Chapter 4. Pharmacology Flashcards
1
Q
- Which of the following is true regarding seizures
as one of the multiple side effects from the use
of opioids?
(A) Morphine and related opioids can cause
seizure activity when moderate doses
are given
(B) Seizure activity is more likely with
meperidine, especially in the elderly
and with renal dysfunction
(C) Seizure activity is mediated through
stimulation of N-methyl-D-aspartate
(NMDA) receptors
(D) Naloxone is very effective in treating
seizures produced by morphine and
related drugs including meperidine
(E) Seizure activity is most likely related
with the fact that opioids stimulate the
production of γ-aminobutyric acid
(GABA)
A
- (B) Extremely high doses of morphine and
related opioids can produce seizures, presumably
by inhibiting the release of GABA
(at synaptic level).
Normeperidine a metabolite of meperidine
is prone to produce seizures and tends to
accumulate in patients with renal dysfunction
and in the elderly.
Naloxone may not effectively treat seizures
produced by meperidine.
2
Q
- Which of the following is true regarding respiratory
depression related to the use of opioids?
(A) Opioid agonists, partial agonists, and
agonist/antagonists produce the same
degree of respiratory depression
(B) Opioids produce a leftward shift of the
CO2 response curve
(C) Depression of respiration is produced
by a decrease in respiratory rate, with a
constant minute volume
(D) Naloxone partially reverses the opioidinduced
respiratory depression
(E) The apneic threshold is decreased
A
- (E) Opioids produce a dose-dependant respiratory
depression by acting directly on the respiratory
centers on the brainstem. Partial agonist
and agonist-antagonist opioids are less likely to
cause severe respiratory depression, as are the
selective K-agonist.
Therapeutic doses of morphine decrease
minute ventilation by decreasing respiratory
rate (as oppose to tidal volume).
Opioids depress the ventilatory response
to carbon dioxide; the carbon dioxide–response
curve shows a decrease slope and rightward
shift.
The apneic threshold is decreased and also
the increase in ventilatory response to hypoxemia
is blunted by opioids.
Naloxone can effectively and fully reverse
the respiratory depression from opioids.
3
Q
- The use of which of the following opioids would
produce the greatest incidence of delayed respiratory
depression?
(A) 25 μg intravenous (IV) fentanyl (bolus)
(B) 4 mg IV morphine (bolus)
(C) 5 μg IV sufentanil (bolus)
(D) 8 mg epidural, preservative free
morphine
(E) 0.05 mg intrathecal, preservative free
morphine
A
- (D) Delayed respiratory depression is likely to
occur with larger dose of epidural opioids, particularly
morphine which is hydrophilic and
therefore subject to spread in the cerebrospinal
fluid (CSF), reaching the respiratory center in
the brainstem.
Intrathecal doses of morphine produce only
a uniphasic pattern of respiratory depression.
4
Q
144. Opioids in general reduce the sympathetic output and produce a dose-dependant bradycardia, EXCEPT (A) morphine (B) fentanyl (C) meperidine (D) sufentanil (E) alfentanil
A
- (C) High doses of any opioid reduce sympathetic
output allowing the parasympathetic
output to predominate. The heart rate decreases
by stimulation of the vagal center, especially
with high-doses.
Meperidine because of its similarity to
atropine may elevate the heart rate after IV
administration
5
Q
- What is the main mechanism by which opioids
produce analgesia?
(A) Coupling of opioid receptors to sodium
and potassium ion channels, therefore
inhibiting neurotransmitter release
(presynaptic) and inhibiting neuronal
firing (postsynaptically)
(B) Coupling of opioid receptor to potassium
and calcium channels, inhibiting
neurotransmitter release (presynaptic),
and inhibiting neuronal firing (postsynaptically)
(C) Coupling of opioid receptors to sodium
and calcium channels, inhibiting
neurotransmitter release (presynaptic),
and inhibiting neuronal firing
(postsynaptically)
(D) Coupling of opioid receptors to potassium
and calcium channels, inhibiting
neuronal firing (presynaptically), and
inhibiting neurotransmitter release
(postsynaptically)
(E) All the options are true
A
- (B) Opioid receptors are coupled to G proteins,
able to affect most of the time, protein phosphorylation
via a second messenger, thereby
altering the conductance of potassium and calcium
ion channels. This is believed to be the
main mechanisms by which endogenous and
exogenous opioids produce analgesia.
The opening of potassium channels—the most
well documented—will inhibit the release of neurotransmitters,
including substance P and glutamate
if the receptors are presynaptic. And will
inhibit neuronal firing by hyperpolarization of the
cell if the receptors are postsynaptic on the neurons.
6
Q
- Main mechanics of spinal opioid analgesia is via
(A) activation of presynaptic opioid receptors
(B) activation of postsynaptic opioid
receptors
(C) activation of opioid receptors on the
midbrain
(D) activation of opioid receptors on the RVM
(E) all of the above
A
- (A) The different type of opioid receptors contribute
in different proportions to the total
opioid receptors in the spinal cord. μ-Receptors
constitute 70%, δ-receptors 24% and κ-receptors
6%. The main mechanism of spinal opioid analgesia
is through presynaptic activation of opioid
receptors.
Opioid receptors are synthesized in small
diameter DRG cell bodies and transported centrally
and peripherally. They are mainly (70%)
located presynaptically on small diameter nociceptive
primary afferents (C and A-δ fibers).
7
Q
147. Opioids act on what type of receptors targets? (A) μ-, δ-, κ-, And ORL receptors (B) Voltage-dependent sodium channels (C) α2B-Adrenoreceptors (D) NMDA receptors (E) All of the above
A
- (E) Opioids produce analgesia primarily through
interaction with μ-receptors. The activation of κ-
and δ-receptors also causes analgesia.The ORL receptor is a member of the opioid
receptors, although ligands do not have the same
high affinity for this type of receptors, but effects
of high-affinity ligands, such as antinociception,
proprioception/hyperalgesia, allodynia and no
effect have been reported.
Analysis has shown that some opioid
actions are not mediated by opioid receptors,
morphine can inhibit voltage-dependant sodium
(Na) current, meperidine can block voltage-
dependant sodium (Na) channels.
Meperidine also has agonist activity at the
α2B-adrenoreceptor subtype.
Methadone, meperidine, and tramadol
inhibit serotonin and norepinephrin reuptake.
High concentrations of opioids, including
morphine, fentanyl, codeine, and naloxone
directly inhibit NMDA receptor.
8
Q
148. Which of the following statements is true regarding the use of oxycodone? (A) Analgesic efficacy is not comparable with that of morphine (B) Typically has been used in combination with nonopioids (C) Not available as a long-acting preparation (D) Lower bioavailability than that of morphine (E) Consistently shows a higher induced rate of hallucinations and itching when compared with morphine
A
- (B) Oxycodone a semisynthetic derivative of
thebaine and has analgesic efficacy comparable
with that of morphine, with a median oxycodone
to morphine dose ratio of 1 to 15.
Oxycodone has been typically used in
combination with nonopioids (acetaminophen,
aspirin) and a long-acting preparation is available,
which has popularized its use in cancer
patients.
It has a higher bioavailability than that of
morphine (approximately 60%).
There are not consistent observations on
reduced rate of hallucinations and itching when
compared with morphine.
9
Q
- One important characteristic of methadone that
has to be considered when prescribing it on an
outpatient basis:
(A) Usually there is a low chance for interactions
on patients taking multiple
medications
(B) Withdrawal symptoms are as severe as
with morphine
(C) Rarely used in opioid addiction
(D) Sedation and respiratory depression can
outlast the analgesic action
(E) Allows rapid titration
A
- (D) Methadone unlike morphine is metabolized
through N-demethylation by the liver
cytochrome P-450 enzyme, which activity can
vary widely in different people.
Methadone should be administered with
caution in patients receiving multiple medications,
specially antivirals and antibiotics.
Methadone’s withdrawal symptoms tend to
be less severe than morphine’s, this and its long
duration of action, good oral bioavailability, and
high potency made it the maintenance drug or
detoxification treatment of opioid addiction.
Methadone has biphasic elimination. Along
β-elimination phase (ranges from 30 to 60 hours)
producing sedation and respiratory depression
can outlast the analgesic action which equates
the α-elimination phase (6-8 hours).This biphasic
pattern explains why methadone is required
once a day for opioid maintenance therapy and
every 4 to 8 hours for analgesia.
