Transcript 1 - RCRMC Family Medicine Residency

neuropathic pain, Ceiliac disease
EVALUATION OF SYNCOPE
Which one of the following features is predictive of
seizure rather than syncope? (check one)
A. Presyncope spells before loss of consciousness.
B. Diaphoresis before a spell.
C. Loss of consciousness with prolonged standing.
D. Witnessed abnormal posturing
Answer
• D. Witnessed abnormal posturing.
EVALUATION OF SYNCOPE
Which of the following clinical features predict an adverse
one-month outcome following an episode of syncope? (check
all that apply)
A. Anemia.
B. Brain natriuretic peptide level ≥ 300 pg per mL (300 ng
per L).
C. Absence of chest pain.
D. Bradycardia.
Correct.
Answer
• A. Anemia.
B. Brain natriuretic peptide level ≥ 300 pg
per mL (300 ng per L).
D. Bradycardia.
EVALUATION OF SYNCOPE
Which of the following generally should be
considered in patients without cardiac disease who
have a syncopal event? (check all that apply)
A. Hospital admission for monitoring and
evaluation.
B. Standard 12-lead electrocardiography.
C. Electrophysiology.
D. Orthostatic vital signs.
Answer
• B. Standard 12-lead electrocardiography.
D. Orthostatic vital signs.
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Syncope
Syncope is a transient and abrupt loss of consciousness with complete return to preexisting
neurologic function.
It is classified as neurally mediated (i.e., carotid sinus hypersensitivity, situational, or
vasovagal), cardiac, orthostatic, or neurogenic.
Older adults are more likely to have orthostatic, carotid sinus hypersensitivity, or cardiac
syncope, whereas younger adults are more likely to have vasovagal syncope.
Common nonsyncopal syndromes with similar presentations include seizures, metabolic and
psychogenic disorders, and acute intoxication.
Patients presenting with syncope (other than neurally mediated and orthostatic syncope) are at
increased risk of death from any cause.
Useful clinical rules to assess the short-term risk of death and the need for immediate
hospitalization include the San Francisco Syncope Rule and the Risk Stratification of Syncope
in the Emergency Department rule.
Guidelines suggest an algorithmic approach to the evaluation of syncope that begins with the
history and physical examination.
All patients presenting with syncope require electrocardiography, orthostatic vital signs, and
QT interval monitoring.
Patients with cardiovascular disease, abnormal electrocardiography, orfamily history of
sudden death, and those presenting with unexplained syncope should be hospitalized for
further diagnostic evaluation.
Patients with neurally mediated or orthostatic syncope usually require no additional testing.
In cases of unexplained syncope, further testing such as echocardiography, grade exercise
testing, electrocardiographic monitoring, and electrophysiologic studies may be required.
Although a subset of patients will have unexplained syncope despite undergoing a
comprehensive evaluation, those with multiple episodes compared with an isolated event are
more likely to have a serious underlying disorder.
Syncope
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Patients with syncope and evidence of heart failure or structural heart disease
should be admitted to the hospital for monitoring and evaluation.
C
All patients presenting with syncope should have orthostatic vital signs and
standard 12-lead electrocardiography.
C
Laboratory testing in the evaluation of syncope should be ordered as clinically
indicated by the history and physical examination.
C
Indications for electrophysiology include patients with coronary artery disease
and syncope, coronary artery disease with an ejection fraction less than 35
percent, and possibly nonischemic dilated cardiomyopathy.
C
Patients at low risk of adverse events (i.e., those with symptoms consistent
with vasovagal or orthostatic syncope, no history of heart disease, no family
history of sudden cardiac death, normal electrocardiographic findings,
unremarkable examination, and younger patients) may be safely followed
without further intervention or treatment.
B
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Causes of SyncopeType of syncopeMean prevalence of syncope (%)*Cardiac
Arrhythmia
14 (4 to 38)
Structural disease
4 (1 to 8)
Neurally mediated
Carotid sinus
1 (0 to 4)
Situational
5 (1 to 8)
Vasovagal
18 (8 to 37)
Neurologic
10 (3 to 32)
Orthostatic
8 (4 to 10)
Psychogenic
2 (1 to 7)
Unknown
34 (13 to 41)
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Risk Stratification in Patients with SyncopeHigh-risk (hospital admission
recommended)*
Clinical history suggestive of arrhythmia syncope (e.g., syncope during
exercise, palpitations at time of syncope)
Comorbidities (e.g., severe anemia, electrolyte abnormalities)
Electrocardiographic history suggestive of arrhythmia syncope (e.g.,
bifascicular block, sinus bradycardia < 40 beats per minute in absence of
sinoatrial block or medications, preexcited QRS complex, abnormal QT
interval, ST segment elevation leads V1 through V3 [Brugada syndrome],
negative T wave in right precordial leads and epsilon wave [arrhythmogenic
right ventricular dysplasia/cardiomyopathy])
Family history of sudden death
Older age†
Severe structural heart or coronary artery disease
Low-risk (outpatient evaluation recommended)‡
Age younger than 50 years†
No history of cardiovascular disease
Normal electrocardiographic findings
Symptoms consistent with neurally mediated or orthostatic syncope
Unremarkable cardiovascular examination
APPROACH TO SEPTIC ARTHRITIS
A 55-year-old woman presents for follow-up after
hospitalization for septic arthritis in her finger from a
cat bite. Which one of the following pathogens is the
most likely cause of infection? (check one)
A. Brucella species.
B. Pasteurella multocida.
C. Pseudomonas aeruginosa.
D. Mycobacterium marinum.
Answer
• B. Pasteurella multocida.
APPROACH TO SEPTIC ARTHRITIS
Which of the following are risk factors for
septic arthritis? (check all that apply)
A. Recent joint surgery.
B. Age older than 80 years.
C. Human immunodeficiency virus infection.
D. Rheumatoid arthritis.
Answer
• Recent joint surgery.
B. Age older than 80 years.
C. Human immunodeficiency virus
infection.
D. Rheumatoid arthritis.
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Prompt diagnosis and treatment of infectious arthritis can help prevent significant morbidity
and mortality.
The acute onset of monoarticular joint pain, erythema, heat, and immobility should raise
suspicion of sepsis.
Constitutional symptoms such as fever, chills, and rigors are poorly sensitive for septic
arthritis.
In the absence of peripheral leukopenia or prosthetic joint replacement, synovial fluid white
blood cell count in patients with septic arthritis is usually greater than 50,000 per mm3.
Isolation of the causative agent through synovial fluid culture is not only definitive but also
essential before selecting antibiotic therapy.
Synovial fluid analysis is also useful to help distinguish crystal arthropathy from infectious
arthritis, although the two occasionally coexist. Almost any microorganism can be pathogenic
in septic arthritis; however, septic arthritis is caused by nongonococcal pathogens (most
commonly Staphylococcus species) in more than 80 percent of patients.
Gram stain results should guide initial antibiotic choice. Vancomycin can be used for grampositive cocci, ceftriaxone for gram-negative cocci, and ceftazidime for gram-negative rods.
If the Gram stain is negative, but there is strong clinical suspicion for bacterial arthritis,
treatment with vancomycin plus ceftazidime or an aminoglycoside is appropriate.
Evacuation of purulent material with arthrocentesis or surgical methods is necessary. Special
consideration should be given to patients with prosthetic joint infection. In this population, the
intraarticular cutoff values for infection may be as low as 1,100 white blood cells per mm3 with
a neutrophil differential of greater than 64 percent.
• Suspicion of septic arthritis should be pursued with
arthrocentesis, and synovial fluid should be sent for white
blood cell count, crystal analysis, Gram stain, and culture.
• C
• In addition to antibiotic therapy, evacuation of purulent
material is necessary in patients with septic arthritis;
arthrocentesis and surgical methods are appropriate.
• C
• Intraarticular white blood cell cutoff values for infection as
low as 1,100 per mm3 (1.10 × 109 per L) with a neutrophil
differential of greater than 64 percent can help diagnose
prosthetic joint infection.
• C
Which of the following is most
likely to cause neuropathic pain?
