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Continuing Education

Pharmacology of Analgesics:
Clinical Considerations
Course Author(s): Anita Aminoshariae, DMD, MS; Géza T. Terézhalmy, DDS, MA
CE Credits: 3 hours
Intended Audience: Dentists, Dental Hygienists, Dental Students, Dental Hygiene Students
Date Course Online: 01/06/2014 Last Revision Date: 06/01/2017 Course Expiration Date: 05/31/2020
Cost: Free Method: Self-instructional AGD Subject Code(s): 16
Online Course: www.dentalcare.com/en-us/professional-education/ce-courses/ce442

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.

Introduction
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 course.
• Dr. Terézhalmy has done consulting work for Procter & Gamble and has served on the
dentalcare.com Advisory Board.

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by the Academy of General Dentistry. The formal continuing education programs of this
program provider are accepted by AGD for Fellowship, Mastership, and Membership
Maintenance Credit. Approval does not imply acceptance by a state or provincial board
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to 7/31/2021. Provider ID# 211886

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Course Contents
• Overview
• Learning Objectives
• Introduction
• Stimulatory Regulation of Nociceptive Pain
• Inhibitory Regulation of Nociceptive Pain
• Role of the Higher Central Nervous System in
Nociceptive Pain
• Pharmacology of Analgesics
N-acetyl-p-aminophenol
Nonsteroidal Anti-inflammatory Drugs
Opioid-receptor Agonists
Opioid-receptor Agonist/Norepinephrine
and Serotonin Reuptake Inhibitors
• Therapeutic Considerations
Mild-to-moderate Odontogenic Pain
Moderate-to-severe Odontogenic Pain
Severe Odontogenic Pain
• Preemptive Analgesia
• Adjuvant Drugs to Enhance the Efficacy of
Analgesics
• Placebo Effect of Analgesics
• Prescription Precautions Associated with the
Use of Analgesics
APAP-related Prescribing Precautions
NSAID-related Prescribing Precautions
Opioid-receptor Agonist-related Prescribing
Precautions
• Summary
• Course Test
• References
• About the Authors
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
a disease-modifying analgesic regimen 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 odontogenic pain,
prescribe the most appropriate analgesic
regimen.
• Discuss potential adverse drug reactions
associated with the use of analgesics.
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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.1,2,3 It is estimated that in the United States
approximately 12% of the population suffers
from odontalgia.1 Pain is the consequence of
a complex series of neuronal,4-6 inflammatory,7
immunological,8,9 vascular,10,11 and morphological
responses11,12 to tissue injury.
Since tissue injury 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 and the factors
that determine its expression, the initiation
of disease-modifying procedures, and the
implementation of sound pharmacological
strategies.
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, while intense heat
or cold activate thermal nociceptors.
However, chemical activators (e.g., protons,
ATP, bradykinin), which directly excite primary
afferent sensory neurons, are the most
important stimuli.14 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).
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 Activation of B2
receptors, which are expressed constitutionally
in neurons, promotes the synthesis of
prostaglandin E2 (PGE2).
In the trigeminal-dorsal root 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 afferent neurons (Figure 2).
Secondary neurons travel to the thalamus and
synapse with tertiary afferent neurons, which
project to the somatosensory cortex and limbic
system responsible for the localization and
emotional aspects of pain, respectively.19,20

Activation of peripheral sensory terminals by
noxious stimuli leads to intracellular sodium and
calcium ion influx and neuronal depolarization
(Figure 1). If the threshold for activation of
voltage-sensitive sodium channels is reached,
neuronal depolarization leads to action potential
generation. There are six types of voltage-gated
sodium channels, four of which are expressed
uniquely in primary afferent sensory fibers and
two of these only respond to high-threshold
peripheral stimuli.
There are three groups of sensory fibers:
groups A (A-α, A-β, A-γ, and A-δ), B, and C.
Fibers in groups A and B are myelinated.
C fibers are nonmyelinated. Nociceptive
information is conducted by A-δ and C fibers.
A-δ fibers conduct information rapidly, i.e., first
pain, which is perceived as sharp, bright, well-
localized pain, but not particularly persistent. C
fibers conduct information slowly, i.e., second
pain, which is perceived as dull, throbbing,
burning, diffuse, and persistent.

Figure 1. Activation of peripheral sensory terminals.

Figure 2. Neurotransmission in the trigeminal nucleus.