Rapid titration is not possible, making this
drug more useful for stable type of pain.
10
Q
150. What property of methadone makes it a good option for opioid rotation, when tolerance develops? (A) Serotonin agonist (B) α2B-Adrenoreceptor agonist (C) μ-Agonist (D) NMDA agonist (E) NMDA antagonist
A
- (E) When tolerance to opioids, usually after
use over long periods of time, opioid rotation,
resting period off opioids, and addition of an
NMDA antagonist are a number of strategies
available.
Opioid rotation, switching from one opioid
to another may be helpful because of partial
cross tolerance between opioids. Because
methadone has NMDA receptor antagonist
properties, makes it a good choice.
Methadone is: μ- and δ-antagonist, NMDA
inhibitor, inhibitor of serotonin and norepinephrine
reuptake.
11
Q
151. Which one of the following is the only opioid with prolonged activity not achieved by controlled-released formulation? (A) Oxycodone (B) Fentanyl (C) Morphine (D) Codeine (E) Methadone
A
- (E) Methadone is the only opioid with prolonged
activity not achieved by controlledrelease
formulation.
Oxycodone can be formulated as controlledrelease.
Codeine half-life is 2 to 4 hours.
12
Q
152. Which of the following opioids is used in the office-based treatment of addiction? (A) Naloxone (B) Morphine (C) Tramadol (D) Buprenorphine (E) Meperidine
A
- (D) Buprenorphine is a semisynthetic opioid
with partial activity at the μ-receptor and very
little activity at the κ- and δ-receptors.
It has high affinity but low intrinsic activity
at the μ-receptor and has a pharmacologic
ceiling owing to its partial agonist activity.
It is available in the United States to be
used in the office-based treatment of addiction.
It can be given for withdrawal of heroin or
methadone, or used as a maintenance of addicts.
13
Q
153. Pharmacologic properties of fentanyl that make it an ideal drug for transdermal and transmucosal administration is (A) high lipid solubility, high molecular weight, and high potency (B) low lipid solubility, high molecular weight, and high potency (C) low lipid solubility, low molecular weight, and low potency (D) high lipid solubility, low molecular weight, and high potency (E) high lipid solubility, low molecular weight, and low potency
A
- (D) Fentanyl is a potent mu agonist, with high
lipid solubility, low molecular weight and high
potency, making it an ideal drug for transdermal
and transmucosal administration.
92% of fentanyl delivered transdermally
reaches the circulation as unchanged fentanyl.
Transmucosal route at the buccal and sublingual
mucosa skips the first pass effect and
overall bioavailability is 50%.
14
Q
- Opioids can have drug interactions with
(A) tricyclic antidepressants (TCAs)
(B) selective serotonin reuptake inhibitor
(SSRIs)
(C) monoamine oxidase inhibitors (MAOIs)
(D) metoprolol
(E) all of the above
A
- (E) Opioids can have interactions with multiple
medications, including all the medications
mentioned above. One of the most remarkable interactions occurs if meperidine and MAOIs are combined,
severe respiratory depression or excitation,
arrhythmias, delusions, hyperpyrexia,
seizures and coma can be seen
15
Q
155. Which of the following is a long and cumbersome research tool for substance abuse and is very good but not very practical in the setting of a busy pain clinic? (A) Screening Tool for Addiction Risk (STAR) (B) Severity of Opiate Dependence Questionnaire (SODQ) (C) Screening Instrument for Substance Abuse Potential (SISAP) (D) Addiction Severity Index (ASI) (E) Prescription Drug Use Questionnaire (PDUQ)
A
- (D) The Addiction Severity Index (ASI) is especially
effective for evaluating the need for
substance-abuse treatment. It is a 200-item,
hour-long assessment of seven potential problem
areas designed to be administered by a
trained interviewer.
16
Q
- An opioid specific five-question self-administered
tool which can be completed in less than 5 minutes
to help predict patients at high-risk for
exhibiting aberrant opioid-related behavior is
(A) Prescription Drug Use Questionnaire
(PDUQ)
(B) Opioid Risk Tool (ORT)
(C) Screener and Opioid Assessment for
Patients with Pain (SOAPP)
(D) Screening Instrument for Substance
Abuse Potential (SISAP)
(E) Severity of Opiate Dependence
Questionnaire (SODQ)
A
- (B) The Opioid Risk Tool (ORT) is a fivequestion
self-administered assessment that can
be completed in less than 5 minutes and used
on a patient’s initial visit. Personal and family
history of substance abuse; age; history of
preadolescent sexual abuse; and the presence of
depression, attention-deficit disorder (ADD),
obsessive-compulsive disorder (OCD), bipolar
disorder, and schizophrenia are assessed. The
ORT accurately predicted which patients were
at the highest and the lowest risk for exhibiting
aberrant, drug-related behaviors associated
with abuse or addiction.
17
Q
157. The opioid which is largely metabolized by CYP3A4 is (A) morphine (B) fentanyl (C) methadone (D) hydromorphone (E) oxymorphone
A
- (B)
18
Q
- Which of the following is correct regarding
patients who are prescribed and taking
hydrocodone and found to have different opioid
in their urine drug-testing results?
(A) Norfentanyl, which is expected
(B) Hydrocodeine, which is expected as a
normal metabolite
(C) Hydromorphone, which is expected as a
normal metabolite
(D) Hydromorphone, which is unexpected
and patient is probably taking another
opioid
(E) Hydrocodeine, which is unexpected and
patient is probably taking another
opioid
A
- (C)
19
Q
- An opioid-specific instrument which may be
useful in predicting opioid misuse and is available
as a 5-, 14-, or 24-item questionnaire as well
as a revised version designed to be less susceptible
to overt deception than the original version is
(A) Prescription Drug Use Questionnaire
(PDUQ)
(B) Opioid Risk Tool (ORT)
(C) Screener and Opioid Assessment for
Patients with Pain (SOAPP)
(D) Screening Instrument for Substance
Abuse Potential (SISAP)
(E) Severity of Opiate Dependence
Questionnaire (SODQ)
A
- (C) Screener and Opioid Assessment for
Patients with Pain (SOAPP) is a survey tool
used to predict opioid abuse and is available as
a 5-, 14-, 24-item questionnaire. Although the
five-item questionnaire [SOAPP V LO-SF (5Q)]
is less sensitive and specific than the longer
version, it may suffice for use in primary care
settings. The SOAPP-SF is scored by adding
up the ratings of each of the five questions. The
SQ SOAPP uses a cutoff score of 4 or above
(of a possible 20) with a score of more than 4,
indicating that the subject may have a potentially
increased risk of opioid abuse.
20
Q
160. Aclassic example of an opioid partial agonist is (A) naltrexone (B) butorphanol (C) nalbuphine (D) buprenorphine (E) pentazocine
A
- (D)
21
Q
- A popular mnemonic for following relevant
domains of outcome in pain management for
patients on long-term opioid therapy is the socalled
4 A’s which include all the following,
EXCEPT
(A) analgesia
(B) activities of daily living
(C) adverse events
(D) affect
(E) aberrant drug-taking behaviors
A
- (D)
22
Q
162. A popular pain assessment scale which is utilized by preverbal toddler and nonverbal children through age 7 years who may be treated with opioids is (A) CRIES (B) APPT (C) FACES (D) FLAC C (E) N-PASS
A
- (D)
23
Q
163. The opioid which has some component of metabolism by CYP1A2 is (A) morphine (B) fentanyl (C) methadone (D) hydromorphone (E) oxymorphone
A
- (C)
24
Q
164. The opioid which is a metabolite of oxycodone via 3-0-demethylation is (A) hydrocodone (B) morphine (C) codiene (D) hydromorphone (E) oxymorphone
A
- (E)
25
Q
- Which of the following two opioids are inherently,
pharmacologically, and relatively longacting?