A) Sprains
B) Postoperative incision site
C) Fibromyalgia
D) Arthritis
Answer
• C) Fibromyalgia
• Pain types: nociceptive— somatic pain; associated with, eg, sprains,
strains, postoperative incisional pain, arthritis; localized pain; easier for
patients to pinpoint; often easier to treat; treated with acetaminophen,
nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose opioids, ice,
and heat;
• neuropathic — vividly described by patients; associated with, eg, nerve
entrapment, shingles, complex regional neuropathic pain syndromes,
fibromyalgia, peripheral neuropathies, central neuropathic pain
syndromes, cancerassociated syndromes
• mixed — important to identify and treat dominant type
• patient may continue to report severe pain from subdominant type
• Pain sensitivity: paresthesia — nonpainful abnormal sensation
• allodynia — pain caused by stimuli that normally do not provoke pain
• hyperalgesia — increased pain response to stimuli that normally do not
cause that level of pain
• hypoalgesia — characterized by numbness
Opioid-induced hyperalgesia can
occur with:
A) Maintenance therapy
B) High escalating doses
C) Low doses
D) All the above
Answer
• D) All the above
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Opioids for neuropathic pain: limit to prevent addiction
crucial to use adjunctive medications that change chemical mediators
many patients present on high doses of opioids
use of opioids as sole therapy can worsen pain and lead to cycle of increased use
Hyperalgesia: can occur with any type of pain but classically associated with
neuropathic pain
often due to upregulation in central nervous system of N-methyl-D-aspartate
(NMDA) receptor; glutamate-activated and upregulated by, eg, opioid, fear, disease
process, or unrelieved pain
upregulation results in hypersensitization of nervous system
opioid-induced hyperalgesia — 3 forms
1) with maintenance therapy (eg, patient with classic chronic pain started on opioid, and
dose increased over time)
results in slow upregulation and mild stimulation of excitatory glutamate system
2) with high escalating doses of opioid (eg, end-of-life patient given high amount of
opioid for pain)
escalating dose of morphine or hydromorphone (eg, Dilaudid, Palladone)
results in accumulation of metabolite (3-glucuronide) that can cause excitatory
intoxication within hours or days
(must switch opioids and clear metabolite with fluid)
3) with low doses of opioid; shown in animal models (not
clearly seen in humans)
Models
of
neuropathic
pain:
diabetic neuropathy and postherpetic neuralgia classic
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• devastating effects on quality of life of older patients
• eg, in patients with pain due toc shingles, average number
of general practice visits, 19 (number of drugs, 14)
• polyneuropathies — eg, diabetes, neurotoxicity from
chemotherapy, alcoholism, or HIV disease
• one-third of cases idiopathic
• in some patients, numbness and loss of balance more
problematic than pain (drugs ineffective)
• efficacy of drugs seen in 30% to 50%
• Patients with symptomatic pain at new diagnosis of
diabetes, 8% (30%-50% after 25 yr)
• poststroke pain associated with ectopic abnormal discharge
of pain sensations
• phantom pain can be associated with, eg, mastectomy,
Choose the correct statement about the risks
of nonsteroidal anti-inflammatory drugs
(NSAIDs).
A) Adverse effects occur only with high
doses
B) Gastrointestinal bleeding is always
preceded by gut pain
C) May decrease bone healing when used too
soon postoperatively
D) Younger patients should be monitored
every 1 to 2 yr
Answer
• C) May decrease bone healing when used
too soon postoperatively
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Nonsteroidal anti-inflammatory drugs
not classically used for neuropathic pain
central and peripheral action
most interact centrally with opioid system, serotonergic system, and cen- tral nitric
oxide mechanisms
weigh risks and benefits
In younger patients (25-50 yr of age), low-dose NSAID as part of multimodal approach
can be effective
prostaglandins thought to sensitize peripheral nociceptors in dorsal horn
may take months to perceive benefit
options include nonselective, selective, and topical forms
consider ibuprofen, 200 to 400 mg 3 times daily
risks—(even with low doses) include gastrointestinal (GI) bleeding, renal toxicity, and
exacerbation of congestive heart failure
monitor younger patients every 6 mo to 1 yr
decreased bone healing when used too soon postoperatively
cardiovascular events in elderly at-risk populations
GI bleeding can be spontaneous without pain in gut
avoid use in frail elderly patients;
topical—eg, creams, transdermal patches
consider in older patients
produce lower blood levels; effective only on area where applied; may be effective in
patients with mixed type of pain (nociceptive and neuropathic
All the following are associated
with dexamethasone,except:
A) Cataracts
B) Hypoglycemia
C) Muscle wasting
D) Insomnia
Answer
• B) Hypoglycemia
Amitriptyline
A) Indicated for diabetic neuropathy and
fibromyalgia
B) Risks include orthostasis, falls, and constipation
in elderly, and weight gain, increased appetite, and
sexual dysfunction in younger patients
C) Approved by Food and Drug Administration for
postherpetic neuralgia; bioavailability decreases
dramatically with doses >600 mg
D) Binds to kappa-opioid receptors and mimics
dynorphin effect effectively
Answer
• B) Risks include orthostasis, falls, and
constipation in elderly, and weight gain,
increased appetite, and sexual dysfunction
in younger patients
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Antidepressants
TCAs— nortriptyline better tolerated than amitriptyline
desipramine more activating than sedating
selective serotonin reuptake inhibitors (SSRIs) — not shown highly beneficial in neuropathic pain
may be effective for migraines and chronic tension headaches;
use of TCAs — effective due to many mechanisms of action (eg, effect on NDMA receptor)
if younger patient can tolerate NSAID, consider pushing TCA dose to 150 to 200 mg for
greater benefit
studies suggest effective whether patient depressed or not
benefit usually seen with lower dose (100 mg; 50 mg in elderly) in 4 to 16 wk;
side effects worst during first week (and pain relief least), then diminish as efficacy increases
efficacy similar between agents
meta-analysis suggests number needed to treat (NNT) to benefit 1 patient with 50% reduction in pain,
3 (with SSRIs, 7); NNT for adverse effect, 1 in 19
side effects include orthostasis, risk for falls, and constipation (especially in elderly)
not highly useful in patients >65 yr of age; beneficial in younger patients
important to select appropriate drug
amitriptyline associated with most adverse effects, then doxepin, nortriptyline, and desipramine
younger patients typically bothered by weight gain, increased appetite (adding chromium picolinate
may be helpful), and sexual dysfunction;
atypical agents — some evidence of efficacy with venlafaxine (patients more energetic with higher
doses needed for pain relief)
one study showed good efficacy of bupropion; duloxetine indicated for diabetic neuropathy and
fibromyalgia (due to risk for side effects [eg, nausea, liver problems], not used as first-line agent by
speaker)
venlafaxine and duloxetine acceptable for postherpetic neuralgia, but efficacy of TCAs higher
Duloxetine
A) Indicated for diabetic neuropathy and
fibromyalgia
B) Risks include orthostasis, falls, and
constipation in elderly, and weight gain,
increased appetite, and sexual dysfunction in
younger patients
C) Approved by Food and Drug
Administration for postherpetic neuralgia;
bioavailability decreases dramatically with
doses >600 mg
D) Binds to kappa-opioid receptors and
mimics dynorphin effect effectively
Answer
• A) Indicated for diabetic neuropathy and
fibromyalgia
Gabapentin
A) Indicated for diabetic neuropathy and
fibromyalgia
B) Risks include orthostasis, falls, and
constipation in elderly, and weight gain,
increased appetite, and sexual dysfunction in
younger patients
C) Approved by Food and Drug
Administration for postherpetic neuralgia;
bioavailability decreases dramatically with
doses >600 mg
D) Binds to kappa-opioid receptors and
mimics dynorphin effect effectively
Answer
• C) Approved by Food and Drug
Administration for postherpetic neuralgia;
bioavailability decreases dramatically with
doses >600 mg
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Anticonvulsants: older agents associated with drug interactions and side effects
newer agents— expensive; partial to “decent” efficacy in studies of neuropathic pain; carbamazepine (eg, Tegretol,
Carbatrol, Epitol) and clonazepam shown beneficial; phenytoin; valproic acid can be used at end of life for sedating
and calming effects (can be given rectally);
gabapentin— available in generic form; studies controversial; 30% to 50% reduction in pain in 1 in 2 or 3
Patients
consider lamotrigine, pregabalin, and topiramate (if one agent ineffective, consider trying another agent)
gabapentin approved by Food and Drug Administration (FDA) for postherpetic neuralgia
limited intestinal absorption (800-900 mg absorbed in single dose; bioavailability decreases dramatically with doses
>600 mg)
Tolerable when titrated up slowly
in younger patients, start at 300 mg once daily at bedtime (does not disrupt sleep architecture), then slowly increase to
3 times daily (if needed, give 600 mg 3 times/day slowly)
for older patients, start slowly with 100 mg once daily at bedtime for 1 wk, then increase to 200 mg once daily at
bedtime (if still no benefit, add 100 mg in morning)
study showed 30% reduction in pain in 33% of patients (dizziness and somnolence in 25%,
edema in 10%)
study saw 33% of patients with poorly controlled diabetes and significant pain had 25% reduction in pain
hyperexcitable nervous system — in patients on opioids, eg, oxycodone (eg, OxyContin, Oxydose, OxyFAST,
Roxicodone) with escalating pain; start low-dose anticonvulsant or TCA and slowly taper opioids to reduce by
50%
ask, “are you better off today than you were 2 or 4 yr ago with your pain?”
pregabalin — mechanism similar to gabapentin option when other agents fail
more linear dosing with quicker onset
75 mg twice daily recommended (speaker recommends starting at 25-50 mg/day to reduce dizziness);
efficacy — varies between types
NNT with carbamazepine lowest of any anticonvulsant, particularly for trigeminal neuralgia (may not be useful in
other neuropathic pain due to need for higher doses and increased risk)
valproic acid associated with more sedation and decreased functionality
topiramate used more for migraine than neuropathic pain
gabapentin, lamotrigine, and pregabalin reasonable
mexiletine not commonly used for neuropathic pain (except in resistant cases) due to risk
Using _______ lidocaine patches
at once can lead to adverse
effects (eg, arrhythmia).