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Inhibitory Regulation of Nociceptive Pain
Depolarization of primary afferent sensory
neurons of sufficient intensity leads to action
potential production and signal generation in
secondary 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.
In response to tissue damage and inflammation
resident immune cells release endogenous
opioids and opioid receptors are up-regulated
on peripheral sensory fibers.21-23 Opioid receptor
activation in primary afferent neurons inhibits
depolarization; in the trigeminal-dorsal root
complex it inhibits the release of glutamate;
in the mid-brain it increases descending
inhibitory activity; and in the brain it alters
mood, produces sedation, and modulates the
emotional response to pain.
Efferent projections from the brainstem to
the spinal cord release norepinephrine and
serotonin 5-HT. Activation of α2-adrenergic
Gi-protein-coupled receptors by norepinephrine,
which are expressed both presynaptically and
postsynaptically, reduces both presynaptic and
postsynaptic neuronal excitation. Similarly,
activation of serotonergic Gi-protein-coupled
receptors, which are also expressed both
presynaptically and postsynaptically, exerts an
inhibitory neuronal effect.
Nociceptive activity in sensory neurons, the
spinal cord, and the periaqueductal grey can
be inhibited by endogenous cannabinoids
(2-arachidonylglycerol and anandamide).24,25
There are two G-protein-coupled cannabinoid
(CB) receptors. CB1 receptors are expressed in
sensory neurons, the spinal cord, and the brain.
CB2 receptors are primarily expressed in immune
cells; but in association with pain they may be
upregulated in the trigeminal-dorsal root complex
and in the central nervous system (CNS).26
Role of the Higher Central Nervous
System in Nociceptive Pain
The term perception, when applied to
pain, refers to the awareness of a noxious
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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 patient’s response to pain.
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. 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 involves memory, discrimination,
and judgment, i.e., matching the present
situation against past experiences and
attributing meaning to the current problem.
Cognition differs from patient-to-patient and
even within the same patient at different times
if the thought processes associated with the
experience are different. Ultimately, patients will
respond to pain congruent with their cultural
heritage and its social consequences.
Pharmacology of Analgesics
Analgesics are specific inhibitors of pain
pathways and include N-acetyl-p-aminophenol
(APAP) or acetaminophen, nonsteroidal
antiinflammatory drugs (NSAIDs), opioid-
receptor agonists, and opioid-receptor agonist/
norepinephrine and serotonin reuptake
inhibitors. Since the quintessential requisite
for odontogenic pain is tissue trauma and
inflammation, the optimal analgesic regimen
should include an agent that suppresses pain
and reduces inflammation, i.e., a disease-
modifying analgesic.
N-acetyl-p-aminophenol
APAP or acetaminophen has analgesic and
antipyretic properties, but it has no clinically
significant anti-inflammatory activity. The likely
mechanism of its analgesic action is related
to N-arachidonoyl-phenolamine (AM404), a
metabolite of APAP, which appears to inhibit
the cellular uptake of anandamide leading to
increased cannabinoid receptor activity.24,25 Its
antipyretic effect also appears to be related
AM404, which inhibits cyclooxygenase activity in
the CNS.27-29
The absorption of APAP following oral
administration is rapid and complete. The onset
of analgesia is about 30 minutes. Plasma protein
binding is low (< 25%); consequently, APAP is
readily distributed throughout the body. APAP
is metabolized primarily by hepatic conjugation.
About 10-15% of APAP is metabolized by the
CYP450 isoenzyme 2E1 into a hepatotoxic
intermediate metabolite, which must be
detoxified by glutathione conjugation.30 Inactive
metabolites of APAP are eliminated in the kidney.
Nonsteroidal Anti-inflammatory Drugs
NSAIDs have analgesic, anti-inflammatory and
antipyretic activity. They variably inhibit the
activities of cyclooxygenase isoenzymes (COX-
1 and COX-2); consequently, the synthesis
of PGE2.31 COX-1 is expressed in all healthy
tissues, including platelets, and has primary
homeostatic or “housekeeping” responsibilities.
COX-2 is expressed primarily in the brain,
kidneys, female reproductive system, and bone;
and it is induced by inflammatory cytokines in
other tissues. COX-2 is not found in platelets.
By reducing the synthesis of PGE2, the prototypical
sensitizing agent, NSAIDs increase the response
threshold of primary afferent sensory neurons
by chemical activators such as protons, ATP,
and bradykinin.14,17,18 By reducing PGE2 synthesis,
NSAIDs also increase vascular tone; and
decrease vascular permeability, the recruitment
of leukocytes, and the synthesis of leukocyte-
derived mediators of inflammation. Consequently,
NSAIDs are disease-modifying analgesics.
Acetylsalicylic acid (ASA) is effective in the
