
sensory neurons or nociceptors?
a. Intense mechanical stimuli
b. Intense thermal stimuli
c. Chemical activators
d. All of the above.

4. Which of the following are chemical activators of nociceptors?

a. Ischemia- and inflammation-associated protons.
b. Cellular injury-associated extracellular ATP.
c. Tissue damage- and inflammation-associated kinins.
d. All of the above.

5. Which of the following statements associated with the kinins (bradykinin) is correct?
a. Kinins directly excite primary afferent fibers.
b. Activation of Gs-protein-coupled bradykinin B2 receptors promote prostaglandin PGE2 synthesis.
c. PGE2 increases the sensitivity of primary afferent sensory neurons to chemical activators.
d. All of the above.

6. Which of the following statements is correct with reference to the activation of peripheral
sensory neurons?
a. Activation of peripheral sensory terminals by noxious stimuli leads to intracellular sodium and
calcium ion influx and neuronal depolarization.
b. Membrane depolarization leads to action potential generation if the activation threshold of
voltage-sensitive sodium channels is reached.
c. Four types of voltage-sensitive sodium channels are expressed in primary afferent sensory fibers
and two of these only respond to high-threshold peripheral stimuli.
d. All of the above.

7. Which of the following statements is correct with reference to neuronal transmission in the
trigeminal nucleus?
a. Incoming action potentials activate pre-synaptic voltage-sensitive calcium channels.
b. Calcium ion influx into the primary sensory neuron terminal leads to synaptic release of
glutamate.
c. Glutamate receptor activation leads to action potential generation in secondary relay neurons.
d. All of the above.

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8. Which of the following statement is correct with respect to secondary or tertiary afferent
neurons?
a. Secondary afferent neurons travel in the lateral aspects of the spinal cord and project to the
thalamus where they synapse with tertiary afferent neurons.
b. Tertiary afferent neurons project to the somatosensory cortex, which is responsible for the
localization of pain.
c. Tertiary afferent neurons project to the limbic system, which is responsible for the emotional
aspects of pain.
d. All of the above.

9. Pain arising slowly after injury, which is perceived as burning, aching, dull, poorly localized,
and persistent, i.e., second pain, is most likely due to the activation of ____________.
a. A-delta fibers
b. C fibers
c. B fibers
d. A-gamma fibers

10. Pain arising rapidly after tissue injury, which is perceived as sharp, bright, well-localized, but
not particularly persistent, i.e., first pain, is most likely due to the activation of ____________.
a. A-delta fibers
b. C fibers
c. B fibers
d. A-gamma fibers

11. Which of the following endogenous ligands are major inhibitory neurotransmitters?
a. Opioid peptides
b. Norepinephrine and serotonin (-5HT)
c. Endogenous cannabinoid, e.g., anandamide and 2-arachidonyglycerol
d. All of the above.

12. The term perception (attention and cognition), when applied to pain refers to the
_______________.
a. awareness of a noxious sensation
b. interpretation and appreciation of negative emotions
c. attribution of meaning to the experience
d. All of the above.

13. Which of the following pharmacological considerations is correct with respect to analgesics?
a. Analgesics are specific inhibitors of pain pathways.
b. Analgesics activate receptors in primary afferent sensory neurons and the central nervous system.
c. Pharmacological treatment with a disease-modifying analgesic should target specific mechanisms
of pain rather than just suppress the symptom.
d. All of the above.

14. All of the following statements are correct with respect to acetaminophen except which one?
a. Acetaminophen has clinically significant analgesic, anti-inflammatory, and antipyretic activity.
b. The antipyretic activity of acetaminophen appears to be related to one of its metabolites, which
inhibits cyclooxygenase activity in the CNS.
c. The likely mechanism of acetaminophen’s analgesic effect is also related to a metabolite, which
appears to indirectly increase cannabinoid receptor activity.
d. Acetaminophen is metabolized primarily by hepatic conjugation, but a small amount is
metabolized by a CYP450 isoenzyme into a potentially toxic metabolite.

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15. Cyclooxygenase inhibitors block the synthesis of prostaglandin PGE2, which is known to
produce all of the following physiological effects except which one? Prostaglandin PGE2
_______________.
a. produces vasodilatation and increase vascular permeability
b. modulates the inflammatory response and body temperature
c. decreases the pain threshold, i.e., increases nociception
d. activates platelets

16. All of the following statements are correct with respect to acetylsalicylic acid (aspirin)
except which one?
a. A single dose of aspirin can irreversibly inhibit platelet function.
b. High doses and chronic use of aspirin can cause GI ulceration.
c. Aspirin decreases the risk of Reye’s syndrome in children and adolescents during viral syndromes.
d. Today, aspirin (in low dose) is used primarily for cardio-protection and stroke prevention.