A) >1
B) >2
C) >3
D) >4
Answer
• D) >4
Response to opioids
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some evidence of efficacy
use of opioid alone can lead to more pain
some short-term (eg, 3-6 mo) studies show average NNT ranges from 2.1 to 3.0 (3.53.9 with tramadol)
Selecting opioids: morphine — consider effect of metabolite with high doses in patients
with poor renal function, or end-of-life patients with insufficient fluid (problem unlikely
in patients 45-50 yr of age on lower doses)
methadone — studies comparing efficacy with morphine conflict
oxycodone — binds to kappa-opioid receptors and may mimic dynorphin effect more
effectively (not proven)
tramadol — blocks reuptake of catecholamines; escalating doses associated with risk for
serotonergic syndrome, especially in combination with other drugs, eg, SSRIs
Using opioids: use adjuvant; do not expect 100% pain relief
start at reasonable dose (acceptable to titrate up
if benefits do not justify use, then taper and stop)
methadone — some benefit in neuropathic pain, but more complex and risky
use conversion tables; long half-life; associated with cardiac toxicity
can be beneficial when monitored and converted properly
watch for drug interactions, accumulation, and cardiac risk
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Topical
approaches
ketamine compounded in pluronic lecithin organogel shown beneficial
topical agents effective locally where applied
lidocaine patch (eg, Lidoderm Patch) — using >4 patches at once can lead to
adverse effect (eg, arrhythmia)
recommended to apply new patch after 12 hr
speaker leaves patch on continuously for 2 to 5 days (off-label use)
if this causes itchiness or rash, remove patch for few hours and wash area
if rash continues, inhaled corticosteroid, eg, beclomethasone [eg, QVAR,
Beconase, Vancenase] applied on skin helpful
takes 7 to 10 days
blood levels low unless 4 to 5 patches used
indicated for postherpetic neuralgia
can be used in diabetes for localized burning feet (off-label use)
effective in patients with healed amputated toes (in addition to oral therapy)
and neuropathic cervical neck pain (off-label use)
Topical capsaicin highly beneficial (depletes substance P; NNT in postherpetic
neuralgia, 3.2 [6.7 in generalized peripheral neuropathic pain])
compounded products — useful, but little evidence; localized effect on nerve
fiber; gels cause absorption of drug and can lead to systemic side effects (eg,
paranoia, hallucinations, and mind-body dissociation with ketamine
Choose the correct statement about
antipsychotic agents for treatment of pain.
A) Directly affect neuropathic pain with high
efficacy rates
B) Studies show haloperidol more effective
for trigeminal neuralgia than for migraine
C) No responses shown to quetiapine
D) One study showed olanzapine effective
for end-of-life pain, but only when pain driven
by fear
Answer
• D) One study showed olanzapine effective
for end-of-life pain, but only when pain
driven by fear
Cannabinoids have been shown
to:
A) Improve pain
B) Be more effective for pain
than NSAIDs
C) Improve function (eg, return
to work)
D) Cause severe hyperalgesia
Answer
• A) Improve pain
• Agents that affect NMDA receptors: methadone and ketamine
effective
• ketamine most effective but with highest risk for side effects
• only small studies in stroke pain, fibromyalgia, ischemia, and phantom
pain
• more effective for allodynia and hyperalgesia than traditional
analgesics;
• speaker uses for patients with hyperexcitable nervous system
• when using ketamine, decrease opioid dose by 50% to reduce risk for
opioid toxicity
• use low doses of oral and topical therapies for nonmalignant pain
• Cannabinoids: shown effective for pain, but not shown more effective
than other agents; not shown to improve function (eg, return to work)
• Neuragen PN: available over-the-counter; geranium oil
• for burning feet of diabetes; $25 to $30; use 1 to 2 drops
According to the National
Institute on Alcohol Abuse and
Alcoholism, _______ drinks per
week constitutes "heavy
drinking" in men.
A) 7
B) 10
C) 12
D) 15
Answer
• D) 15
Crack cocaine is available only as
a hard-based form, while
methamphetamine is available
only as a powder.
A) True
B) False
Answer
• B) False
Individuals who abuse
prescription pills primarily obtain
them from:
A) Primary care and pain
medicine physicians
B) Internet
C) Friends and family
D) Street dealers
Answer
• A) Primary care and pain medicine
physicians
Which of the following groups
are at increased risk for gambling
addiction?
A) Blacks
B) Disabled individuals
C) Unemployed individuals
D) All the above
Answer
• D) All the above
Choose the correct statement about treatment
of addiction.
A) Disulfiram is used to target the core
pathophysiology of alcohol dependence
B) Methadone is the gold standard for opiate
addiction in pregnant women
C) Nicotine replacement therapies are more
effective than varenicline
D) Modafinil is approved by the Food and
Drug Administration (FDA) for treatment of
stimulant dependence
Answer
• B) Methadone is the gold standard for
opiate addiction in pregnant women
_______ is the most psychoactive
component of marijuana.
A) 2-arachidonoyl glycerol
B) Anandamide
C) Δ-9-tetrahydrocannabinol
(THC)
D) Δ-8-THC
Answer
• C) Δ-9-tetrahydrocannabinol (THC)
Inhibiting endogenous
cannabinoids has been shown to:
A) Suppress feeding and lead to
weight loss
B) Decrease anxiety
C) Decrease duration of
wakefulness
D) improve short-term memory
Answer
• A) Suppress feeding and lead to weight loss
In 1986, the FDA approved
dronabinol for the treatment of
which of the following?
A) Weight loss
B) AIDS-related anorexia
C) Nausea and vomiting
associated with chemotherapy
D) Chronic low back pain
Answer
• C) Nausea and vomiting associated with
chemotherapy
All the following are features of
classic celiac disease
(CD),except:
A) Weight loss
B) Diarrhea
C) Steatorrhea
D) Defects in dental enamel
Answer
• D) Defects in dental enamel
CD
• Clinical scenario: 27-yr-old woman presents with intermittent bloating
and loose bowel movements several times a month
• Symptoms and findings (stable weight, mild iron deficiency, and
slightly abnormal transaminases) suggest irritable bowel syndrome
(IBS)
• current guidelines for diagnosing IBS include testing for CD
• Pathophysiology: small intestine 7 m long, 2 cm in diameter
• total absorptive surface area 300 m
• contains numerous villi; villi lined with enterocytes; enterocytes
produced at base of crypts of Lieberkuhn and migrate up onto villi,
where they function as absorptive cells; villous tips shed enterocytes
every 3 to 5 days, and then process renews
• in CD, villi become flattened when lymphocytes infiltrate and destroy
enterocytes due to allergic reaction (immune response) to gluten
protein
CD
• Features: villous atrophy; crypt hyperplasia; infiltration of
intraepithelial lymphocytes; responds well to gluten-free diet;
• Classic disease— symptoms of malabsorption (eg, steatorrhea, nutrient
deficiencies); resolution of symptoms and pathology (usually in weeks
to months) seen with gluten-free diet
• Patients have diarrhea, weight loss, and positive celiac antibodies
• atypical disease—minor gastrointestinal (GI) complaints; anemia;
osteoporosis and osteomalacia; defects in dental enamel; arthritis;
elevated transaminases; neurologic symptoms; female infertility;
• positive celiac antibodies; intestinal mucosal pathology
• silent disease—relative with diagnosis of CD; no overt symptoms;
positive celiac antibodies; intestinal pathology present on biopsy
specimen (probably mild); patients tend to feel better (more energetic)
after initiating gluten-free diet
Atypical CD is more commonly
seen in _______ than in _______.