(A) Morphine and oxycodone
(B) Morphine and oxymorphone
(C) Oxycodone and fentanyl
(D) Methadone and levorphanol
(E) Methadone and oxymorphone
A
- (D)
26
Q
- Oral transmucosal fentanyl citrate (OTFC) is
applied against the buccal mucosa. The percentage
of the total dose which is absorbed
from the gastrointestinal (GI) tract but escapes
hepatic and intestinal first-pass elimination is
(A) 25%
(B) 33%
(C) 50%
(D) 65%
(E) 75%
A
- (A)
27
Q
167. OTFC is applied against the buccal mucosa. The total apparent bioavailability is (A) 25% (B) 33% (C) 50% (D) 65% (E) 75%
A
- (C)
28
Q
168. The fentanyl buccal tablet (FBT) utilizes an effervescent drug delivery system and achieves an absolute bioavailability of (A) 25% (B) 33% (C) 50% (D) 65% (E) 75%
A
- (D)
29
Q
- After intramuscular administration of fentanyl
citrate, the time to onset of analgesia is roughly
(A) 1 to 3 minutes
(B) 7 to 15 minutes
(C) 15 to 30 minutes
(D) 20 to 40 minutes
(E) 30 to 50 minutes
A
- (B)
30
Q
170. The oral bioavailability of morphine is roughly (A) 10% to 20% (B) 25% to 35% (C) 35% to 45% (D) 40% to 55% (E) 50% to 60%
A
- (B)
31
Q
171. In humans, methadone acts as (A) an agonist-antagonist (B) a pure μ-agonist (C) a μ-agonist but also with significant actions at the δ-opioid receptor (D) a μ-agonist but also with significant actions at the κ-receptor (E) a μ-, δ-, and κ-agonist
A
- (B)
32
Q
172. Atool which documents a quantitative assessment of various opioid-adverse effects is the (A) Pain Assessment and Documentation Tool (PADT) (B) Translational Analgesic Score (TAS) (C) SAFE score (D) Numerical Opioid Side Effect (NOSE) (E) Severity of Opioid Dependence Questionnaire (SODQ)
A
- (D)
33
Q
173. Which of the following is the best opioid to administer for analgesia in a patient with chronic kidney disease stage V? (A) Codeine (B) Meperidine (C) Morphine (D) Fentanyl (E) Propoxyphene
A
- (D)
34
Q
- Which of the following is the most prescribed
opioid in the United States, which also undergoes
O-demethylation to dihydromorphine and
its major metabolites excreted into the urine are
dihydrocodeine and nordihydrocodeine?
(A) Codeine
(B) Dihydrocodeine
(C) Hydrocodone
(D) Hydromorphone
(E) Morphine
A
- (C)
35
Q
- Which of the following is essentially responsible
for opioid-induced respiratory depression?
(A) μ-Receptor
(B) δ-Receptor
(C) κ-Receptor
(D) σ-Receptor
(E) ORL 1 receptor
A
- (A)
36
Q
- Propoxyphene napsylate has a higher maximum
daily dose than propoxyphene hydrochloride
because
(A) propoxyphene napsylate is less potent
than propoxyphene hydrochloride
(B) propoxyphene napsylate is less toxic
than propoxyphene hydrochloride
(C) propoxyphene napsylate is cleared
faster than propoxyphene hydrochloride
(D) the napsylate salt tends to be absorbed
more slowly than the hydrochloride
(E) the napsylate salt makes propoxyphene
less active
A
- (D)
37
Q
177. When considering opioid rotation to methadone, which of the following is the most appropriate next step? (A) Maintain the equianalgesic dose (B) Reduce the dose by 10% to 25% (C) Reduce the dose by 25% to 50% (D) Reduce the dose by 50% to 75% (E) Reduce the dose by 75% to 90%
A
- (E)
38
Q
178. When considering opioid rotation to fentanyl, which of the following is the most appropriate step? (A) Maintain the equianalgesic dose (B) Reduce the dose by 10% to 25% (C) Reduce the dose by 25% to 50% (D) Reduce the dose by 50% to 75% (E) Reduce the dose by 75% to 90%
A
- (A)
39
Q
179. The equianalgesic conversion ratio of oral oxymorphone to intravenous morphine is (A) 1 to 1 (B) 1 to 2 (C) 1 to 3 (D) 1 to 4 (E) 1 to 5
A
- (A)
40
Q
- By approximately what percentage is codeine
ineffective as an analgesic in the Caucasian
population owing to genetic polymorphisms
in CYP2D6 (the enzyme necessary to Omethylate
codeine to morphine)?
(A) 2%
(B) 5%
(C) 10%
(D) 25%
(E) 33%
A
- (C)
41
Q
- Which of the following is the correct statement
regarding the pharmacologic properties of
NSAIDs?
(A) They readily cross the blood–brain
barrier
(B) Their chemical structure consists of aromatic
rings connected to basic functional
groups
(C) They act mainly in the periphery
(D) They have a high renal clearance
(E) They are not metabolized by the liver
A
- (C) The NSAIDs are weak organic acids, consisting
in one or two aromatic rings connected to
an acidic functional group. They do not cross
the blood–brain barrier, are 95% to 99% bound
to albumin, are extensively metabolized by the
liver and have low renal clearance (
42
Q
- What are the advantages of COX-2 inhibitors
versus NSAIDs?
(A) Protective renal effects
(B) Less GI side effects
(C) Protective cardiovascular effects
(D) Inhibits production of thromboxane A2
(E) Increases production of lipooxygenase
A
- (B) Coxibs do not have any advantages in
terms of renal effects.
COX-2 inhibitors are associated with less
GI toxicity than standard NSAIDs but they are
more expensive.
There is a possible increased risk of myocardial
infarction (MI) and thrombotic stroke events
associated with the continuosly long-term use of
coxibs. Those concerns led to rofecoxib and
valdecoxib being withdrawn from the market in
the year 2004 and 2005, respectively.
Regular NSAIDs inhibit the synthesis of
TXA2 by inhibiting COX-1, which is spared
with the use of COX-2 inhibitors.
43
Q
183. Which of the following best fits the pharmacologic mechanisms of action of “traditional” NSAIDs? (A) Inhibition of phospholipase A2 (B) Inhibition of COX-2 (C) Inhibition of lipoxygenase (D) Inhibition of arachidonic acid (E) Inhibition of prostaglandin G/H synthase enzymes
A
- (E) NSAIDs inhibits the prostaglandin G/H
synthase enzymes, colloquially known as the
COX, therefore inhibiting the synthesis of
prostaglandin E, prostacyclin, and thromboxane.
NSAIDs inhibit the production of not only
COX-2 but also COX-1.
Steroids inhibit phospholipase A2.
44
Q
- The main role of prostaglandins in pain is
(A) as important primary pain mediators
(B) sensitization of central nociceptors
(C) sensitization of peripheral nociceptors
(D) facilitation of the production of pain
mediators (ie, bradykinin, somatostatin,
histamine)
(E) stimulation of κ-receptors on the spinal
cord
A
- (C) Prostaglandins are not important primary
pain mediators, they do cause hyperalgesia by
sensitizing peripheral nociceptors (to mechanical
an chemical stimulation) to the effects of pain
mediators, such as bradykinin, somatostatin,
and histamine, producing hyperalgesia. They
do so by lowering the threshold of the polymodal
nociceptors of C fibers.
NSAIDs act mainly in the periphery, but
they may have a central effect. COX-2 induction
within the spinal cord may play an important
role in central sensitization. The acute
antihyperalgesic action of NSAIDs has been
shown to be mediated by the inhibition of constitutive
spinal COX-2, which has been found
to be upregulated in response to inflammation
and other stressors.
45
Q
185. The effects of NSAIDs on the kidneys function or renal function may include (A) increase in renal blood flow (B) promotion of salt and water excretion (C) chronic interstitial nephritis (D) increased glomerular filtration rate (GFR) (E) chronic papillary necrosis
A
- (C) In the kidney, prostaglandins help to maintain
GFR and blood flow.
They also contribute to the modulation of
renin release, excretion of water, and tubular
ion transport. In patients with normal renal
function NSAID-induced renal dysfunction is
extremely rare.
Risk factors for NSAID-induced renal
dysfunction are:
• Prolonged and excessive NSAID use
• Older patients
• Chronic renal dysfunction
• Congestive heart failure
• Ascites
• Hypovolemia
• Treatment with nephrotoxic drugs (aminoglycosides
and vancomycin)
In these scenarios NSAIDs may decrease
rapidly the GFR, release of renin, which can
progress to renal failure. Sodium, water retention,
hyperkalemia, hypertension, acute papillary
necrosis, chronic interstitial nephritis,
and nephrotic syndrome can also occur.
Coxibs (COX-2 inhibitors) have similar
renal effects and it should be closely monitored,
as is required for conventional NSAIDs.