17. All of the following statements are correct with respect to COX-inhibitors except which one?
a. Ibuprofen and naproxen formulations have analgesic, anti-inflammatory, but no antipyretic activity.
b. The oral formulation of ketorolac is restricted to those patients who have received the drug
parenterally during the perioperative period.
c. Oral formulations of NSAIDs, other than ibuprofen or naproxen, offer no apparent advantage
over ibuprofen or naproxen.
d. Celecoxib, a selective COX-2 inhibitor, offers no advantage over NSAIDs in treating odontogenic
pain.

18. Which of the following statements is correct with respect to NSAIDs? NSAIDs are
_______________.
a. rapidly absorbed from the stomach and upper small intestine
b. distributed throughout the body and cross the placenta
c. metabolized in the liver by first-order kinetics; however, after large dose, the enzymes become
saturated, which leads to zero-order kinetics and increased half-lives
d. All of the above.

19. Which of the following statements is correct with respect to opioid-receptor agonists?
a. Opioid-receptor agonists produce analgesia by acting primarily at μ-receptors, which are found
in the brain, brain stem, spinal cord, and primary afferent sensory neurons.
b. Presynaptic μ-receptor activation inhibits calcium influx into primary sensory neurons, which
decreases neurotransmitter release.
c. Post-synaptic μ-receptor activation increases K+ conductance, which decreases post-synoptic
response to excitatory neurotransmission.
d. All of the above.

20. All of the following statements are correct with respect to morphine or oxycodone except
which one?
a. Morphine is a naturally occurring strong full μ-receptor agonist, which after oral administration
has very high bioavailability.
b. Oxycodone is a semi-synthetic full μ-receptor agonist, which after oral administration has high
bioavailability.
c. Oxycodone is metabolized by glucuronidation to noroxycodone and by the CYP450 isoenzyme
2D6 into oxymorphone.
d. Oxycodone is primarily responsible for its analgesic effect.

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21. Which of the following statement are correct with respect to codeine?
a. Codeine is a naturally occurring weak full μ-receptor agonist and its analgesic action is largely
dependent on its hepatic demethylation to morphine.
b. The metabolism of codeine is subject to genetic polymorphism, up to 10% of the patients are
poor metabolizers and do not experience analgesia.
c. About 10% of patients rapidly convert codeine to morphine, which can lead to severe toxicity
(including death), even with therapeutic doses.
d. All of the above.

22. All of the following statements are correct with respect to hydrocodone except which one?
a. Hydrocodone is a synthetic weak full μ-receptor agonist with good bioavailability after oral
administration.
b. Hydrocodone is demethylated by the CYP450 isoenzyme 2D6 into hydromorphone.
c. Hydromorphone has a much weaker affinity for μ-receptors than hydrocodone.
d. It has been proposed that hydrocodone is a prodrug.

23. Which of the following statements are correct with respect to tramadol or tapentadol?
a. Tramadol is a weak-centrally acting μ-receptor agonist/norepinephrine and serotonin reuptake
inhibitor.
b. Tapentadol is a weak-centrally acting μ-receptor agonist/norepinephrine reuptake inhibitor.
c. Tapentadol has low bioavailability after oral administration due to extensive hepatic first-pass
metabolism.
d. All of the above.

24. Which of the following segments are correct with respect to the use of adjuvant drugs in
pain management?
a. Caffeine in doses greater than 100 mg. enhances the analgesic effect of NSAIDs and
acetaminophen.
b. Hydroxyzine (an antihistamine) in dose of 25 to 50 mg. enhances the analgesic effect of opioids
and significantly reduces the incidence of opioid-induced nausea and vomiting.
c. Corticosteroids can enhance analgesia in patients with pain of inflammatory origin.
d. All of the above.

25. All of the following statements are correct with respect to the placebo effect of analgesics
except which one?
a. The placebo effect of analgesics and its magnitude can be modulated by psychological factors
such as conditioning and expectancy.
b. The placebo response of analgesics cannot be blocked pharmacologically by naloxone (an
opioid receptor antagonist).
c. The clinician’s words (attitude) affect the patient’s expectations and associated neurobiological
changes can result in enhanced analgesia.
d. The placebo effect of analgesics can lead to a reduction in drug intake with maintenance of
clinical effect.

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26. Based on available evidence, all of the following statements are correct with respect to the
treatment of mild odontogenic pain except which one?
a. Ibuprofen, 200 mg, is more effective than aspirin, 650 mg; or acetaminophen, 650 mg; or
naproxen, 200 to 220 mg.
b. Ibuprofen, 400 mg, is more effective than ibuprofen, 200 mg; and it is equianalgesic to naproxen,
400 to 440 mg.
c. A full dose of ibuprofen, and presumably naproxen, in combination with a full dose of
acetaminophen is more effective than either of the components alone.
d. In patients with mild odontogenic pain, acetaminophen should be considered the analgesic of choice.