A) Children; adults
B) Adults; children
Answer
• B) Adults; children
Children vs adults
• children —commonly have more overt symptoms (eg, intermittent
diarrhea, abdominal pain; features of atypical disease uncommon)
• diagnosis primarily based on symptoms and growth deficiencies
• increase in breastfeeding in early childhood and guidelines on
introduction of gluten into diet thought to have reduced incidence of
pediatric CD
• adults — most have atypical variety
• Non-GI clues to diagnosis: recurrent aphthous ulcers (canker sores);
dermatitis herpetiformis (DH) —herpetic lesions on elbows and knees
• 85% of patients with DH have CD
• however, only small percentage of patients with CD have DH
• Lesions tend to respond well to gluten withdrawal
• Epidemiology: incidence of 1:300 to 1:500 among whites of northern
European descent; study in United States (US) found 1 of 250 blood
donors positive for antiendomysial antibodies (antiEMAs)
• in parts of western Ireland, incidence 1:100 to 1:150
• 1% of US population estimated to have some form of CD
Importance of making diagnosis
• even with subclinical disease, patients with CD have increased risk for
cancer (gluten-free diet appears to reduce risk)
• risk for nutrient deficiencies
• low birth weight in children of mothers with CD
• association with other autoimmune conditions; improvement in well
being possible after change to gluten-free diet
• gluten-free diet difficult to adhere to and expensive (so best to
prescribe only with confirmed diagnosis)
• Cancer risk: early studies showed 2-fold increase in risk for lymphoma
• recent large epidemiologic studies showed relative risk of 1.3
(primarily for lymphoma, but also for esophageal squamous cell
carcinoma and adenocarcinoma of small bowel)
• Risk for breast cancer possibly reduced (reason unknown
Patients with CD may have a
reduced risk of developing:
A) Lymphoma
B) Adenocarcinoma of the small
bowel
C) Breast cancer
D) Esophageal squamous cell
carcinoma
Answer
• C) Breast cancer
Screening for IgA _______
antibodies to diagnose CD is
generally no longer
recommended because of this
test's low sensitivity and
specificity.
A) Antigliadin
B) Antiendomysial
C) Anti-tissue transglutaminase
Answer
• A) Antigliadin
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Pathophysiology
gliadins—protein fragments of gluten
Poorly digested by patients with CD
bind to antigen-presenting cells with select HLA molecules to induce inflammatory response
receptors on enterocytes transport gliadins across mucosa to lamina propria T cells
tissue transglutaminase (tTG) — secreted by endothelium and inflammatory cells
crosslinks glutamine-rich proteins (creates larger fractions of immunogenic molecules)
removes amine groups from glutamine molecules and converts them to glutamate (increases binding
to HLA molecules, activates T and B cells, and creates antibodies, thereby activating destructive
process)
Genetic testing: performed when serologic testing equivocal
HLA-DQ2 and HLA-DQ8 serotypes present in 98% of people with CD, but also in 30% to 40% of
whites without disease
used to rule out CD (ie, absence of alleles rules out CD)
Serologic testing: IgA anti-EMA or anti-tTG both good tests for CD
testing for antigliadin antibodies not as sensitive or specific, so no longer recommended (although
new version of test in development)
patient must be on gluten-rich diet when tested (antibodies wane 1-12 mo after initiation of glutenfree diet)
positive serology—in patient with DH, no further testing necessary (initiate gluten-free diet)
in patients without DH, upper endoscopy and biopsy of duodenum (4 samples in 3-4 locations)
recommended
combination of positive serology and biopsy confirm diagnosis; negative serology but still
Positive serologic testing for CD:
A) Is 100% diagnostic and never requires
further testing
B) Must always be followed with upper
endoscopy and duodenal biopsies
C) Must be followed with upper endoscopy
and duodenal biopsies in patients with
dermatitis herpetiformis (DH)
D) Requires no further testing in patients with
DH
Answer
• D) Requires no further testing in patients
with DH
Gluten-free diet
• barley and rye not recommended for
patients with CD
• oats appear to be safe, but only when
prepared in areas free of contamination by
contraindicated products
• Celiac Sprue Association and Healthy Villi
group disagree on acceptability of oats in
diet of patients with C
Studies have shown that rates of
mucosal healing and symptom
relief are _______ with proton
pump inhibitors (PPIs) than with
histamine-2 receptor antagonists
(H2RAs).
A) No different
B) Worse
C) Much better
Answer
• C) Much better
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Efficacy of proton pump
inhibitors (PPIs) vs other agents
mechanism of action —PPIs block hydrogen potassium adenosine triphosphatase
(ATPase) enzyme system in gastric parietal cells; meta-analysis (in 1990s) comparing
PPIs, histamine-2 receptor antagonists (H2 RAs), and placebo
showed that H2 RAs more efficacious than placebo for esophageal and mucosal healing,
and PPIs much more efficacious than H2
RAs and placebo for mucosal healing and relief of symptoms at all time points (findings
confirmed in 2005 study)
symptom relief optimal during first 2 wk of treatment
with PPIs and H2 RAs; PPIs recommended as first-line therapy over H2 RAs for many
GI-related diseases (eg, gastroesophageal reflux disease [GERD], eradication of
Helicobacter pylori, esophageal strictures, ulcerations);
efficacy of PPIs in combination with H2 RAs —when treatment of GERD with
omeprazole (20 mg, 2 times daily for 2 wk) compared with same regimen of omeprazole
plus ranitidine at nighttime, excellent acid suppression initially seen with combination
therapy, but effect lost after 1 wk
PPIs in primary care setting— commonly prescribed (10%-60% of outpatients), but rate
of inappropriate use high (70% of cases)
Long-term PPI therapy is
associated with an increased
prevalence of:
A) Colorectal adenomas
B) Colorectal cancer
C) Colorectal dysplasia
D) Fundic gland polyps
Answer
• D) Fundic gland polyps
Some data suggest that long-term
PPI use (≥5 yr) is associated with
an increased risk for bone
fractures.
A) True
B) False
Answer
• A) True
Gastroenteritis associated with
PPI use is most commonly
caused by _______ infections.
A) Campylobacter and Salmonel
la
B) Escherichia
coli and Clostridium
C) Shigella and Staphylococcus
D) Yersinia and Aeromonas
Answer
• A) Campylobacter and Salmonella
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PPIs and risk for cancer: blockage of hydrogen potassium ATPase results in increased level of gastrin (thought by
some to be potentially carcinogenic)
studies have found no clear association between increased gastrin from PPI use and increased incidence of many
upper- or lower-tract GI malignancies (including colorectal adenomas, colorectal cancer, and dysplasia) in humans
Patients on PPI therapy found to have smaller and fewer hyperplastic polyps (significance unclear); however, longterm PPI therapy associated with increased prevalence of polyps in fundic gland (generally benign); no association
between PPIs and higher risk
for dysplasia in fundic gland polyps, except in patients with familial adenomatous polyposis; conclusion—no change
or recommendations for cancer surveillance necessary in long-term users of PPIs
PPIs and risk for bone fractures: impairment of dissolution and absorption of calcium and inhibition of hydrogen
potassium
ATPase pumps in osteoclasts (and impairment of effects of osteoclasts) associated with increased risk; increased use
of PPIs results in hypergastrinemia, which enhances bone resorption via parathyroid gland hypoplasia; short-term
use—modestly linked
to increased risk (strength of association higher with escalating doses of PPI therapy
H2 RA therapy also positively associated with hip fractures)
long-term ( 5 yr) use—some data suggest association with increased risk (however, data derived from retrospective
case-controlled studies, results of which possibly affected by confounding factors and effect modification)
Ensure that patient actually requires long-term therapy and that lowest possible dose used; critical to assess patients
for other risk factors for osteoporosis and risk for falls
Use of PPIs and risk for infection: GI tract—studies have shown increased risk for gastroenteritis in long-term users
(Campylobacter and Salmonella infections most common) and for Clostridium difficile–associated colitis
elderly appear to be at greatest risk; respiratory tract —possible increased risk for infection (intestinal pathogens can
colonize oral space and
gain access to lower respiratory tract secondary to chronic acid
suppression; PPIs present in human laryngeal cells and lung mucous glands can break down suppression and cause
bacterial colonization; PPIs can inhibit function of polymorphonuclear cells and activity of natural killer cells)
studies have shown modest increased risk (odds ratio <2) of developing community-acquired pneumonia (CAP)
greatest risk in first few days after initiation of therapy and with higher PPI doses
(results possibly affected by confounding factors, or subgroup of patients in study possibly more susceptible to
developing CAP while on PPIs
PPI use by women during the
preconception period may
increase the risk for birth defects.