treatment of most types of mild-to-moderate
pain. However, ASA irreversibly inhibits platelet
function, precipitates asthma-like symptoms in
susceptible patients, and increases the risk of
Reye’s syndrome in children and adolescents
during viral syndromes. High doses and chronic
use can also cause GI ulceration. Since more
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effective and less toxic analgesics are available,
ASA is used primarily for cardio-protection and
stroke prevention.
Ibuprofen is the gold standard against which
new analgesics are evaluated. Other oral
NSAIDs such as naproxen and naproxen
sodium offer no apparent advantage over
ibuprofen.31 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, a selective
COX-2 inhibitor, offers no advantage over other
NSAIDs in treating odontogenic pain.31
NSAIDs are rapidly absorbed from the stomach
and the upper small intestine. The onset of
analgesia is 30 to 60 minutes. 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 primarily by acting
at μ-receptors found in primary afferent sensory
neurons, the spinal cord, the brainstem, and the
brain.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 neurotransmission.
Morphine is a naturally occurring strong,
full μ-receptor agonist. 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, oxycodone and not oxymorphone is
primarily responsible for analgesia.
Codeine is a naturally occurring weak, full
μ-receptor agonist. Its analgesic action is
largely dependent on its hepatic demethylation
to morphine. Demethylation by the CYP450
isoenzyme 2D6 is subject to genetic
polymorphism. Up to 10% of the general
population are poor metabolizers of codeine
and do not experience analgesia in response to
treatment; while another 10% rapidly convert
codeine to morphine, which can lead 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. Hydrocodone is demethylated by the
CYP450 isoenzyme 2D6 to hydromorphone,
which has a much stronger affinity for the
μ-receptor than hydrocodone and is primarily
responsible for hydrocodone’s analgesic effect.
Patients who are CYP450 isoenzyme 2D6
deficient and those on CYP450 isoenzyme 2D6
inhibitors may not achieve adequate analgesia.
Opioid-receptor Agonist/Norepinephrine
and Serotonin Reuptake Inhibitors
Tramadol is a weak, centrally acting
μ-receptor agonist/norepinephrine and
serotonin reuptake inhibitor.33 After oral
administration, tramadol is readily absorbed
from the gastrointestinal tract. It reaches
appreciable plasma concentrations in 60
minutes. Tramadol’s bioavailability is high
and it is readily distributed from the vascular
compartment to all tissues. Tramadol is
metabolized in the liver.33 The unchanged
fraction of the drug and its metabolites are
excreted in the kidneys.33
Tapentadol is also a weak, centrally acting
μ-receptor agonist/norepinephrine and
serotonin reuptake inhibitor.34 It is rapidly
absorbed after oral administration, although
the bioavailability of the drug due to first-pass
metabolism is low.34,35 Tapentadol is readily
distributed from the vascular compartment
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
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Therapeutic Considerations
Satisfactory relief of odontogenic pain
can be attained through an approach that
incorporates primary dental care in conjunction
with intraoperative local anesthesia and the
administration of a postoperative analgesic
regimen based on a disease-modifying agent.
Therefore, unless otherwise contraindicated,
NSAIDs are first-line drugs for the treatment of
all odontogenic pain. It is of note that response
to an analgesic can vary widely; i.e., some
individuals respond better to one analgesic than
to another.
Consider the efficacy of NSAIDs vis-à-vis other
available options when prescribing analgesics.
Since direct head-to-head trials of the various
analgesics are not always available, an
alternative is to consider the numbers needed
to treat (NNT), i.e., the number of patients
who need to receive the active drug for one
to achieve at least 50% pain relief over 4 to 6
hours compared with a placebo in randomized,
double-blind, single-dose studies in patients
with moderate-to-severe pain (Table 1).36
Analgesics should be administered on
schedule. The “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 optimal dose of an analgesic
that will provide adequate pain relief must be
established by titration. The dosage interval is
predicated on the drug’s elimination half-life.
Mild-to-moderate Odontogenic Pain
Ibuprofen, 200 mg, is somewhat more effective
than naproxen sodium, 220 mg, and both are
more effective than APAP, 650 mg (Table 2).36-40
Consequently, over-the-counter NSAIDs are the
drugs of choice for the treatment of mild-to-
moderate odontogenic pain. Since APAP has
no significant anti-inflammatory activity, in the
treatment of odontogenic pain APAP should
only be considered as an alternative analgesic,
i.e., when NSAIDs are contraindicated.
Moderate-to-severe Odontogenic Pain
Prescription strength ibuprofen, naproxen,
 Table 1. The Oxford League Table for Analgesic Efficary.36

