neuropathic pain, Ceiliac disease

EVALUATION OF SYNCOPEWhich 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 SYNCOPEWhich 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 SYNCOPEWhich 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. 

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• 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

• 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)

• 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 ARTHRITISA 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 ARTHRITISWhich 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. 

• 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 gram-positive 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

• 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

• 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, colon resection, tooth extraction (early treatment beneficial

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

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

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

• 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• 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 (3.5-• 3.9 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

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

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 gluten-free 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

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 

• 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, long-term 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

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• 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)

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

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 (3.5- 3.9 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

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, amoxicillin-

clavulanate, 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 chromosome-positive 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 cisplatin-vinorelbine 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• 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 well-established 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 patient’s treatment

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

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 K-ras 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• however, dramatic benefit seen in those with wild-type gene

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

• 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

• 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

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 follow-up 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

• 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)

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

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