46
Q
- Platelet dysfunction secondary to the use of
NSAIDs is a known effect, in long-term treatment
with standard NSAIDs. What laboratory
value is most compatible with these effects?
(A) Prolonged prothrombin time (PT)
(B) Prolonged partial thromboplastin time
(PTT)
(C) Prolonged activated clotting time (ACT)
(D) Severely prolonged bleeding time
(E) Below the upper limits of normal to
mildly prolonged bleeding time
A
- (E) Platelets are very susceptible to COX inhibition,
which also inhibits the endogenous procoagulant
thromboxane. Long-term use of standard
NSAIDs produces a consistently prolonged
bleeding time, but the prolongation is mild and
values tend to remain below the upper limits of
normal.
47
Q
- The duration of aspirin effect is related to the
turnover rate of COX in different target tissues,
because aspirin
(A) competitively inhibits the active sites of
COX enzymes
(B) nonirreversibly inhibits COX activity
(C) irreversibly inhibits COX activity
(D) noncompetitively inhibits the active
sites of COX enzymes
(E) acetylates COX-1
A
- (C) Aspirin covalently acetylates COX-1 and
COX-2, irreversibly inhibiting COX activity. This
makes the duration of aspirin’s effects related to
the turnover rate of COX in different target
tissues.
NSAIDs competitively inhibit the active
site of COX enzymes which relates its duration
more directly to the time course of drug
disposition.
48
Q
- The unique sensitivity of platelets to inhibition
by low doses of aspirin (as low as 30 mg/d) is
related to
(A) first pass of aspirin through the liver
(B) presystemic inhibition of platelets in the
portal circulation
(C) irreversible inhibition of COX
(D) constitutively expression of COX-1 in
platelets
(E) good oral absorption
A
- (B) The unique sensitivity of platelets to inhibition
by low doses of aspirin, as low as 30 mg/d
is related to their presystemic inhibition in the
portal circulation before aspirin is deacetylated
to salicylate on first pass through the liver.
Aspirin irreversibly inhibits COX activity,
making the aspirin’s effect related to the
turnover rate of COX in different target tissues.
Enzyme turnover is most notable in platelets
because they are anucleated with a marked limited
capacity for protein synthesis. Therefore the
inhibition of platelet COX-1 (COX-2 is expressed
only in megakaryocytes) last for the lifetime of the platelet, 8 to 12 days (10 days average) after
therapy has been stopped.
In general NSAIDs are well absorbed orally,
but that is not the reason for high platelet
sensitivity to ASA.
49
Q
189. How long before surgery NSAIDs are advised to be stopped? (A) 12 hours (B) 2 to 3 days (C) 7 days (D) 10 days (E) 14 days
A
- (B) The antiplatelet effect of NSAIDs is rapidly
reversible, 24 hours cessation is probably sufficient,
although 2 to 3 days cessation is advised.
Aspirin because of its irreversible
antiplatelet effect should be stopped 10 days
before elective surgery.
50
Q
190. Which of the following NSAIDs is as effective as morphine? (A) Ketoprofen (B) Indomethacin (C) Ibuprofen (D) Ketorolac (E) Diclofenac
A
- (D) Ketorolac is one of the few NSAIDs that the
FDA approved for parenteral use. It is highly
efficacious, with efficacy close to that of morphine
and other opioids for simple outpatient
procedures to major operations.
Ketorolac’s side effects, like other NSAIDs
include GI bleeding, other bleeding problems,
and reversible renal dysfunction (Possibly
related with use of high doses or failure to recognize
its contraindications).
Nonunion, deleterious effects in bone osteogenesis
during bone repair are some other side
effects, more likely to occur if ketorolac was
administered after surgery, compared with no
use of NSAIDs. Decreased posterior spine fusion
rates have been demonstrated in rat models,
with the long-term use of indomethacin, but
even the short-term administration of NSAIDs
may possibly significantly affect spinal fusion.
These findings have not been confirmed in
humans, but many surgeons prefer to avoid the
use of NSAIDs in the postoperative period of
bone fusion, especially in the spine. COX-2
inhibitors can have similar effects, which is
unlikely with short-term perioperative use in
humans. No human studies to date document
that coxibs have these negative effects in bone
healing.
51
Q
191. Rare side effect of NSAIDs is (A) GI side effects (B) platelet dysfunction (C) potentially fatal hepatic necrosis (D) renal dysfunction/failure (E) all of the above
A
- (C) All are well-known and not uncommon
side effects of NSAIDs. Borderline increases of
one or more liver tests, may occur in up to 15%
of patients taking NSAIDs, approximately 1%
of patients taking NSAIDs have shown notable
increases in alanine aminotransferase (ALT) or
aspartate aminotransferase (AST) (X3 or more
the upper limit of normal). These findings may
progress, remain unchanged, or be transient
with continuing therapy. Rare cases of severe
hepatic reactions, including jaundice and fatal
fulminant hepatitis, liver necrosis, and hepatic
failure (some with fatal outcome), have been
reported with NSAIDs.
52
Q
192. Which of the following is (are) true regarding oxcarbazepine? (A) It has more adverse effects than carbamazepine (B) It is a sodium channel blocker (C) Oxcarbazepine’s dose adjustment is unnecessary for renal insufficiency (D) Its most frequent adverse effects is weight loss and dizziness (E) none of the above
A
- (B) Oxcarbazepine [10, 11-dihydro-10-oxo-5Hdebenz
(b, f) azepine-5-carboxanide] is an analogue
of carbamazepine with a keto group at
the 10 carbon position. It is roughly 50% protein
bound in the plasma. The dose should be
at least cut by half if the patient has significant
renal insufficiency.
The most frequent adverse effects experienced
include dizziness and vertigo, weight
gain and edema, GI symptoms, fatigue, and
allergic-type reactions. Cross-allergy to carbamazepine
occurs in about 25% of patients and
may be severe.
53
Q
193. Which of the following is a typical adverse effect of pregabalin? (A) Constipation (B) Dizziness (C) Blurred vision (D) Dry mouth (E) All of the above
A
- (E)
54
Q
- Which of the following is (are) false regarding
gabapentin?
(A) It is a first-line drug for the treatment of
PHN and PDN (painful diabetic neuropathy)
(B) Its dose should be reduced in renal
insufficiency
(C) It blocks NMDA receptors
(D) It is thought to inhibit voltagedependent
calcium channels
(E) It has a chemical structure similar to
that of GABA
A
- (C) A structural analogue of GABA is considered
by many practitioners to be a first-line
drug for treatment of PHN and PDN because
of its tolerability and efficacy. Dose should be
reduced in renal dysfunction. Dose increases
are usually made every 3 to 4 days.
55
Q
- Which of the following is true about zonisamide?
(A) It is a sulfonamide drug
(B) It is a sodium channel blocker
(C) It is 40% to 50% protein bound
(D) It may potentially lead to renal calculi
(E) All of the above
A
- (E)
56
Q
- Which of the following is true about antiepileptic
drugs (AED)?
(A) AEDs have analgesic effect in all subjects
with neuropathic pain
(B) If one AED is ineffective, it is not necessary
to try another one
(C) Newer AEDs have more side effects
than older ones
(D) AEDs could be combined with antidepressants
to treat neuropathic pain
(E) All of the above
A
- (D)
57
Q
197. The antidepressant with the least anticholinergic and least sedating effect is (A) trazodone (B) desipramine (C) imipramine (D) doxepin (E) amitriptyline
A
- (B) Anticholinergic side effects are generally
very significant for TCAs.
58
Q
- Which of the following antidepressant agent
selectively inhibits serotonin reuptake with
minimal effect on norepinephrine reuptake?
(A) Duloxetine
(B) Protriptyline
(C) Paroxetine
(D) Amoxapine
(E) Desipramine
A
- (C) Antidepressants which selectively inhibit
serotonin with minimal effects on norepinephrine
reuptake are referred to as SSRIs (eg, paroxetine).
Protriptyline, desipramine, and amoxapine
are secondary amine TCAs. Duloxetine inhibits
both norepinephrine and serotonin (SNRIs).
59
Q
199. The most common adverse effects associated with TCA are (is) (A) anticholinergic effects (B) seizures (C) arrhythmias (D) hepatotoxicity (E) nephrotoxicity
A
- (A) Side effects of antidepressants include anticholinergic
effects, antihistaminergic effects, α1-
aderenergic receptor bloackade, and cardiac
effects. Individual may possess significant side
effects in one specific area (eg, doxepin is a strong
antihistaminergic agent). As a generalization,the most common adverse effects associated
with TCAs are anticholinergic in nature.