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 Table 2. Over-the-counter Analgesics for
Mild-to-moderate Odontogenic Pain.

Table 3. NSAIDs for Moderate-to-severe Odontogenic Pain.

and naproxen sodium are more effective than
codeine with APAP, 60/650 mg (Table 3).36
Consequently, full doses of NSAIDs are the drugs
of choice for the treatment of moderate-to-
severe odontogenic pain.37-43 It is also of note that
full doses of NSAIDs administered concurrently
with APAP (325 to 650 mg) are more effective for
the treatment of odontogenic pain than full dose
of a NSAID or APAP (650 mg) alone.44,45,46
“add-on” doses of APAP, a weak, full μ-receptor
agonist such as fixed-dose hydrocodone w/
ibuprofen, 5/200 mg, with “add-on” doses of
ibuprofen (and APAP) should be considered
(Table 4). When NSAIDs are contraindicated
alternative options include fixed-doses of
hydrocodone w/APAP, 5/325 mg, or codeine
w/APAP, 30/325 mg, up to a maximum of two
tablets per dose and no “add-on” doses of APAP.

If moderate-to-severe odontogenic pain is Severe Odontogenic Pain

not relieved with full doses of ibuprofen with For the treatment of severe odontogenic

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 Table 4. Weak, Full μ-receptor Agonists for Moderate-to-
severe Odontogenic Pain.

Table 5. Strong Full μ-receptor Agonists for Severe

Odontogenic Pain.

pain, a strong, full μ-receptor agonist such as
fixed-dose oxycodone w/ibuprofen with “add-
on” doses of ibuprofen (and APAP) may be
considered (Table 5). Oxycodone w/ibuprofen,
5/400 mg, is more effective than oxycodone
w/APAP, 5/650 mg; or hydrocodone w/APAP,
7.5/500 mg.47,48 Fixed-dose oxycodone w/APAP,
5/325 mg, up to a maximum of two tablet per
dose and no “add-on” APAP is an alternative,
i.e., when NSAIDs are contraindicated.
Tramadol w/APAP, 75/650 mg, is as effective
for the management of postsurgical dental
pain as hydrocodone w/APAP, 10/650 mg.49
However, ibuprofen, 200 mg, is more effective
than tramadol w/APAP, 112/650 mg.36
Ibuprofen, 400 mg, is more effective for the
management of postsurgical dental pain than
tapentadol, 200 mg.50 Clearly, neither tramadol
nor tapentadol should be considered preferred
analgesics for postsurgical odontogenic pain.