A) True
B) False
Answer
• A) True
• PPIs and pregnancy: variety of conditions during pregnancy may
require PPI therapy
• 40% to 80% of patients experience exacerbation or new symptoms of
GERD during pregnancy; animal vstudies have shown that PPIs cross
placenta
• safety during pregnancy demonstrated in many small studies (no
increased risk for spontaneous abortion or preterm delivery associated
with PPI use)
• studies have found no association between PPI use in first trimester
and birth defects
• however, PPIs may have teratogenic potential when used in
preconception period (noted only with lansoprazole [Prevacid])
• implications—women of childbearing age taking PPIs may need to be
counseled on possibility of birth defects
• PPI with better safety profile should be prescribed for women of
childbearing age
• lifestyle modifications and over-the-counter antacids still first-line
treatment of GERD during pregnancy
Plavix and PPI
• important to assess risk for GI bleeding in
patients on combined antiplatelet therapy
(must address and modify identified risk
factors)
• consider instructing patient to take drugs 2
hr apart to prevent pharmacokinetic
interaction
Introduction
• patients commonly want opioids for
neuropathic pain, but opioids should be “the
caboose not the engine” that drives pharmacology
• incidence of neuropathic pain (eg, pain due to
diabetic neuropathy or poststroke pain) high
• must understand mechanisms and differences
between neuropathic pain, nociceptive pain, and
visceral pain
• comorbid conditions include depression, anxiety,
and sleep disorders (must be cotreated)
Pain types
• nociceptive—somatic pain; associated with, eg, sprains, strains,
postoperative incisional pain, arthritis
• Localized pain
• easier for patients to pinpoint
• often easier to treat
• treated with acetaminophen, nonsteroidal anti-inflammatory drugs
(NSAIDs), low-dose opioids, ice, and heat
• neuropathic—vividly described by patients
• Associated with, eg, nerve entrapment, shingles, complex regional
neuropathic pain syndromes, fibromyalgia, peripheral neuropathies,
• central neuropathic pain syndromes, cancer associated syndromes
• mixed—important to identify and treat dominant type
• patient may continue to report severe pain from subdominant type
Pain sensitivity
• paresthesia—nonpainful abnormal
sensation
• allodynia—pain caused by stimuli that
normally do not provoke pain
• hyperalgesia—increased pain response to
stimuli that normally do not cause that level
of pain
• hypoalgesia—characterized by numbness
Mechanisms of neuropathic pain
• transmitted from periphery into central
compartment
• involves ectopic discharge within periphery
and dorsal root, then central sensitization
• Change in hyperexcitable nervous system
and full benefit of medications may take
weeks to months
• chemical mediators include upregulators
(eg, substance P, sodium channels,
• glutamate, interleukins, cholecystokinin)
and downregulators
• (eg, -aminobutyric acid, opioid peptides)
Opioids for neuropathic pain
• limit to prevent addiction
• crucial to use adjunctive medications that
change chemical mediators; many patients
present on high doses of opioids
• use of opioids as sole therapy can worsen
pain and lead to cycle of increased use
Visceral pain
• somatic pain
• difficult to describe and locate
• associated with smooth muscle reaction, typically in
internal organs (eg, bowel, bladder, liver)
• opioid injections in emergency department effective for,
eg, renal colic or gallbladder pain, but oral therapy often
insufficient for smooth muscle relaxation
• anticholinergic drugs—consider tricyclic antidepressants
(TCAs; eg, nortriptyline, amitriptyline)
• use, eg, dicyclomine (eg, Bentyl, Antispas, Byclomine) to
block smooth muscle spasms agents that do not cross
blood-brain barrier (eg, tolterodine [Detrol]) effective in
elderly patients
• corticosteroids—effective in end-of-life care
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Hyperalgesia
can occur with any type of pain but classically associated with neuropathic
pain
often due to upregulation in central nervous system of N-methyl-D-aspartate
(NMDA) receptor; glutamate-activated and upregulated by, eg, opioid, fear,
disease process, or unrelieved pain; upregulation
results in hypersensitization of nervous system; opioid- induced
hyperalgesia—3 forms; 1) with maintenance therapy (eg, patient with classic
chronic pain started on opioid, and dose increased over time)
results in slow upregulation and mild stimulation of excitatory glutamate
system
2) with high escalating doses of opioid (eg, end-of-life patient given high
amount of opioid for pain)
escalating dose of morphine or hydromorphone (eg, Dilaudid, Palladone)
results in accumulation of metabolite (3-glucuronide) that can cause excitatory
intoxication within hours or days
(must switch opioids and clear metabolite with fluid)
3) with low doses of opioid; shown in animal models (not clearly seen in
humans)
Models of neuropathic pain
• diabetic neuropathy and postherpetic neuralgia classic devastating
effects on quality of life of older patients; eg, in patients with pain due
to shingles, average number of general practice visits, 19 (number of
drugs, 14)
• polyneuropathies—eg, diabetes, neurotoxicity from chemotherapy,
alcoholism, or HIV disease
• one-third of cases idiopathic
• in some patients, numbness and loss of balance more problematic than
pain (drugs ineffective); efficacy of drugs seen in 30% to 50%
• Patients with symptomatic pain at new diagnosis of diabetes, 8%
(30%-50% after 25 yr)
• poststroke pain associated with ectopic abnormal discharge of pain
sensations
• phantom pain can be associated with, eg, mastectomy, colon resection,
tooth extraction (early treatment beneficial)
Pharmacologic Management Options
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Nonsteroidal anti-inflammatory drugs
not classically used for neuropathic pain
central and peripheral action
most interact centrally with opioid system, serotonergic system, and central nitric oxide
mechanisms
weigh risks and benefits; in younger patients (25-50 yr of age), low-dose NSAID as part
of multimodal approach can be effective
prostaglandins thought to sensitize peripheral nociceptors in dorsal horn
may take months to perceive benefit
options include nonselective, selective, and topical forms
consider ibuprofen, 200 to 400 mg 3 times daily
risks—(even with low doses) include gastrointestinal (GI) bleeding, renal toxicity, and
exacerbation of congestive heart failure
monitor younger patients every 6 mo to 1 yr
decreased bone healing when used too soon postoperatively
cardiovascular events in elderly at-risk populations
GI bleeding can be spontaneous without pain in gut
avoid use in frail elderly patients
topical—eg, creams, transdermal patches; consider in older patients; produce lower
blood levels; effective only on area where applied; may be effective in patients with
mixed type of pain (nociceptive and neuropathic)
Glucocorticoids
• Beneficial
• long-term use risky
• oral agents useful for neuropathic pain in patients at end
of life
• dexamethasone—high doses used (mineralocorticoid
activity minimal)
• fluid retention dramatically reduced
• Can be given once daily in morning (minimizes risk of
interrupting sleep)
• used intra-articularly for nociceptive pain
• risks—cataracts; muscle wasting; insomnia; edema;
hyperglycemia; steroid psychosis (with increased doses)
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Antidepressants
TCAs—nortriptyline better tolerated than amitriptyline
desipramine more activating than sedating
selective serotonin reuptake inhibitors (SSRIs)—not shown highly beneficial in neuropathic pain
may be effective for migraines and chronic tension headaches
use of TCAs—effective due to many mechanisms of action (eg, effect on NDMA receptor)
if younger patient can tolerate NSAID, consider pushing TCA dose to 150 to 200 mg for greater benefit
studies suggest effective whether patient depressed or not
benefit usually seen with lower dose (100 mg; 50 mg in elderly) in 4 to 16 wk
side effects worst during first week (and pain relief least), then diminish as efficacy increases
efficacy similar between agents
meta-analysis suggests number needed to treat (NNT) to benefit 1 patient with 50% reduction in pain, 3 (with SSRIs,
7)
NNT for adverse effect, 1 in 19
side effects include orthostasis, risk for falls, and constipation (especially in elderly)
not highly useful in patients >65 yr of age
Beneficial in younger patients
important to select appropriate drug
amitriptyline associated with most adverse effects, then doxepin, nortriptyline, and desipramine
younger patients typically bothered by weight gain, increased appetite (adding chromium picolinate may be helpful),
and sexual dysfunction
atypical agents—some evidence of efficacy with venlafaxine (patients more energetic with higher doses needed for
pain relief)
one study showed good efficacy of bupropion
duloxetine indicated for diabetic neuropathy and fibromyalgia (due to risk for side effects [eg, nausea, liver
problems], not used as first-line agent by speaker)
venlafaxine and duloxetine acceptable for postherpetic neuralgia, but efficacy of TCAs higher
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Anticonvulsants
older agents associated with drug interactions and side effects
newer agents—expensive
partial to “decent” efficacy in studies of neuropathic pain
Carbamazepine (eg, Tegretol, Carbatrol, Epitol) and clonazepam shown beneficial
phenytoin; valproic acid can be used at end of life for sedating and calming effects (can be given rectally)
gabapentin—available in generic form
30% to 50% reduction in pain in 1 in 2 or 3 patients
consider lamotrigine, pregabalin, and topiramate (if one agent ineffective, consider trying another agent)
gabapentin approved by Food and Drug Administration (FDA) for postherpetic neuralgia
limited intestinal absorption (800-900 mg absorbed in single dose
Bioavailability decreases dramatically with doses >600 mg)
Tolerable when titrated up slowly
in younger patients, start at 300 mg once daily at bedtime (does not disrupt sleep architecture), then slowly increase to 3 times daily (if
needed, give 600 mg 3 times/day slowly)
for older patients, start slowly with 100 mg once daily at bedtime for 1 wk, then increase to 200 mg once daily at bedtime (if still no
benefit, add 100 mg in morning)
study showed 30% reduction in pain in 33% of patients (dizziness and somnolence in 25%, edema in 10%)
study saw 33% of patients with poorly controlled diabetes and significant pain had 25% reduction in pain
hyperexcitable nervous system—in patients on opioids, eg, oxycodone (eg, OxyContin, Oxydose, Oxy- FAST, Roxicodone) with
escalating pain
start low-dose anticonvulsant or TCA and slowly taper opioids to reduce by 50%
ask, “are you better off today than you were 2 or 4 yr ago with your pain?”