60
Q
200. The least common adverse effects associated with TCA are (is) (A) dry mouth (B) seizure (C) urinary retention (D) blurred vision (E) aconstipation
A
- (B)
61
Q
201. Compared to TCAs, SSRIs (A) are more effective in the treatment of pain (B) have more side effects (C) have less side effects (D) have more serious consequence of overdosage (E) none of the above
A
- (C)
62
Q
202. Which of the following is false regarding tramadol? (A) It has opioid characteristics (B) There is a dose limit of 400 mg/d (C) It is a centrally acting analgesic (D) No effect on norepinepherine or serotonin (E) Inhibits the reuptake of norepinephrine and serotonin
A
- (D) Tramadol hydrochloride is a centrally
acting analgesic which is thought to provide
analgesia via at least two mechanisms: some
analgesia may be derived from the relatively
weak interaction of tramadol with the μ-opioid
receptor. The second and major mechanism,
which is thought to account for at least 70% of
tramadol’ s analgesic activity, is via inhibiting
the reuptake of norepinephrine and serotonin
63
Q
203. The benzodiazepine which is used to treat various neuropathic pain syndromes is (A) diazepam (B) midazolam (C) clonazepam (D) flunazepam (E) lorazepam
A
- (C) Clonazepam is a benzodiazepine—which
binds to the GABAB receptor (other benzodiazepines
bind to the GABAA receptor) and has
been utilized to treat various neuropathic pain
syndrome and lower extremity muscle conditions.
64
Q
- Which of the following about carisoprodol is true?
(A) Naloxone may be a useful antidote to its
toxicity
(B) Flumazenil may be a useful antidote to
its toxicity
(C) It is safe to use as a long-term treatment
of musculoskeletal disorders
(D) It is a GABAB receptor agonist
(E) It has no abuse potentia
A
- (B) Carisoprodol may be useful for the short-term
treatment of acute musculoskeletal disorders,
especially in combination with acetaminophen,
aspirin, or NSAIDs. Carisoprodol is primarily
metabolized in the liver to several metabolites,
including meprobamate. This metabolic conversion,
although relatively small, has been postulated
to be the reason that carisoprodol may have
abuse potential. The formation of meprobamate
from carisoprodol is by N-dealkylation via
CYP2C19. Poor metabolizers of mephenytoin
have a diminished ability to metabolize carisoprodol
and therefore may be at increased risk of
developing concentration-dependent side effects
(eg, drowsiness, hypotension, CNS depression)
at “usual” adult doses.
Although the precise mechanisms of action
of carisoprodol (as well as meprobamate) are
uncertain, one theory is that they act as indirect
agonists at the GABAA receptor, yielding CNS
chloride ion channel conduction effects similar
to benzodiazepines. Therefore, flumazenil may
be a potentially useful antidote to carisoprodol
toxicity.
65
Q
- Which of the following is true regarding
tizanidine?
(A) It is structurally related to clonipine
(B) It is GABAB receptor agonist
(C) It is GABAA receptor agonist
(D) Its excretion occurs primarily through
the liver
(E) It is α2 agonist
A
- (E) Tizanidine is an imidazoline derivative that
is structurally related to clonidine. Its action is
primarily derived from agonism at the α2-
adrenoreceptor.
Metabolism of tizanidine occurs primarily
in the liver through oxidative processes, and
metabolites of the parent compound have no
known pharmacologic activity. Excretion of
tizanidine and its metabolites occurs primarily
via the kidneys (53%-66%).
66
Q
- Which of the following is a false statement
about ziconotide?
(A) It is derived from conus sea snail venom
(B) It is the synthetic form of cone snail
peptide (conotoxin)
(C) It is effective when given intravenously
or orally
(D) It is N-type calcium channel blocker
(E) Its common side effects are dizziness,
confusion, and headache
A
- (C)
67
Q
- Which of the following is true regarding
capsaicin?
(A) It is a member of the vanilloid family
which binds to the TRPV1 receptor
(B) It is commercially available in 0.025%
and 0.075% concentrations
(C) It is the active component of chili
peppers
(D) It depletes presynaptic substance P
(E) All of the above
A
- (E)
68
Q
208. The following are some of the side effects of lidocaine 5% patches, EXCEPT (A) methemoglobin (B) edema (C) erythema (D) abnormal sensation (E) exfoliation
A
- (A)
69
Q
209. Calcitonin may be used as an adjuvant drug for all the following, EXCEPT (A) phantom limb pain (B) sympathetically maintained pain (C) cancer bone pain (D) postoperative pain (E) osteoporosis pain
A
- (D)
70
Q
- Regarding the effects produced by the different
subtypes of opioid receptors, which of the following
is (are) true?
(1) κ-Receptors produce more respiratory
depression than μ-receptors
(2) Opioid receptors mostly affect phosphorylation
through G protein coupling
(3) The stimulation of μ2-receptors to produce
analgesia without respiratory
depression, has been supported by
several studies
(4) Opioid receptors act both presynaptically
and postsynaptically
A
- (C) The previously proposed classification of μ-
receptors into μ1 and μ2 subtypes, with the
rationale that selective μ1-agonist could produce
analgesia without the undesirable effects
of respiratory depression has not been proven.
Gene experiments have demonstrated that μ-
receptors mediate all morphine activities
including analgesia, tolerance, dependence,
and respiratory depression.
Opioid receptors are coupled to G proteins
and they act mostly through phosphorylations
via a second messenger.
Opioids act pre- and postsynaptically.
Presynaptically, inhibit the release of neurotransmitters
including substance P and glutamate.
Postsynaptically inhibit neurons by
hyperpolarization, through the opening of
potassium channels
71
Q
- The use of pure opioid agonists are preferred in
chronic pain patients because of their
(1) low association with addiction
(2) superior analgesic efficacy
(3) low potential for nausea and vomiting
(4) easier titratable nature
A
- (C) When choosing between partial agonists (ie,
buprenorphine) and mixed agonist-antagonists
(ie, pentazocine, nalorphine) versus pure agonists,
pure opioid agonists are preferred, especially
in chronic pain patients, because of their
superior efficacy and easier titratable nature
72
Q
212. The systemic administration of opioids exerts its analgesic effects at what level(s)? (1) Brain cortex (2) Brainstem and medulla (3) Dorsal horn of the spinal cord (4) Sensory neuron (peripheral nervous system)
A
- (E) Analgesic effects of systemic administration
of opioids result from receptor opioid
activity at different sites, including: - The sensory neuron in the peripheral nervous
system. - The dorsal horn of the spinal cord (inhibition
of transmission of nociceptive information). - The brainstem medulla (potentiates descending
inhibitory pathways that modulate ascending
pain signals). - The cortex of the brain (decreases the perception
and emotional response to pain).
73
Q
- Which of the following condition(s) increase
the likelihood of opioid-related toxicity?
(1) Pregnancy
(2) Renal disease
(3) Cardiac heart failure
(4) Cirrhotic liver disease
A
- (C) The liver metabolizes opioids by dealkylation,
glucuronidation, hydrolysis, and oxidation,
any hepatic disease can increase the
accumulation of toxic metabolites, that is,
morphine-6-glucuronide, normeperidine (CNS
toxicity), norpropoxyphene (cardiac toxicity).
Kidneys account for 90% of opioid excretion.
Therefore any hepatic or renal disease
increases the likelihood of opioid-related
toxicity.
74
Q
- Which of the following is (are) true concerning
the use of epidural morphine?
(1) A biphasic respiratory depression pattern
can develop, with the initial phase
within 30 minutes of the bolus dose and
a second phase 2 to 4 hours later
(2) Initial phase within 2 hours of the bolus
dose and a second phase 6 to 12 hours
later
(3) Patients should be closely monitored for
48 hours after the administration of
epidural morphine
(4) Patients should be closely monitored for
24 hours after the administration of
epidural morphine
A
- (C) The use of hydrophilic opioids like morphine
in the epidural space produces a biphasic
respiratory depression pattern. One portion
of the initial bolus is absorbed systemically,
accounting for the initial phase, which usually
occurs within 2 hours of the bolus dose. The
second phase occurs 6 to 12 hours later owing
to the slow rostral spread of the remaining drug
as it reaches the brainstem.