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Preemptive Analgesia
Preoperative doses of NSAIDs reduce
postoperative pain and the need for postoperative
opioids analgesics.51,52 It also appears that
there may be a window-period, and the timely
administration NSAID, i.e., within an hour of a
procedure, will provide a similar benefit.53 It has
also been reported that when treating irreversible
pulpitis, the administration of ibuprofen one hour
before administering a local anesthetic agent is an
effective strategy for achieving deep anesthesia.54
Adjuvant Drugs to Enhance the Efficacy
of Analgesics
Adjuvant drugs enhance the efficacy of analgesics
or have analgesic activity of their own.55 Caffeine
in doses greater than 100 mg enhances
the analgesic effect of NSAIDs and APAP.
Hydroxyzine, a first generation antihistamine,
in doses of 25 to 50 mg enhances the analgesic
effect of opioids and reduces the incidence
of opioid-induced nausea and vomiting.
Corticosteroids, through their phospholipase-
inhibitory effects, enhance analgesia in patients
with pain of inflammatory origin.
Placebo Effect of Analgesics
The placebo effect of analgesics and its
magnitude can be modulated pharmacologically
by naloxone (an opioid-receptor antagonist)
and psychologically by hidden injections.56 The
clinician’s positive attitude toward an analgesic
also affects the patient’s expectations and
associated neurobiological changes can result
in enhanced analgesia and lead to a reduction
in drug intake with maintenance of clinical
effect.56 Consequently, the placebo effect can be
harnessed to the patient’s advantage.
Prescription Precautions Associated
with the Use of Analgesics
There are no “absolutely” safe biologically active
therapeutic agents, i.e., drugs seldom exert
their beneficial effects without also causing
adverse drug reactions (ADRs). It is axiomatic
that analgesics, like other therapeutic agents,
even after the administration of a single dose,
may produce ADRs. However, there is also
supporting evidence that analgesic-related ADRs
are more likely to be associated with prolonged
use, high doses, the presence of comorbidities,
and polypharmacy.
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APAP-related Prescribing Precautions
A Food and Drug Administration (FDA) Drug
Safety Communication published on January
13, 2014 states that “acetaminophen-containing
prescription products are safe and effective
when used as directed, though all medications
carry some risks”.57 Indeed, during the past
decade, APAP has been identified as the leading
cause of acute liver failure (ALF) in the United
States and up to 50% of the cases are due to
unintentional overdose.58-61
Concerns about the incidence of ALF prompted
the FDA to require a Boxed Warning highlighting
the potential for severe liver toxicity with APAP.
The FDA also mandated that the Boxed Warning
highlight the potential for allergic reactions and
for severe liver injury in patients who drank
alcohol while taking APAP containing products.57
Manufactures were also instructed to revise
their labeling (package insert) to include a
warning about potential increased bleeding in
patients taking warfarin.62
The FDA also set a limit of 325 mg of APAP
per tablet, capsule, or other dosage units in
prescription drug products, e.g., opioid analgesics
w/APAP. The FDA also called upon healthcare
professionals to discontinue prescribing
combination drug products containing more than
325 mg of APAP (may still prescribe 650 mg per
dose).57,63 On March 26, 2014 the FDA formally
mandated the withdrawal of all prescription
combination drug products from the market
containing more than 325 mg of APAP.64
Recent evidence also suggests that APAP is
a hormone disrupter, e.g., it interferes with
reproductive and thyroid hormone functions
essential for normal brain development. APAP
taken during pregnancy has been associated with
an increased risk of attention-deficit/hyperactivity
disorder (ADHD)-like behavioral problems or
hyperkinetic disorders (HKDs) in children.65 A
summary of potential ADRs associated with the
use of APAP is presented in Table 6.
NSAID-related Prescribing Precautions
Intolerance to NSAIDs is most likely in individuals
with a history of asthma, nasal polyps, and
chronic urticaria.66 A history of rhinorrhea,
urticaria, angioedema, or bronchospasm
 Table 6. Potential APAP-associated Adverse Drug Reactions.