pregabalin—mechanism similar to gabapentin
option when other agents fail
more linear dosing with quicker onset
75 mg twice daily recommended (speaker recommends starting at 25-50 mg/day to reduce dizziness)
efficacy—varies between types
NNT with carbamazepine lowest of any anticonvulsant, particularly for trigeminal neuralgia (may not be useful in other neuropathic
pain due to need for higher doses and increased risk)
valproic acid associated with more sedation and decreased functionality
topiramate used more for migraine than neuropathic pain
gabapentin, lamotrigine, and pregabalin reasonable
mexiletine not commonly used for neuropathic pain (except in resistant cases) due to risk
Response to opioids
• some evidence of efficacy
• use of opioid alone can lead to more pain
• some short-term (eg, 3-6 mo) studies show
average NNT ranges from 2.1 to 3.0 (3.53.9 with tramadol)
Selecting opioids
• morphine—consider effect of metabolite with
high doses in patients with poor renal function, or
end-of-life patients with insufficient fluid
(problem unlikely in patients 45-50 yr of age on
lower doses)
• methadone—studies comparing efficacy with
morphine conflict
• oxycodone—binds to kappa-opioid receptors and
may mimic dynorphin effect more effectively (not
proven)
• tramadol—blocks reuptake of catecholamines
• Escalating doses associated with risk for
serotonergic syndrome, especially in combination
Using opioids
• use adjuvant
• do not expect 100% pain relief
• start at reasonable dose (acceptable to titrate up; if benefits
do not justify use, then taper and stop)
• methadone—some benefit in neuropathic pain, but more
complex and risky
• use conversion tables
• long half-life
• associated with cardiac toxicity
• can be beneficial when monitored and converted properly
• watch for drug interactions, accumulation, and cardiac risk
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Topical approaches
ketamine compounded in pluronic lecithin organogel shown beneficial
topical agents effective locally where applied
lidocaine patch (eg, Lidoderm Patch)—using >4 patches at once can lead to adverse
effect (eg, arrhythmia)
recommended to apply new patch after 12 hr
speaker leaves patch on continuously for 2 to 5 days (off-label use)
if this causes itchiness or rash, remove patch for few hours and wash area
if rash continues, inhaled corticosteroid, eg, beclomethasone [eg, QVAR, Beconase,
Vancenase] applied on skin helpful; takes 7 to 10 Days blood levels low unless 4 to 5
patches used
Indicated for postherpetic neuralgia can be used in diabetes for localized burning feet
(off-label use) effective in patients with healed amputated toes (in addition to oral
therapy) and neuropathic cervical neck pain (off-label use)
Topical capsaicin highly beneficial (depletes substance P; NNT in postherpetic
neuralgia, 3.2 [6.7 in generalized peripheral neuropathic pain])
compounded products—useful, but little evidence
localized effect on nerve fiber
gels cause absorption of drug and can lead to systemic side effects (eg, paranoia,
hallucinations, and mind-body dissociation with ketamine)
End of life
• lidocaine infusions (admit patient for 1-2
days) highly beneficial in some patients
who have had no benefit from other agents
(use load, then infuse at rate 25%-33% of
that typically given for cardiac arrhythmias;
safe)
• No electrocardiography monitoring
• monitor serum levels and check for signs of
toxicity
Antipsychotics
• no direct effect on neuropathic pain
• Haloperidol (Haldol)—mainly effective in
migraine
• causes irritability, agitation, motor
restlessness, and sedation
• atypical agents—mild to moderate
responses with olanzapine or quetiapine in
studies of fibromyalgia
• one study showed olanzapine effective for
end-of-life pain, but only when pain driven
by fear
Agents that affect NMDA receptors
• methadone and ketamine effective
• ketamine most effective but with highest risk for side effects
• only small studies in stroke pain, fibromyalgia, ischemia, and phantom
pain
• more effective for allodynia and hyperalgesia than traditional
analgesics
• speaker uses for patients with hyperexcitable nervous system;
• when using ketamine, decrease opioid dose by 50% to reduce risk for
opioid toxicity
• use low doses of oral and topical therapies for nonmalignant pain
• Cannabinoids: shown effective for pain, but not shown more
effective than other agents; not shown to improve function (eg, return
to work)
• Neuragen PN: available over-the-counter; geranium oil; for
burning feet of diabetes; $25 to $30; use 1 to 2 drops
Which of the following clinical
signs is shown to be most
specific to the diagnosis of acute
otitis media (AOM)?
A) Bulging tympanic membrane
(TM)
B) Erythema of TM
C) Limited mobility of TM
D) Earache
Answer
• A) Bulging tympanic membrane (TM)
Which of the following children with
uncomplicated AOM can be managed with
observation alone?
A) Infant 5 mo of age
B) Child 1 yr of age with certain diagnosis of
nonsevere AOM
C) Child 1 yr of age with uncertain diagnosis
of nonsevere AOM
D) Child 3 yr of age with certain diagnosis of
severe disease
Answer
• C) Child 1 yr of age with uncertain
diagnosis of nonsevere AOM
Which of the following
antibiotics is often preferred by
parents and children because of
its appearance, smell, texture, and
taste?
A) Amoxicillin-clavulanate
B) Cefpodoxime
C) Cefdinir
D) Cefuroxime
Answer
• C) Cefdinir
Patients with non-IgE-mediated
or anaphylactic reactions to
penicillin may be given
amoxicillin, amoxicillinclavulanate, or cephalosporins.
A) True
B) False
Answer
• A) True
Choose the correct statement about
intramuscular ceftriaxone.
A) 50 mg/kg dose recommended for children
who are vomiting or unable to tolerate oral
therapy
B) Must be given with topical therapy to treat
conjunctivitis
C) Not shown to eradicate Haemophilus
influenzae
D) Largely ineffective after failure of initial
treatment if give for <3 days
Answer
• A) 50 mg/kg dose recommended for
children who are vomiting or unable to
tolerate oral therapy
Which of the following has been
shown to be most effective in the
prevention of AOM in infants?
A) Eliminating supine bottle
feeding
B) Encouraging breast feeding
over bottle feeding
C) Eliminating pacifier use
D) Giving xylitol gum
Answer
• B) Encouraging breast feeding over bottle
feeding
Overuse of which of the
following treatments of acute
viral rhinosinusitis is associated
with rhinitis medicamentosa?
A) Topical steroids
B) Topical decongestant sprays
C) First-generation
antihistamines
D) Saline irrigation
Answer
• B) Topical decongestant sprays
A 10-day course of _______ is
first-line treatment of acute
bacterial rhinosinusitis.
A) Diphenhydramine
B) Cefdinir
C) Amoxicillin
D) Clindamycin
Answer
• C) Amoxicillin
A trial showed that topical or oral
antifungal therapy was effective
in most patients with eosinophilic
fungal sinusitis.
A) True
B) False
Answer
• B) False
Which of the following
is not recommended for chronic
sinusitis?
A) Saline irrigation
B) Oral prednisone
C) Intranasal steroids
D) Topical antibiotics
Answer
• D) Topical antibiotics
Which of the following is the
most lethal form of cancer for
men and women?