27. Which of the following statements is correct with respect to acetaminophen?

a. In healthy people, acetaminophen at usual doses has virtually no adverse effects.
b. Generally, the occasional use of acetaminophen during pregnancy is considered safe.
c. Acetaminophen is the preferred analgesic in patients with liver disease.
d. All of the above.

28. Based on available evidence, all of the following statements are correct with respect to the
treatment of moderate odontogenic pain except which one?
a. Ibuprofen, 400 mg, is more effective than codeine with aspirin, 60/650 mg; or codeine with
acetaminophen, 600/600 mg.
b. Ibuprofen, 400 mg, is equianalgesic to naproxen, 400 to 440 mg, and naproxen 500 to 550 mg.
c. Ibuprofen, 600 to 800 mg, is no more effective than either ibuprofen, 400 mg, or naproxen 400 to
440 mg, and naproxen 500 to 550 mg.
d. If pain is not controlled adequately with full doses of a NSAID/acetaminophen combination,
fixed-dose formulation of a weak full μ-receptor agonist with “add-on” doses of a NSAID or
acetaminophen may be considered.

29. Based on available evidence, which of the following statements is correct with respect to the
preemptive effect of NSAIDs?
a. Meta-analysis has shown that NSAIDs have a preemptive effect and reduce postoperative
analgesic requirements.
b. The preemptive effect of NSAIDs has been shown in association with periodontal surgical
procedures.
c. Deep anesthesia during RCT of teeth with irreversible pulpitis has been attributed to ibuprofen
administered 1 hour before the administration of local anesthesia.
d. All of the above.

30. All of the following statements with respect to NSAID-related prescribing precautions are
correct except which one?
a. Intolerance to NSAIDs is most likely to occur in individuals with a history of asthma, nasal polyps,
and chronic urticaria.
b. Therapeutic doses of NSAIDs may cause nausea and vomiting; and have been associated with
abdominal pain, diarrhea, and dyspepsia.
c. NSAIDs impair platelet adhesion to tissue components and platelet aggregation primarily through
the inhibition of thromboxane A2.
d. The antiplatelet effect of NSAIDs is transient and is not likely to contribute to serious bleeding in
patients with bleeding diatheses.

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31. Which of the following statements with respect to NSAID-related prescribing precautions is
correct?
a. Adverse hepatic effect have been reported in association with NSAIDs, but they appear to be
idiosyncratic and often dose related.
b. Decreased synthesis of renal prostaglandins can result in decrease renal blood flow, fluid
retention and increase blood pressure, and renal failure.
c. According to the FDA, NSAIDs, like selective COX-2, should be used with caution in patients
with HTN, ischemic heart disease, heart failure, and stroke.
d. All of the above.

32. All of the following statements with respect to NSAID-related prescribing precautions are
correct except which one?
a. NSAIDs at the time of conception may increase the risk of miscarriage.
b. NSAIDs should not be prescribed during the third trimester of pregnancy.
c. In breastfeeding women, ibuprofen and naproxen are contraindicated.
d. The primary concern when children are administered NSAIDs is dosage errors resulting in
overdose.

33. Based on available evidence, which of the following statements is correct with respect to
the treatment of severe odontogenic pain?
a. Oxycodone with acetaminophen, 5/500 mg, is as effective as codeine with acetaminophen,
60/1000 mg.
b. Oxycodone with ibuprofen, 5/400 mg, is more effective than oxycodone with acetaminophen,
5/650 mg.
c. Oxycodone with ibuprofen, 5/400 mg, is more effective than hydrocodone with acetaminophen,
7.5/500 mg.
d. All of the above.

34. Based on available evidence, which of the following statements is correct with respect to
the use of tramadol or tapentadol in the treatment of odontogenic pain?
a. Tramadol with acetaminophen, 75/650 mg, is as effective as hydrocodone with acetaminophen,
10/650 mg.
b. Tramadol with acetaminophen, 112/650 mg, is less effective than ibuprofen, 200 mg.
c. Tapentadol, 200 mg, is less effective than ibuprofen, 400 mg.
d. All of the above.

35. Which of the following statements with respect to opioid-receptor agonist-related

prescribing precautions is correct except?
a. Allergic reactions to opioid analgesics are rare.
b. Opioid analgesics may induce histamine release, which does not appear to have an
immunological basis.
c. Histamine release may produce pruritis, dilation of cutaneous blood vessels around “blush
areas”, and peripheral vasodilation-induced orthostatic hypotension.
d. All of the above.

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36. Which of the following statements with respect to opioid-receptor agonist-related prescribing
precautions is correct?
a. Nausea and vomiting are common adverse effect associated with the initiation of opioid
analgesic therapy.
b. With chronic use of opioid analgesics, constipation is the most common adverse gastrointestinal
effect.
c. Opioid-induced constipation is dose related and patients do not develop tolerance to this effect.
d. All of the above.