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occurring within 3 hours after exposure to a
NSAID is an acceptable method of confirming
intolerance. Even a single dose of a NSAID can
precipitate asthma in susceptible patients.67
Intolerance is related to the inhibition of
cyclooxygenase and the consequent shunting of
arachidonic acid down the lipoxygenase pathway
resulting in increased levels of leukotrienes, a
family of inflammatory mediators.68
NSAIDs may cause nausea, vomiting,
abdominal pain, diarrhea, dyspepsia. Mucosal
injury related to the blockade of prostaglandin
synthesis can exacerbate peptic ulcer disease
(PUD).66,69 Ibuprofen appears to have the lowest
risk of NSAID-associated gastrointestinal toxicity.39
NSAIDs also impair platelet function through the
inhibition of thromboxane A2 (TXA2) synthesis.66
The risk of bleeding with PUD is increased with
the concomitant use of aspirin, clopedigrel, and
corticosteroids; with anticoagulants, NSAIDs
increase the International Normalized Ration
(INR) by as much as 15%.69,70
Hepatotoxicity has been reported in association
with the use of NSAIDs, but it appears to
be idiosyncratic and often dose-related.66,71
Predisposing factors for toxic reactions include
advanced age, concomitant liver disease,
decreased renal function, and collagen vascular
diseases. Hepatotoxicity, like most ADRs, occurs
within 6-12 weeks of initiation of long-term
therapy.72 Patients with the liver disease also
have impaired hemostasis associated with
reduced synthesis of coagulation factors and the
administration of NSAIDs may further increase
the risk of bleeding.
NSAIDs decrease the synthesis of renal
prostaglandins. Consequently, NSAIDs
decrease renal blood flow causing fluid
retention and increase blood pressure, and
may precipitate renal failure in susceptible
patients.66 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.73
Nephrotic syndrome, acute interstitial
nephritis, and an increased incidence of end-
stage renal disease have been reported in
patients treated chronically with NSAIDs.74
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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 variably, the FDA
considers cardiovascular risk a class effect.39
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.75
Rarely, NSAIDs may cause dizziness, anxiety,
drowsiness, confusion, disorientation,
depression, and severe headaches. These central
nervous system-related adverse drug reactions
may be seen with therapeutic doses of NSAIDs
most commonly in older persons. Tinnitus
appears to be a sign of high blood levels of
NSAIDs.66 Aseptic meningitis has been reported
in persons with systemic lupus erythematosus
who were taking ibuprofen or naproxen.76,77
NSAIDs at the time of conception may increase
the risk of miscarriage.66,78 During pregnancy, low
dose intermittent administration of NSAIDs, in
general, is considered to be safe. NSAIDs during
the third trimester may prolong gestation and
labor and increase peripartum bleeding.79,80
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.
In children, the primary concern when
prescribing NSAIDs is dosing errors resulting
in overdose, which may lead to significant
morbidity and even death.66 Educating the
caregivers (parents, guardians, others) about
the importance of correct dosing and dosage
intervals, avoiding concurrent use of other
medications that may contain NSAIDs (e.g.,
combination cold remedies), and proper
storage of analgesics (as other medications) in
childproof containers can minimize the risk.
Drug-drug interactions all seem to have 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.81-85
NSAIDs also interfere with the anti-platelet
effect of low dose ASA (i.e., 81 mg per day)
by blocking the access of ASA to its active
site, potentially rendering ASA less effective
when used for cardio-protection and stroke
prevention.86 To avoid significant interference,
oral healthcare providers should advise patients
regarding the appropriate concomitant use of
NSAIDs and ASA, i.e., at least 2 hours should
elapse after ASA dosing before taking a NSAID
and at least 8 hours should elapse after NSAID
dosing before taking an ASA.87
Opioid-receptor Agonist-related Prescribing
Precautions
The United States is in the midst of an opioid
overdose epidemic. Opioid analgesics and
heroin killed more than 33,000 people in 2015,
more than during any other year on record.
Nearly half of all opioid overdose deaths were
related to prescription opioid analgesics.88 The
hallmark of opioid overdose is the presence
of the “opioid overdose triad,” i.e., (1) pinpoint
pupils (miosis), (2) unconsciousness, and (3)
respiratory depression.89 Respiratory depression
is related to mu-receptor activation in the
brainstem, which decreases the sensitivity of
respiratory chemoreceptors to carbon dioxide.90
The sine qua non of opioid intoxication in
a patient who is not in physiologic sleep,
particularly when accompanied by miosis and
lethargy, is respiratory depression defined
as less than 12 breaths/min.91,92 Patients with
respiratory rates less than 12 breath/min 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.91 Once the respiratory
rate improves, the patient should remain under
observation for 4 to 6 hours.
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Mu-receptor activation in the brain causes
dizziness, drowsiness, sedation, and cognitive
changes.93,94 Cognitive chances present
primarily in patients who already have cognitive
dysfunction. Paradoxical CNS effects in the
elderly are not uncommon. To avoid toxic and
paradoxical effects in the elderly, dosages may
have to be reduced by as much as one-half to
one-fourth. Opioid analgesics also modulate
mood and behavior, causing euphoria in
some; and anxiety or dysphoria in others.
Mu-receptor activation in the oculomotor nerve
causes pupillary constriction.90
Repeated use of a constant dose opioid-
receptor agonist can lead to tolerance or
decreased therapeutic efficacy.95 Tolerance
appears to be either innate, i.e., genetically
determined; or acquired, which appears to
have a pharmacokinetic or pharmacodynamic
basis.96,97 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 is a potential hazard of opioid
use. However, patients who take opioids for
acute pain rarely experience euphoria and even
less likely to develop psychological or physical
dependence. Clinically significant physical
dependence is more likely to develop after
several weeks of treatment with relatively large
doses of an opioid.98,99 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.96
Opioid analgesic-related allergic reactions are
rare. However, opioid-receptor agonists appear
to directly activate mast cells and the release of
vasoactive substances does not appear to have
an immunologic basis.93 Opioid intolerance
may manifest as μ-receptor agonists-associated
histamine release causing pruritus and dilation
of cutaneous blood vessels around the “blush
areas,” such as the face, neck, and upper thorax.
Histamine release can also lead to peripheral
vasodilatation and orthostatic hypotension.
Antihistamines, e.g., diphenhydramine, are
effective to manage symptoms.
Nausea and vomiting, as a result of μ-receptor
activation in the medullary chemoreceptor trigger
zone, are common adverse effect associated
with the initiation of opioid analgesic therapy.
With chronic use, constipation is the most ADRs.
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.100
As mentioned earlier, mu-receptor activation
in the brainstem depresses respiratory
chemoreceptor sensitivity to carbon dioxide.90
Concurrent administration of oxygen may
cause apnea. Carbon dioxide retention produces
intracranial vasodilatation leading to increased
intracranial pressure; consequently, opioids
should be used with extreme caution in patients
with head injury. In patients with pulmonary
disease, e.g., severe asthma or chronic
obstructive pulmonary disease, opioids suppress
the cough reflex, impair of ciliary activity,
and aggravate bronchospasm.
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 w/APAP is appropriate for
the management of moderate-to-severe
odontogenic pain. However, if the mother is a
rapid metabolizer, i.e., genetic polymorphism
related to CTP450 isoenzyme 2D6, she may
produce much more morphine than those with
normal metabolic activity.101 This, in 2 to 3 days,
can lead to symptoms compatible with morphine
overdose.101
Drug-drug interactions all seem to have either
a pharmacodynamic or a pharmacokinetic basis.
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The most serious ADR to opioid analgesics
therapy is respiratory depression.90 Consequently,
the risk of respiratory depression is increased with
concurrent prescriptions of other central nervous
system depressants such as benzodiazepines,
other sedative-hypnotic agents, and alcohol.
Drug-drug interactions between opioid analgesics,
alcohol, and sedatives are often present in fatal
drug overdoses.
Summary
Analgesic efficacy in a given patient is
determined by the degree of analgesia
produced following dose escalation limited by
the development of ADRs. Start with a disease-
modifying analgesic when treating odontogenic
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 analgesic, i.e., onset and duration of action
and maximum safe dosages.
Currently available analgesic formulations are
not optimal. Emphasizing the importance of
individualized approach to pain control; at times,
clinicians may have to prescribe more than one
class of analgesic concurrently to achieve maximal
results. The concurrent administration of drugs
with different mechanisms of action is good
medicine; for example, ibuprofen w/APAP in full
doses or fixed-dose opioids with “add-on” doses
of ibuprofen and/or APAP will result in enhanced
analgesia.
Administer analgesics regularly, i.e., “around-
the-clock.” ADRs should be carefully watched
for and the dosage adjusted or symptomatic
therapy initiated. Although rare in oral healthcare
settings, watch for signs of opioid tolerance.
Increasing dosage or frequency of administration
or switching to an alternate regimen may be
necessary to maintain analgesic effect. Finally,
when prescribing analgesics: 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/professional-education/ce-courses/ce442/start-test