75
Q
- Opioids should be used with caution in which
of the following scenarios?
(1) Emphysema
(2) Kyphoscoliosis
(3) Chronic obstructive pulmonary disease
(COPD)
(4) Obstructive sleep apnea
A
- (E) Opioids should be used with caution in any
situation with decrease respiratory reserve, that
is, emphysema, obesity, scoliosis. Opioids that
release histamine (ie, morphine) may precipitate
bronchospasm, especially in asthma.
76
Q
- Indicate what part differs largely among the μ-,
δ-, κ-, and ORL (opioid-receptor-like) receptors?
(1) Transmembrane domains
(2) Extracellular loops
(3) Intracellular loops
(4) N or C terminal tails
A
- (C) The opioid receptors, μ-, δ-, κ-, ORL receptors
are highly similar, their genes have been
cloned in many species, including humans.
The molecular structure of these G
protein–coupled receptors (GPCRs) comprises
7 hydrophobic transmembrane domains interconnected
by short loops, an intracellular
C-terminal tail and an extracellular N-terminal
domain.
The transmembrane domains and intracellular
loops have amino acid sequences that
are 65% identical or similar, whereas the amino
(N), carboxy (HOOC) terminal and the extracellular
loops are very different
77
Q
- Opioids modify and relieve the perception of
pain without detriment of other sensory mode
types. While the pain is still present there is a
dissociation of the emotional and sensory
aspects of pain, making the patients feel more
comfortable. Select the best reason(s) from the
following:
(1) Action of opioids on supraspinal structures,
brainstem [ie, PAG (periaqueductal
gray) the RVM (rostroventral medulla)],
and midbrain
(2) Action of opioids on peripheral structures
via presynaptic receptors
(3) Enhanced inhibitory activity on
descending controls terminating in the
dorsal horn of the spinal cord
(4) Pronounced reduction in activity of OFF
cells and decreased activity of ON cells
A
- (B) When noxious stimuli are produced, they
are transmitted to higher centers through
spinal routes arriving at the parabrachial area,
central gray, and the amygdala. The pathways
which project to these supraspinal sites and
the sites themselves contribute mostly to the
emotional aspects of pain, whereas those which
project to the thalamus and somatosensory
cortex produce the sensory aspects of pain.
Opioids suppress both pathways but the
dissociation of the emotional and sensory
aspects of pain is most likely produced by
brain mechanisms.
Opioids can also prevent the supraspinal
activation by noxious stimuli through increased
activity in inhibitory descending controls terminating
in the dorsal horn of the spinal cord.
The action of opioids on peripheral structures
does not abolish the emotional aspects of
pain.
There is a hypothesis describing two major
populations of RVM output neurons, ON cells
and OFF cells. ON cells activity coincides with
spinal reflexes and OFF cell activity is associated
with the suppression of those reflexes.
Morphine produces a pronounced reduction
in the activity of ON cells.
78
Q
- Opioids exert their analgesic effects through
(1) their central action within the central
nervous system (CNS), inhibiting directly
the ascending transmission of painful
stimuli from the dorsal horn at the
spinal cord
(2) their central action within the CNS activating
pain control circuits descending
from the midbrain via the RVM to the
spinal cord dorsal horn
(3) their peripheral actions on opioid receptors
and the release of endogenous
opioid-like substances
(4) their action on the spinal cord at a
presynaptic level only
A
- (A) Opioids exert their analgesic effects through
central and peripheral mechanisms. Although it
was believed that opioids act exclusively within
the CNS, there are opioid receptors outside the
CNS able to produce analgesic effects in the
periphery. The opioid receptors are synthesized
in the dorsal root ganglia (DRG) and transported
toward the peripheral sensory nerve
endings. These peripheral actions are enhanced
under inflammatory conditions. Immune cells
may release endogenous opioid-like substances,
which act on opioid receptors located on the
primary sensory neuron.
Centrally, the opioids inhibit directly the
ascending transmission of painful stimuli
arising from the spinal cord (dorsal horn) and
activate circuits that descend from the midbrain
via the RVM to the dorsal horn.
79
Q
- Which of the following is (are) true regarding
pharmacologic characteristics of opioids?
(1) Opioids are the primary pain medication
with ceiling effects
(2) Opioids are the primary pain medication
with no ceiling effects
(3) There are sex related differences in
opioid-mediated responsiveness
(4) There are no sex related differences in
opioid-mediated responsiveness
A
- (C) Opioids are a primary pain medication that
has no ceiling effect , and there is no “mild”
opioids, because they can be titrated to produce
equianalgesic effects. Although some opioids
have been considered “mild” because of dose-related side effects or because commercial
preparations are combined with adjuvant
drugs (ie, aspirin or acetaminophen) limiting its
dosing.
There is evidence indicating that morphine
has greater potency but slower speed of
onset and offset in women.
Opioids acting in μ- and κ-receptors constrict
the pupil by exciting the Edinger Westphal
nucleus (parasympathetic). Long-term opioid
use can produce tolerance to miotic effects of
opioids.
80
Q
- Tramadol has some different characteristics
when compared to some other opioids including
(1) same side effects as morphine
(2) risk of respiratory depression is lower at
equianalgesic doses from that produce
with conventional opioids
(3) less incidence of nausea and vomiting
(4) low abuse potential
A
- (C) Tramadol has a different profile from that of
conventional opioids. It is very effective in the
treatment of severe pain, with fewer side effects
than morphine.
The risk of respiratory depression is lower
at equianalgesic doses; the risk of fatal respiratory
depression is minimal at appropriate
oral dosing, and limited essentially to patients
with severe renal failure.
Tramadol has a low abuse potential, however,
nausea and vomiting occur at the same
rate as with other opioids.
81
Q
221. Morphine should be used with caution in which situations/conditions? (1) Short bowel syndrome (2) Mild liver dysfunction (3) Vomiting or severe diarrhea (4) Renal dysfunction
A
- (D) Morphine is metabolized by the liver to
morphine-6-glucuronide which is more potent
than morphine itself and has a longer half-life,
resulting in additional analgesia. Morphine is
also metabolized to morphine-3-glucuronide
which causes adverse effects and is inactive
according to others.
Renal dysfunction can produce accumulation
of morphine-6-glucuronide, with subsequent
opioid effects, including respiratory
depression, so morphine should be used with
care in renal dysfunction.
Patients with liver failure can tolerate morphine
(even in hepatic precoma), because glucuronidation
is rarely impaired.
Short bowel syndrome and vomiting and
diarrhea limit the efficacy of controlled-release
morphine, which relies in slow absorption
from the GI tract
82
Q
- The transdermal fentanyl patch has differences
versus sustained-release morphine in patients
with cancer and chronic pain:
(1) It can be used when the oral route can
not be used
(2) It is 80 times as potent as morphine
(3) It causes less constipation than
sustained-release morphine
(4) Peak plasma concentration occurs in
6 to 12 hours
A
- (A) Fentanyl is 80 times as potent as morphine.
Transdermal fentanyl is extremely useful as a
treatment in chronic pain especially in cancer
patients. It causes less constipation than
sustained-release morphine. Ninety-two percent
of fentanyl delivered transdermally reaches systemic
circulation as unchanged fentanyl.
Peak plasma concentration after application
is 12 to 24 hours and a residual depot
remains in subcutaneous tissues for about
24 hours after removal of the patch, therefore
care needs to be taken with the use of transdermal
system.
83
Q
- Which of the following is (are) correct regarding
the use of meperidine?
(1) The use of meperidine should be limited
to 1 to 2 days in the management of
acute pain
(2) Normeperidine is a neurotoxic metabolite
of meperidine
(3) Meperidine should be avoided in the
management of chronic pain
(4) The use of meperidine is recommended
in elderly patients
A
- (A) Normeperidine is a neurotoxic metabolite
of meperidine; its accumulation is more likely
in patients with poor renal function, especially
in the elderly. The use of meperidine should be
limited to 1 to 2 days for acute pain and should
be avoided in chronic pain management.
84
Q
- Which of the following is (are) true regarding
opioids distribution and biotransformation
(metabolism)?