A) Pancreatic
B) Colorectal
C) Lung
D) Hepatocellular carcinoma
Answer
• C) Lung
Radiotherapy is _______
postoperative lung cancer
care.
A) An essential
component of
B) Contraindicated for
Answer
• B) Contraindicated for
Which of the following targeted
therapies is for the treatment of
Philadelphia chromosomepositive chronic myelogenous
leukemia?
A) Tamoxifen
B) Rituximab
C) Trastuzumab
D) Imatinib
Answer
• D) Imatinib
If a growth pathway is
overutilized by a tumor,
inhibition at any point in the
pathway should have a clinically
significant impact.
A) True
B) False
Answer
• B) False
Which of the following is the
most significant side effect of the
new antimonoclonal antibodies
(mAbs) centuximab and
panitumumab?
A) Rash on back, trunk, and face
B) Alopecia
C) Nausea and vomiting
D) Myelosuppression
Answer
• A) Rash on back, trunk, and face
The most important component
of follow-up care for breast
cancer survivors is:
A) Prevention
B) Surveillance
C) Intervention
D) Coordination
Answer
• B) Surveillance
Guidelines from the American
Society of Clinical Oncology for
follow-up of breast cancer
patients state that routine
_______ are neither necessary
nor indicated.
A) Laboratory tests
B) Computed tomography
C) Bone scans
D) All the above
Answer
• D) All the above
Research indicates that all the
following antidepressants should
be avoided in breast cancer
patients taking tamoxifen,except:
A) Paroxetine
B) Sertraline
C) Citalopram
D) Fluoxetine
Answer
• C) Citalopram
Osteoporosis _______ a
contraindication to placing
a breast cancer patient on
an aromatase inhibitor.
A) Is
B) Is not
Answer
• B) Is not
The only lifestyle intervention
that has been consistently shown
to reduce breast cancer
recurrence is:
A) Increased consumption of
protein
B) Increased intake of calcium
C) Exercise
D) Reduced consumption of
alcohol
Answer
• C) Exercise
Introductory remarks
• cancer as major health issue
• Cancer is expected to surpass heart disease
in 2010 as leading cause of death in United
States
• lifetime probability of developing cancer 1
in 2 for men, 1 in 3 for women
• most common new cancers prostate in men
and breast in women
• however, lung cancer most lethal type for
both sexes
Impact of chemotherapy on patients with curable lung cancer:
• surgery only consistently curative treatment for lung cancer
• however, few patients surgical candidates, and surgery fails to cure
majority of these
• patient with stage 1 lesion has <50% chance of 5-yr survival (more
advanced-stage tumors have much worse outcomes)
• multiple trials found postoperative radiotherapy increases risk for
death after surgery
• historically, hard to show advantage of postoperative chemotherapy,
but routinely used in patients with metastatic disease; study design—
482 patients randomized to undergo observation or 4 mo of cisplatinvinorelbine after surgery
• results showed 15% improvement in 5-yr survival with chemotherapy
• conclusions—in postoperative care of patients with lung cancer, clear
survival advantage with postoperative or adjuvant chemotherapy
(toxicity manageable in majority of patients)
• quality of life (QOL) only temporarily affected
• postoperative radiotherapy contraindicated
Differences in outcome based on histology
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chemotherapy can extend survival in patients with advanced non-small cell
lung cancer (NSCLC)
multiple palliative treatment options exist, but toxicities not trivial
treatment must be personalized based on toxicity profile
4 to 5 different subtypes of NSCLC previously undistinguished when planning
treatment
however, data suggest need for distinction
study design—patients randomized to receive cisplatin plus gemcitabine or
cisplatin plus pemetrexed, and stratified based on histology results—no
significant difference in median overall survival (OS) between treatment
regimens
however, when broken down by histologic subtypes, significant differences in
response to regimens emerged
first randomized controlled trial to show survival difference based on histologi
subtype
provides evidence-based rationale for more specific patient selection to
optimize therapeutic outcomes
Differences in outcome based on genetics
• study evaluated multigene assay to predict recurrence of
tamoxifen-treated node-negative breast cancer prognosis vs
prediction—several good and bad prognostic factors wellestablished for breast cancer
• established predictive factors include presence of estrogen
receptors (ER) or progesterone receptors (PR), and human
epidermal growth factor receptor 2 (HER2-neu) status
• molecular profiling—Oncotype DX (multigene) assay
examines genome of tumors and looks for differences in
gene expression
• can identify 5 types of breast cancer that look identical
microscopically but differ significantly in their molecular
profile
• test score (based on tumor’s genetic signature) used to
place patient in 1 of 3 categories for risk for recurrence
(low, intermediate, or high), which in turn helps to tailor
Sorafenib in advanced hepatocellular
carcinoma (HCCA)
• HCCA most common gastrointestinal
malignancy worldwide
• no effective systemic therapy despite
decades of attempts
• study design—600 patients with previously
untreated HCCA randomized to receive
sorafenib (400 mg/day orally) or placebo
• results—drug produced significant
improvements in median OS, time to
radiographic progression, and QOL
Targeted Therapies
• Rationale: development of specific agents to
negatively affect cancer, but not patient
• next generation is oral therapy;
• examples—ER-positive breast cancer treated with
tamoxifen or aromatase inhibitors (AIs)
• Philadelphia chromosome-positive chronic
myelogenous leukemia treated with imatinib
(Gleevec)
• CD20 antigen-positive B cell lymphoma treated
with rituximab (Rituxan)
• antiepidermal growth factor receptor therapies (eg,
trastuzumab [targets HER2-neu])
Tumor cell stimulation
• transmembrane receptors play role in
cellular communication and growth
• series of signal transductions within normal
cell initiate replication
• however, cancer cells can hijack system
• if uninterrupted, cancer may progress in
unregulated fashion
• strategies to inhibit signaling—
• tyrosine kinase inhibitors
• antimonoclonal antibodies (mAbs)
• antiligand mAbs
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mAbs (“abs”) and small molecular
inhibitors (“ibs”)
abs—eg, rituximab, cetuximab, trastuzumab, panitumumab
intra- venous (IV) medications
side effects dependent on target
proteins (therefore have potential to cause hypersensitivity
or allergic reaction)
ibs—eg, sunitinib, imatinib, sorafenib
Oral medications
side effects dependent on enzymes inhibited
future—120 mAbs and tyrosine kinase inhibitors currently
in phase I or preclinical trials
each has different target (with indication approved by Food
and Drug Administration)
Expected to change landscape of cancer treatment
Where to target therapy
• drugs currently available that can affect
almost any point on signal transduction
pathway that leads to oncogenesis
• previously thought that if growth pathway
overutilized by tumor, inhibition at any
level should have clinically significant
impact (disproved by recent study with
cetuximab)
• results patient-specific (targeting must be
• individually tailored)
Side effects of mAbs
• do not cause those of standard
chemotherapies, but produce
rash on back, trunk, and face
(severity of rash correlates with
efficacy of therapy)
Treatment of colorectal cancer (CRC)
• 2 new mAbs (centuximab and panitumumab) developed and
approved for treatment of metastatic CRC
• both agents show efficacy, but not to extent anticipated
• research has shown that efficacy depends on status of Kirsten rat
sarcoma viral oncogene homolog (K-ras)
• gene encodes K-ras enzyme, which acts as molecular “on-off” switch
• if patient has wild-type gene, enzyme
• Inactivated
• with mutated form of gene, switch stuck in “on” position (drives tumor
growth)
• interrupting signal pathway not effective for tumors with mutated Kras gene
• Study: patients with refractory CRC treated with cetuximab vs basic
supportive care
• previous results showed mild improvement
• no clinical markers predicted which patients would benefit
• tumor samples subsequently analyzed for Kras gene status
• patients with K-ras mutation derived no benefit from medication
Conclusions
• need to be exact in understanding specific
biology of patient’s cancer
• personalized oncology will be based on
molecular profiles of patient and tumor
• application to earlier stages of disease,
screening, and prevention will have greatest
impact on patient care and society
Health Issues in Breast Cancer Survivors
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Three “seasons” of survivorship
Acute
extended (after completion of treatment)
permanent (late effects)
Survivorship issues: costs of being long-term cancer
survivor
• (physical, emotional, spiritual, and financial)
• due to large number of breast cancer survivors and
growing number of treatments available for patients with
metastatic disease, medical oncologists overwhelmed
(need to develop system to transition survivors back into
community to their primary care physician [PCP], or to
specialized survivorship clinics)
Health Issues in Breast Cancer Survivors
• Differences in follow-up care for cancer (world
perspective)
• In many other countries, access to subspecialists
limited, and PCPs and physician extenders play
larger role in health care in general
• supported by studies in United Kingdom and
Canada 2005 Institute of Medicine guidelines on
survivorship
• Key recommendation—each patient should receive
survivorship care plan reimbursed by insurers
• includes detailed documentation of past treatment,
complications, and current maintenance regimen
Health Issues in Breast Cancer Survivors
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Practice considerations and barriers
lack of training in follow- up care
absence of agreed-upon standards of care
reimbursement issues
Essential components of survivorship
care
• prevention
• surveillance
• (most important); intervention; coordination
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Breast Cancer Staging
Stage I
Stage I describes invasive breast cancer (cancer cells are breaking through to or invading neighboring normal tissue) in which:
the tumor measures up to 2 centimeters, AND
no lymph nodes are involved
Stage II
Stage II is divided into subcategories known as IIA and IIB.