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 stimuli
b. transduction of noxious stimuli
c. neuronal transmission of noxious stimuli
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 bradykinin is correct?

a. Bradykinins directly excite primary afferent fibers.
b. Activation of Gs-protein-coupled bradykinin B2 receptors promotes 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.

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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.

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 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

10. 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

11. Which of the following endogenous ligands are major inhibitory neurotransmitters?
a. Opioid peptides.
b. Norepinephrine and serotonin (-5HT).
c. Endogenous cannabinoid.
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. The optimal analgesic regimen should include an agent that suppresses pain and reduces
inflammation, i.e., a disease-modifying analgesic.
d. All of the above.

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

15. Cyclooxygenase inhibitors block the synthesis of prostaglandin PGE2, which is known to
produce all of the following physiological effects except which one? 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 ASA except which one?
a. A single dose of ASA can irreversibly inhibit platelet function.
b. High doses and chronic use of ASA can cause GI ulceration.
c. ASA decreases the risk of Reye’s syndrome in children and adolescents during viral syndromes.
d. Today, ASA (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.

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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.

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. 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. Based on available evidence, which of the following statement is correct with respect to
the treatment of mild odontogenic pain?
a. Ibuprofen, 200 mg, is somewhat more effective than naproxen sodium, 220 mg, and both
are more effective than APAP, 650 mg.
b. Over-the-counter NSAIDs are the drugs of choice for the treatment of mild-to-moderate
odontogenic pain.
c. Since APAP has no significant anti-inflammatory activity; it should only be considered an
alternative analgesic, i.e., when NSAIDs are contraindicated.
d. All of the above.

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25. Based on available evidence, which of the following statements is correct with respect
to the treatment of moderate odontogenic pain?
a. Prescription strength ibuprofen, naproxen, and naproxen sodium are more effective than
codeine with APAP, 60/650 mg.
b. Full doses of NSAIDs are the drugs of choice for the treatment of moderate-to-severe
odontogenic pain.
c. Full doses of NSAIDs administered concurrently with APAP (325 to 650 mg) are more
effective pain than full dose of a NSAID or APAP (650 mg) alone.
d. All of the above.