(1) Fentanyl is highly protein bound
(2) Fentanyl distributes to fat tissue and
redistributes from there into the systemic
circulation
(3) Opioids are metabolized by the liver,
CNS, kidney, lungs, and placenta
(4) Opioid distribution is independent of
protein binding and lipophilicity
A
- (A) Opioid distribution is a function of lipophilicity
and plasma protein binding. Fentanyl is both
lipophilic and highly protein bound. Fentanyl
also distributes to fat tissue and redistributes
slowly from there into the systemic circulation.
The opioids are mainly metabolized in the
liver and to a minor extent in CNS, kidneys,
lung, and placenta.
85
Q
- What is (are) the neuroendocrine effects produced
by opioids?
(1) Hypogonadism
(2) Hypothyroidism
(3) Decreased cortisol levels
(4) Decreased pituitary release of prolactin
A
- (B) Investigations have showed that endogenous
and exogenous opioids can bind to opioid receptors
primarily in the hypothalamus but also in the
pituitary gland and testes, decreasing the release
of gonadotropin-releasing hormone (GnRH),
luteinizing hormone–follicle-stimulating hormone
(LH–FSH), and testosterone-testicular
interstitial fluid, respectively. Clinically this will
manifest as hypogonadism, including: loss of
libido, impotence, infertility (males and females),
depression, anxiety, loss of muscle strength,
fatigue, amenorrhea, irregular menses, galactorrhea,
osteoporosis, and fractures.
Opioids have also been found to decrease
cortisol levels and cortisol responses, but they
do not modify thyroid function.
Opioids also have been shown to increase
pituitary release of prolactin in preclinical studies
and one study also documented decreased
growth hormone (GH), without clear clinical
significance.
86
Q
226. Which of the following drugs may show interactions with NSAIDs/COX-2 inhibitors? (1) Angiotensin-converting enzyme (ACE) inhibitors (2) Furosemide (3) Warfarin (4) Lithium
A
- (E) NSAIDs may diminish the antihyperptensive
effects of ACE inhibitors (ACEIs) and the natriuretic effect of furosemide and thiazides in
some patients.
Anticoagulant therapy with warfarin
should be monitored, especially in the first
few days of changing therapy, because all the
currently available COX-2 inhibitors may
increase serum warfarin levels.
Lithium levels may also increase with
celecoxib, valdecoxib, and rofecoxib.
87
Q
227. Which of the following is (are) contraindicated in patients allergic to sulfonamides? (1) Rofecoxib (2) Valdecoxib (3) Meloxicam (4) Celecoxib
A
- (C) All sulfonamides can be regarded to one of
the two main biochemical categories, arylamines
or nonarylamines. The sulfonamide
allergicity is thought to be related to the formation
of hydroxylamine a metabolite of the
nonarylamine group. Celecoxib and valdecoxib
belong to the former group and are contraindicated
in patients allergic to sulfonamides.
88
Q
- Anti-inflammatory agent(s) which may possess
advantages when GI side effects are a concern
include
(1) ibuprofen
(2) nabumetone
(3) diclofenac
(4) coxibs
A
- (C) Nabumetone (nonacidic prodrug metabolized
to a structural analogue of naproxen) is
minimally toxic to the GI tract, and it is the
choice when GI side effects are a special concern.
Coxibs are also a good choice if there is
any history of GI symptoms. Coxibs are associated
with less GI toxicity than standard
NSAIDs, since they do not inhibit the constitutive
COX-1 and therefore the production of the
cytoprotective PGI2 in the stomach mucosa.
89
Q
- Which of the following is (are) true for coxibs
versus NSAIDs?
(1) Coxibs are associated with less GI side
effects
(2) Coxibs have similar renal effects
(3) Coxibs are not associated with platelet
dysfunction
(4) Coxibs are associated with increased
incidence of nonunion and delayed
bone healing
A
- (A) Coxibs show less GI side effects, and have
similar renal effects to those of standard
NSAIDs.
COX-2 is not present in platetelets, and
up-to-date under most conditions, coxibs are
not associated with platelet dysfunction.
There is no documentation in humans that
the coxibs impairs bone remodeling and delay
fracture healing.
90
Q
- Which of the following NSAIDs have higher
potency (either analgesic or anti-inflammatory
or both) compared to ASA?
(1) Diflunisal
(2) Indomethacin
(3) Ketorolac
(4) Diclofenac
A
- (E) The potency of NSAIDs in general is similar
or equipotent to ASA, except for diflunisal,
indomethacin, ketorolac, and diclofenac.
Diflunisal is a difluorophenyl derivative
of salicylic acid, more potent than aspirin in
anti-inflammatory tests in animals. It is used
primarily as analgesic in osteoarthritis and musculoskeletal
sprains, where is 3 to 4 times more
potent than ASA. It also produces fewer and less
intense GI and antiplatelet effects than ASA.
Indomethacin is 10 to 40 times more
potent inhibitor of COX than ASA, but intolerance
limits its dosing to short-term. It also may
have a direct, COX-independent vasoconstrictor
effect. Some studies have suggested the
possibility of increased risk of MI and stroke,
but controlled trials have not been performed.
Ketorolac is a potent analgesic, poor antiinflammatory.
Has been used as a short term
alternative (less than 5 days) to opioids, for
moderate to severe pain.
Diclofenac is more potent than ASA; its
potency against COX-2 is substantially greater
than that of indomethacin, naproxen, or several
other NSAIDs.
Naproxen is more potent in vitro.
91
Q
231. Scenarios in which the adjunct use of NSAIDs can be beneficial in postoperative pain: (1) Use of opioids (2) No history of induced-opioid side effects (3) Preexisting ventilatory compromise (4) History of GI bleeding
A
- (B) Amultimodal approach (the combination of
different, appropriate pain treatments) seems to
be the best approach in terms of synergy and
reducing the side effects of each.
The opioid sparing effects of NSAIDs use
in postoperative pain, has been confirmed in
multiple controlled trials. This can be of particular
benefit when the opioids side effects
are especially undesirable, including preexisting
ventilatory compromise, strong history of
opioid induced side effects and the very
young
92
Q
232. Options that can be offered to patients with increased risk of GI toxicity: (1) Diclofenac with enteric coat (2) NSAIDs combined with GI prophylaxis (3) NSAIDs combined with antacids (4) Coxibs
A
- (C) Coxibs are a good choice in patients with a
history of GI symptoms or sensitivity to NSAIDs,
because they are associated with less GI side
effects than standard NSAIDs. Although they
are more expensive and they carry the concern
of increase cardiovascular risk (increased
thrombotic events: MI, stroke), with continuous
and prolonged used.
Standard NSAIDs combined with GI prophylaxis
seems to be equally effective in terms of
efficacy and freedom from GI toxicity. The GI
prophylaxis can consist of: parietal cell inhibitors
(acid inhibitors, ie, omeprazole), prostaglandin
analogues (misoprostol), and H blockers (ie, ranitidine,
cimetidine).
Diclofenac is available in combination with
misoprostol, retaining the efficacy of diclofenac
while reducing the frequency of GI toxicity; it is
cost effective relative to coxibs despite the cost
of added misoprostol. Diclofenac with enteric coat does not offer a marked less GI toxicity.
93
Q
233. Which of the following is (are) NSAID’s role in cancer? (1) Synergistic effect of NSAIDs and opioids (2) Bone and soft tissue pain relief (3) Ability to reduce the side effects of opioids (4) Visceral pain relief
A
- (E) The combination of opioid/nonopioid (ie,
NSAIDs) for mild to moderate cancer pain is
synergistic and has the ability to reduce the
side effects of each drug.
NSAIDs in advanced cancer, are particularly
useful for bone pain (distension of the
periosteum by metastases, for soft tissue pain
(distension or compression of tissues), and
for visceral pain (irritation of the pleura or
peritoneum).
ASA and other salicylates are contraindicated
in children and young adults (younger than
20 years) with fever associated with viral illness,
owing to the association with Reye syndrome.
Acetaminophen: nonacidic, crosses the
blood–brain barrier, acts mainly in the CNS,
peripheral, and anti inflammatory effects are
weak
94
Q
- Anti-inflammatory agent(s) which do not interfere
with the cardioprotective effects of “lowdose”
aspirin include
(1) naproxen
(2) ibuprofen
(3) ketorolac
(4) celecoxib
A
- (D) Unlike ibuprofen, naproxen, and ketorolac,
celecoxib does not interfere with the inhibition
of platelet COX-1 activity and function
by aspirin.