Stage IIA describes invasive breast cancer in which:
no tumor can be found in the breast, but cancer cells are found in the axillary lymph nodes (the lymph nodes under the arm), OR
the tumor measures 2 centimeters or less and has spread to the axillary lymph nodes, OR
the tumor is larger than 2 centimeters but not larger than 5 centimeters and has not spread to the axillary lymph nodes
Stage IIB describes invasive breast cancer in which:
the tumor is larger than 2 but no larger than 5 centimeters and has spread to the axillary lymph nodes, OR
the tumor is larger than 5 centimeters but has not spread to the axillary lymph nodes
Stage III
Stage III is divided into subcategories known as IIIA, IIIB, and IIIC.
Stage IIIA describes invasive breast cancer in which either:
no tumor is found in the breast. Cancer is found in axillary lymph nodes that are clumped together or sticking to other structures, or cancer
may have spread to lymph nodes near the breastbone, OR
the tumor is 5 centimeters or smaller and has spread to axillary lymph nodes that are clumped together or sticking to other structures, OR
the tumor is larger than 5 centimeters and has spread to axillary lymph nodes that are clumped together or sticking to other structures
Stage IIIB describes invasive breast cancer in which:
the tumor may be any size and has spread to the chest wall and/or skin of the breast AND
may have spread to axillary lymph nodes that are clumped together or sticking to other structures, or cancer may have spread to lymph nodes
near the breastbone
Inflammatory breast cancer is considered at least stage IIIB.
Stage IIIC describes invasive breast cancer in which:
there may be no sign of cancer in the breast or, if there is a tumor, it may be any size and may have spread to the chest wall and/or the skin of
the breast, AND
the cancer has spread to lymph nodes above or below the collarbone, AND
the cancer may have spread to axillary lymph nodes or to lymph nodes near the breastbone
Stage IV
Stage IV describes invasive breast cancer in which:
the cancer has spread to other organs of the body -- usually the lungs, liver, bone, or brain
Case example
• 56-yr-old postmenopausal woman diagnosed with stage I invasive
ductal carcinoma
• treated with lumpectomy, sentinel lymph node dissection, and
irradiation of breast
• recently started on AI
• patient presents to PCP for routine health care with concerns about
recurrence
• wants to have diagnostic testing to make sure cancer has not returned
• Recommended management: patient has <5% chance of dying of
breast cancer in next 10 yr
• breast cancer follow-up guidelines—American Society of Clinical
Oncology (ASCO) guidelines state that routine laboratory tests,
computed tomography, or bone scans neither necessary nor indicated
• use of tumor markers not recommended for patient’s disease stage
• imaging recommendations—various organizations recommend followup mammography of affected breast every 6 to 12 mo for first 5 yr
(and annually thereafter) in setting of breast-conserving surgery
• only limited indications for magnetic resonance imaging of breast
Critical issues in breast cancer survivorship
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physical effects
emotional effects
practical issues
Cardiovascular (CV) and thrombotic effects in breast
cancer survivors
risk for CV or thrombotic adverse effects associated
with anthracycline-based chemotherapy well known (but
possibly overestimated)
trastuzumab therapy also associated with some risk for CV
damage and congestive heart failure
potential CV effects of hormonal therapies controversial
With current techniques, radiotherapy has little CV effect
Persistent peripheral neuropathy after
taxane chemotherapy
• major problem in breast cancer patients
• study of 35 patients receiving adjuvant
paclitaxel found that those who experienced
severe neuropathy during treatment most
likely to experience persistent symptoms
• >60% had significant persistent neuropathy
>1 yr after completion of therapy
Potential effects of tamoxifen and AIs
• tamoxifen associated with increased risk for endometrial cancer (also
likely overestimated)
• greatest impact seen on QOL
• acute effects on menopausal symptoms—prospective study found
tamoxifen and AIs both increased severity of hot flushes;
musculoskeletal pain most frequent complaint with AIs (also
associated with increased vaginal dryness, dyspareunia, and decreased
sexual interest) Tamoxifen: efficacy affected by efficiency in
metabolizing via cytochrome P450 2D6 (varies among patients)
• certain antidepressants (paroxetine [Paxil], sertraline [Zoloft],
fluoxetine [Prozac, Sarafem]) should be avoided in patients on
tamoxifen
• associated with thrombotic effects (however, patients <50 yr of age do
not appear to have significantly increased risk for CV events
• majority of women placed on drug premenopausal)
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Potential effects of tamoxifen and AIs
Ais
proven superior to tamoxifen in reducing risk for disease recurrence in postmenopausal women
can be given in several regimens (eg, 5 yr of AI therapy as substitute for tamoxifen
tamoxifen for 2-3 yr, followed by 2-3 yr of AI [shown more effective than 5 yr of tamoxifen alone]
5 yr tamoxifen, followed by 5 yr of AI)
Musculoskeletal effects: interventions (eg, nonsteroidal antiinflammatory drugs, exercise) often of
limited benefit
Bone health—AIs reduce systemic levels of estrogen below that
of normal menopause (associated with decline in bone mineral
density [BMD] and increased risk for fracture
also accelerate progressive loss of BMD)
in contrast, tamoxifen may preserve BMD
patients with osteopenia or osteoporosis
before therapy may be at greatest risk for further drop in BMD while on AI
ASCO guidelines state that most patients should have bone density tested within 1 yr of starting AI
patients with normal BMD at baseline should take calcium and vitamin D and do weight–bearing
exercises
Patients with osteopenia or osteoporosis should have BMD rechecked 1 yr later to assess any change
osteoporosis not contraindication to taking AI; studies have suggested that IV biphosphonates (eg,
zoledronic acid) may decrease AI associated bone loss and, possibly, risk for breast cancer
recurrence
arthralgias—also significantly more common with AIs than with tamoxifen
onset typically within 2 mo of starting treatment
symptoms often resolve over time
Potential effects of tamoxifen and AIs
• Vasomotor symptoms
• hot flushes and sleep disturbance common with
hormonal therapy
• hot flushes—many studies have demonstrated
significant placebo effect
• results with phytoestrogens mixed
• progestational agents (eg, megestrol
• acetate [Megace]) appear to reduce hot flushes
(good option for patients with metastatic breast
cancer)
• other agents with proven efficacy include
venlafaxine, fluoxetine, paroxetine, and
gabapentin
Sexual dysfunction
• extremely common
• cause multifactorial
• management of vaginal dryness—studies show topical
nonestrogenic lubricants (eg, Replens) safe and effective
alternative to estrogen vaginal cream
• safety of vaginal estrogens questionable in breast cancer
patients (small study of estradiol hemihydrate [eg,
Vagifem] suggests agent contraindicated in women on
AIs)
• decreased libido—studies of use of transdermal
testosterone suggest little benefit
• atrophic vaginitis—pilot study of use of vaginal
testosterone cream showed improvement in vaginal
dryness, dyspareunia, itching, and irritation
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Other long-term health and QOL issues
weight gain
Possible development of unfavorable lipid profiles on Ais
Persistent cognitive effects
chronic fatigue
Potential impact of lifestyle factors on survivorship
Diet and weight—great deal of evidence that obesity and
increasing weight associated with increased rates of breast
cancer and cancer recurrence (especially in premenopausal
women and in women who gained weight after diagnosis)
exercise—only intervention consistently shown to reduce
breast cancer recurrence
alcohol consumption—associated with increased risk for
breast cancer
guidelines suggest women diagnosed with breast cancer
should consume <7 alcoholic beverages per week
Takeaway messages for PCPs of
breast cancer survivors
• cancer patients face many long-term
complications and symptoms related to their
treatment
• most breast cancer patients cured of their
disease
• not all symptoms indicative of recurrence
• before ordering scan or test, contact
patient’s treating oncologist to discuss
which would be most appropriate