37. Which of the following statements with respect to opioid-receptor agonist-related prescribing
precautions is correct?
a. Mu-receptor activation in the brain stem depresses respiratory chemoreceptor sensitivity to
carbon dioxide.
b. The concurrent administration of an opioid analgesic and oxygen may cause apnea.
c. Opioids should be used with great caution in the elderly, the debilitated, and those with
pulmonary disease, particularly severe asthma.
d. All of the above.

38. Which of the following statements with respect to opioid-receptor agonist-related prescribing
precautions is correct?
a. Patients who take opioids for acute pain rarely experience euphoria and even more rarely do
they develop psychological dependence or addiction.
b. Clinically significant physical dependence is more likely to develop after several weeks of
treatment with relatively large doses of an opioid.
c. In patients with physical dependence abrupt cessation of treatment results in withdrawal syndrome.
d. All of the above.

39. Which of the following statements with respect to opioid-receptor agonist-related prescribing
precautions is correct?
a. The sine qua non of opioid intoxication is respiratory depression.
b. A respiratory rate of ≤12 breaths per minute in a patient who is not in physiologic sleep strongly
suggests opioid intoxication.
c. Patients with respiratory rates ≤12 breaths per minute and stupor should be ventilated with a
bag-valve mask and administered naloxone.
d. All of the above.

40. Which of the following statements with respect to opioid-receptor agonist-related prescribing
precautions is correct?
a. In general, the use of opioids in the pregnant or nursing patient is discouraged because of their
general CNS depressant effects on the fetus and infant.
b. In pregnant patients, the short-term use of codeine with acetaminophen is appropriate for the
management of moderate-to-severe odontogenic pain.
c. If a pregnant or nursing patient is a rapid metabolizer of codeine, she may produce more
morphine than those with normal metabolism; this, in 2 to 3 days, can lead to morphine
overdose in the fetus or neonate.
d. All of the above.

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About the Authors

Anita Aminoshariae, DMD, MS

Dr. Aminoshariae is a full-time assistant professor and director of predoctoral
endodontics at Case Western Reserve University. She also works in an endodontic
private practice. Her dental career began when she was accepted to the Pre-
Professional Scholars Program, Six-Year Dentistry at Case School of Dental Medicine
which was followed by working as a contract dentist for the United States Navy. Dr.
Aminoshariae obtained her endodontic training, certificate and masters degree from
Virginia Commonwealth University in 2001. She became a Diplomate of the American
Board of Endodontics in 2005.

Dr. Aminoshariae was elected to the American Association of Endodontists Board of Directors during the
organization’s recent Annual Session in Boston. Dr. Aminoshariae represents AAE District IV, comprised
of Illinois, Indiana, Kentucky, Michigan, Ohio, West Virginia and Wisconsin.

Dr. Aminoshariae is a member of the American Dental Association, Ohio Dental Association and Ohio
Association of Endodontists. She is the treasurer and secretary of the Greater Cleveland Dental Society
and Alternate Delegate of the Ohio Dental Association. She is also a member of the National Board
Endodontics Test Construction Committee for Joint Commission on National Dental Examinations,
chair of the American Dental Education Association Endodontic Section, and a member of the Scientific
Advisory Boards for the Journal of Endodontics and Journal of the American Dental Association. Dr.
Aminoshariae previously served on the AAE Evidence-Based Endodontics Committee.

Email: anita.aminoshariae@case.edu

Géza T. Terézhalmy, DDS, MA

Professor and Dean Emeritus
School of Dental Medicine
Case Western Reserve University

Dr. Terézhalmy is Professor and Dean Emeritus, School of Dental Medicine, Case
Western Reserve University. In addition, he is a Consultant, Naval Postgraduate
Dental School, National Naval Medical Center; and Civilian National Consultant for
Dental Pharmacotherapeutics, Department of the Air Force.

Dr. Terézhalmy earned a B.S. degree from John Carroll University; a D.D.S. degree from Case
Western Reserve University; an M.A. in Higher Education and Human Development from The George
Washington University; and a Certificate in Oral Medicine from the National Naval Dental Center. Dr.
Terézhalmy is certified by the American Board of Oral Medicine and the American Board of Oral and
Maxillofacial Radiology (Life).

Dr. Terézhalmy has many professional affiliations and over the past 40 years, has held more than
30 positions in professional societies. He has served as editor or contributing editor for several
publications, co-authored or contributed chapters for several books and has had over 200 papers
and abstracts published. Dr. Terézhalmy has accepted invitations to lecture before many local, state,
national, and international professional societies.

Email: TEREZHALMY@uthscsa.edu

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