95
Q
- Which of the following is (are) true regarding
carbamazepine?
(1) It blocks voltage-dependent sodium
channels
(2) Bicuculline antagonizes its antinociceptive
effect
(3) It was first used for trigeminal neuralgia
(4) All of the above
A
- (E)
96
Q
236. Pregabalin is Food and Drug Administration (FDA) approved for (1) diabetic neuropathy (2) postherpetic neuralgia (PHN) (3) fibromyalgia (4) none of the above
A
- (A) The drug was approved by the European
Union in 2004. Pregabalin received US FDA
approval for use in treating epilepsy, diabetic
neuropathy pain, and pain in June 2005, and
appeared on the US market in 2005. In June
2007 the FDA approved it as a treatment for
fibromyalgia. It was the first drug to be
approved for this indication and remained the
only one, until duloxetine gained FDA approval
for the treatment of fibromyalgia in 2008.
97
Q
- Which of the following is (are) true regarding
gabapentin?
(1) It has chemical a structure similar to
GABA
(2) It acts directly at GABA-binding site in
the CNS
(3) It inhibits voltage-dependent calcium
channels
(4) It is the drug of choice for fibromyalgia
A
- (B) GBP has a chemical structure similar to
GABA. It seems not to act directly at the GABAbinding
site in the CNS, however. The mechanism
of action is still unclear. It may enhance the
release or activity of GABA and seems to inhibit
voltage-dependent sodium channels
98
Q
- Which of the following is (are) true regarding
clonazepam?
(1) It is a benzodiazepine
(2) It is effective as anxiolytic and musclerelaxing
agent
(3) It may be useful for phantom limb pain
(4) It has short half-life
A
- (A) Case report evidence suggests that clonazepam
may have a useful effect in treatment
of the shooting pain associated with phantom
limb pain. Somnolence is a predominant side
effect, and with this drug’s long half-life, daytime
sedation may complicate use. As it
belongs to the benzodiazepine group of drugs,
anxiolysis and muscle relaxation may also be
produced by its use, and this combination of
properties may, in some patients, be useful.
99
Q
- Which of the following is true about
lamotrigine?
(1) It is an anticonvulsive agent
(2) It is an NSAID
(3) A rapid titration may result in skin rash
(4) More than 300 mg/d is always needed
for analgesia
A
- (B) Case report evidence suggests that lamotrigine
may reduce the symptoms of complex
regional pain syndrome (type 1), with the sudomotor
changes seen in this condition being alleviated
along with pain and allodynia. Perhaps
the major side effect limiting rapid titration to
a therapeutic dose is skin rash.
Higher doses may be used, but, if no effect
is observed at 300 mg/d, further increases are
unlikely to produce analgesia. In view of the
relatively long half-life of lamotrigine, oncedaily
dosing may be appropriate.
100
Q
240. The antidepressant(s) which is (are) tertiary amine(s) TCA: (1) Imipramine (2) Nortriptyline (3) Doxepin (4) Desipramine
A
240. (B) The TCAs can be divided into tertiary
amines and their demethylated secondary
amine derivatives.
Tertiary amine TCAs ("ACID T ")
Amitriptyline
Imipramine
Tripramine
Clomipramine
Doxapin
Secondary amine TCAs ("PAND")
Nortriptyline
Desipramine
Protriptyline
Amoxapine
101
Q
- Which of the following is true about the analgesic
properties of TCAs?
(1) The analgesic effects of TCA are independent
of their effects on clinical
depression
(2) Onset of analgesia with TCA ranges
from 3 to 7 days
(3) Analgesia tends to occur at lower doses
and plasma levels than that needed for
antidepressant effects
(4) TCA’s analgesic property is superior to
that of SSRI’s
A
- (E)
102
Q
- Which of the following is (are) true about
TCAs?
(1) They interact significantly with the
opioid and benzodiazepine
(2) They do not have potential for addiction
(3) They block calcium channels
(4) They can cause insomnia, restlessness
and dry mouth
A
- (C)
103
Q
243. Symptoms of TCA toxicity includes which of the following? (1) Hyperthermia (2) Tachycardia (3) Seizures (4) Hypertension
A
- (A)
104
Q
- When prescribing antidepressants for pain
(1) explain to the patient that you are primarily
treating the pain not depression
(2) explain to the patient that it will not
work immediately
(3) explain to the patient that it may help
sleep
(4) none of the above
A
- (A)
105
Q
- Which of the following is (are) true regarding
acetaminophen?
(1) It is an aniline derivative
(2) Induced analgesia is centrally mediated
(3) It has peripheral mechanism of action
(4) It is a drug of choice for relieving mild
to moderate musculoskeletal pain
A
- (E)
106
Q
246. Which of the following is (are) true regarding acetaminophen toxicity? (1) The liver gets the major insult (2) The heart gets the major insult (3) N-acetylcysteine is beneficial for treatment (4) Adrenergic agonists are beneficial for treatment
A
- (B) The liver receives the major insult from acetaminophen
toxicity, with the predominant lesion being acute centrilobular hepatic necrosis. It is
suggested the use of the glutathione precursor
of N-acetylcysteine for the treatment of acetaminophen
intoxication in efforts to maintain
hepatic reduced glutathione concentrations
and adrenergic agonists may lower hepatic glutathione
significantly.
107
Q
247. Which of the following is (are) true about baclofen? (1) It is good for muscle rigidity and spasticity (2) It is used for neuropathic pain (3) It is GABAB receptor agonist (4) It is GABAA receptor agonist
A
- (A) Baclofen is the ρ-chlorophenyl derivative of
GABA. Baclofen is a GABAB agonist that has
been used for muscle spasms and spasticity, neuropathic
pain, and so on. Baclofen may enhance
the effectiveness of antiepileptic drugs in certain
neuropathic pain states. Side effects include sedation,
weakness, and confusion. Abrupt cessation
may cause a withdrawal syndrome, such as hallucinations,
anxiety, tachycardia, or seizures.
108
Q
- Which of the following is (are) true regarding
botulinum toxin A?
(1) The analgesic mechanism of action is
well known
(2) It can be administered intrathecally
(3) Botox, Myobloc, and Dysport are available
in the United States
(4) Its effect lasts for about 3 to 6 months
A
- (D) The two clinically available botulinum toxins
in the United States are botulinum toxin type A
and botulinum toxin type B. A different formulation
of botulinum toxin Ais used in Europe as
well as a version used in China but are currently
not available in the United States. Effects seem to
last for roughly 3 to 6 months after injection, at
which point a repeat injection generally reproduces
the effect.
Although it is generally accepted that botulinum
toxins may lead to diminished pain in
patients with painful muscle spasms or cervical
dystonia by diminishing muscle tone, it
is also felt that botulinum toxin may itself
possess analgesic properties. The mechanism
of botulinum toxin–induced analgesia are
unknown.
The most evident mechanism of botulinum
toxin-induced analgesia is via reduction
of muscle spasm by cholinergic chemodenervation
at motor end plates and by inhibition of
gamma motor endings in muscle spindles.
Future uses of botulinum toxins for analgesia
may lead to redesign toxins for intrathecal
use.
109
Q
- Which of the following is false regarding
cyclobezaprine?
(1) It is structurally similar to anticonvulsive
agents
(2) It has cholinergic side effects
(3) It does not require dose adjustment for
elderly patients
(4) It can produce sinus tachycardia
A
- (A) Cyclobenzaprine is structurally similar to
TCAs and, as such, demonstrates significant
anticholinergic side effects. It exhibits a sideeffect
profile similar to that of the TCAs, including
lethargy and agitation, although it usually
does not appear to produce significant dysrhythmias
beyond sinus tachycardia. Elderly
patients seem to tolerate cyclobenzaprine less
well and may develop hallucinations as well as
significant anticholinergic side effects, such as
sedation. The use of significant lower dosing
schedules in elderly patients may be prudent.
110
Q
250. Which of the following is (are) false about lidocaine 5% topical patch? (1) Treatment for postherpetic neuralgia (2) It may not use more than 1 patch per day (3) It is used 12 hours ON and 12 hours OFF (4) High plasma levels are normally achieved through the skin
A
- (C)
111
Q
- Steroids produce analgesia by
(1) anti-inflammatory effects
(2) suppressing ectopic discharge from
injured nerves
(3) reducing edema
(4) blocking sodium channels
A
- (A)