26. Based on available evidence, which of the following statements is correct with respect
to the treatment of moderate odontogenic pain?
a. If moderate-to-severe odontogenic pain is not relieved with full doses of ibuprofen with
“add-on” doses of APAP, a weak, full μ-receptor agonist such as fixed-dose hydrocodone w/
ibuprofen, 5/200 mg, with “add-on” doses of ibuprofen (and APAP) should be considered.
b. When NSAIDs are contraindicated the therapeutic options include fixed-doses of hydrocodone
w/APAP, 5/325 mg, up to a maximum of two tablets per dose and no “add-on” APAP.
c. When NSAIDs are contraindicated the therapeutic options include fixed doses of codeine w/
APAP, 30/325 mg, up to a maximum of two tablets per dose and no “add-on” APAP.
d. All of the above.

27. Based on available evidence, which of the following statements is correct with respect
to the treatment of severe odontogenic pain?
a. For the treatment of severe odontogenic pain, a strong, full μ-receptor agonist such as
fixed-dose oxycodone w/ibuprofen with “add-on” doses of ibuprofen (and APAP) should be
considered.
b. Oxycodone w/ibuprofen, 5/400 mg, is more effective than oxycodone w/APAP, 5/650 mg.
c. Fixed-dose oxycodone w/APAP, 5/325 mg, up to a maximum of two tablet per dose and no
“add-on” APAP is an alternative, i.e., when NSAID is contraindicated.
d. All of the above.

28. 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 w/APAP, 75/650 mg, is as effective for the management of postsurgical dental
pain as hydrocodone w/APAP, 10/650 mg.
b. Ibuprofen, 200 mg, is more effective than tramadol w/APAP, 112/650 mg.
c. Ibuprofen, 400 mg, is more effective for the management of postsurgical dental pain than
tapentadol, 200 mg.
d. All of the above.

29. Based on available evidence, which of the following statements is correct with respect
to the preemptive effect of NSAIDs?
a. It has shown that NSAIDs have a preemptive effect and reduce postoperative analgesic
requirements.
b. It also appears that there may be a window-period, and timely administration NSAID, i.e.,
within an hour of a procedure, will provide a similar benefit.
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.

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30. 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 APAP.
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.

31. Which of the following statements is correct with respect to the placebo effect of
analgesics?
a. The placebo response of analgesics cannot be blocked pharmacologically by naloxone (an
opioid receptor antagonist).
b. The clinician’s attitude toward an analgesic affects the patient’s expectations and associated
neurobiological changes can result in enhanced analgesia. and lead to a reduction in drug
intake with maintenance of clinical effect.
c. The placebo effect can lead to a reduction in drug intake with maintenance of clinical effect.
d. All of the above.

32. Which of the following statements is correct with respect to APAP?

a. According to a Food and Drug Administration (FDA) Drug Safety Communication
“acetaminophen-containing prescription products are safe and effective when used as directed”.
b. During the past decade, APAP has been identified as the leading cause of acute liver failure
(ALF) in the United States and up to 50% of acetaminophen-related cases of ALF are due to
unintentional overdose.
c. The FDA and the pharmaceutical industry have taken action to protect consumers from
the risk of severe liver damage by formally withdrawing from the market all prescription
combination drug products with more than 325 mg of APAP.
d. All of the above.

33. 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 in combination with anticoagulants they
are not likely to increase the International Normalized Ration (INR).

34. Which of the following statements with respect to NSAID-related prescribing

precautions is correct?
a. Hepatotoxicity has 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. In general, NSAIDs should be used with caution in patients with a history of hypertension,
ischemic heart disease, stroke, or congestive heart failure.
d. All of the above.

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35. 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.

36. Which of the following statements related to opioid overdose is correct?

a. Nearly half of all opioid overdose deaths are related to prescription opioid analgesics.
b. The hallmark of opioid overdose is the presence (1) pinpoint pupils, (2) unconsciousness,
and (3) respiratory depression, i.e. the “opioid overdose triad.”
c. Respiratory depression is related to mu-receptor activation in the brain stem, which
decreases the sensitivity of respiratory chemoreceptors to carbon dioxide.
d. All of the above.

37. 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.

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

prescribing precautions is correct?
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.

39. 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.

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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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8. Hahn CL, Liewehr FR. Innate immune responses of the dental pulp to caries. J Endod. 2007
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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

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. Dr. Terézhalmy earned a BS
degree from John Carroll University; a DDS degree from Case Western Reserve
University; an MA 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 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 225 papers
and abstracts published. Dr. Terézhalmy has accepted invitations to lecture before many local,
state, national, and international professional societies.

Email: gtt2@case.edu

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