The medical letter on drugs and therapeutics september 1 2014

The Medical Letter

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on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 56

ISSUE
ISSUE
No.

1433
1450
Volume 56

September 1, 2014

IN THIS ISSUE

Statins and Diabetes Risk .......................................................................................... p 79
Drugs for Osteoarthritis ............................................................................................. p 80
In Brief: New Polio Vaccination Guidance for Travelers............................................... p 84

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 56

ISSUE

ISSUE No.

1433
1450
Volume 56

▶

September 1, 2014
Take CME Exams
ALSO IN THIS ISSUE

Drugs for Osteoarthritis ............................................................................................. p 80
In Brief: New Polio Vaccination Guidance for Travelers............................................... p 84

Statins and Diabetes Risk

In 2012, the FDA required manufacturers of HMG-CoA
reductase inhibitors (statins) to add a warning to their
labels about reports of increased blood glucose and
glycosylated hemoglobin (HbA1c) levels.1 Since then,
several new studies have been published.
MECHANISM — No mechanism for a diabetogenic
effect of statins has been established. Some investigators have proposed that statins may cause an immune
response that interferes with insulin signaling.2
NEW-ONSET DIABETES RISK — A meta-analysis of
5 primary or secondary cardiovascular prevention
studies in a total of 51,619 non-diabetic patients, with
median follow-up times ranging from 1.9-5.0 years,
found that 4.0% of patients taking statins and 3.5% of
those taking placebo developed diabetes.3 In another
meta-analysis of 13 studies that included a total of
91,140 non-diabetic patients, new-onset diabetes
occurred 9% more frequently among those taking
statins than among those not taking statins.4 Both
differences were statistically significant.
In one large placebo-controlled primary prevention

trial, the increased risk of diabetes with rosuvastatin
20 mg was confined to patients with at least one major
risk factor for the disease.5
A cohort study examined the relationship between
statin adherence rate and diabetes incidence in
115,709 non-diabetic 40- to 80-year-old patients.
Compared to patients with adherence rates of <25%,
those with adherence rates of 25-49%, 50-74%, and
≥75% were, respectively, 12%, 21%, and 32% more
likely to develop diabetes. All of these differences were
statistically significant.6

INTENSITY OF STATIN THERAPY — A meta-analysis
of 5 trials including a total of 32,752 non-diabetic
patients compared the effects of high-intensity
and moderate-intensity statin therapy on newonset diabetes and cardiovascular event rates. (The
studies used slightly different definitions of high-,
moderate-, and low-intensity statin therapy.) Over
a mean follow-up period of 4.9 years, patients on
high-intensity statin therapy experienced 2.0 more
cases of new-onset diabetes and 6.5 fewer first
major cardiovascular events per 1000 patient-years
than those on moderate-intensity therapy, both
statistically significant differences.There was no
difference in all-cause mortality between the two
treatment groups.7
Table 1. Treatment Intensity of Statin Doses*
Intensity

Daily Dose

High (≥50% decrease in LDL-C)

Atorvastatin 40-80 mg
Rosuvastatin 20-40 mg

Moderate (30-<50% decrease
in LDL-C)

Atorvastatin 10-20 mg
Fluvastatin 80 mg
Lovastatin 40 mg
Pitavastatin 2-4 mg
Pravastatin 40-80 mg
Rosuvastatin 5-10 mg
Simvastatin 20-40 mg

Low (<30% decrease in LDL-C)

Fluvastatin 20-40 mg
Lovastatin 20 mg
Pitavastatin 1 mg
Pravastatin 10-20 mg
Simvastatin 10 mg

* NJ Stone et al. 2013 ACC/AHA guidelines on the treatment of blood
cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am
Coll Cardiol 2014; 63:2889.

A meta-analysis of 8 cohort studies in 136,966 nondiabetic patients ≥40 years old who were newly

prescribed a statin after hospitalization for a major
cardiovascular event found that patients taking higherintensity statin therapy had a 15% higher incidence of
79

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new-onset diabetes than those on a lower-intensity
statin regimen (p=0.003). The difference in new-onset
diabetes rates between the higher- and lower-intensity
groups was greatest in the first 120 days after starting
a statin and was nonsignificant after the first year of
statin treatment.8
OLDER WOMEN — A post-hoc analysis of data in
153,840 non-diabetic postmenopausal women from
the Women’s Health Initiative who were followed for
a mean of 6.5 years found that women taking statins
at baseline were significantly more likely to develop
diabetes than those not taking statins (HR 1.71).9 Concomitant metabolic syndrome may have contributed
to the large increase in risk in these women.
PRE-DIABETES – A retrospective analysis of 9055
patients with impaired glucose metabolism (“prediabetes”) who were followed for a mean of 4.1 years
found that statin use was associated with a 20% increase
in diabetes incidence, but also with a 30% reduction in
the incidence of major cardiovascular events.10
CONCLUSION — Many patients who take statins have

risk factors for diabetes. Statins may slightly increase
the risk of new-onset diabetes, but not as much as
they reduce the risk of cardiovascular disease. Patients who have indications for statins, including those
with risk factors for diabetes, should take them. ■
1. FDA Drug Safety Communication: Important safety label
changes to cholesterol-lowering statin drugs. Available at
www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed
July 17, 2014.
2. BD Henriksbo et al. Fluvastatin causes NLRP3 inflammasomemediated adipose insulin resistance. Diabetes 2014 June 10
(epub).
3. SN Rajpathak et al. Statin therapy and risk of developing type 2
diabetes: a meta-analysis. Diabetes Care 2009; 32:1924.
4. N Sattar et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;
375:735.
5. PM Ridker et al. Cardiovascular benefits and diabetes risks of
statin therapy in primary prevention: an analysis from the Jupiter trial. Lancet 2012; 380:565.
6. G Corrao et al. Statins and the risk of diabetes: evidence from
a large population-based cohort study. Diabetes Care 2014;
37:2225.
7. D Preiss et al. Risk of incident diabetes with intensive-dose
compared with moderate-dose statin therapy: a meta-analysis.
JAMA 2011; 305:2556.
8. CR Dormuth et al. Higher potency statins and the risk of new
diabetes: multicentre, observational study of administrative
databases. BMJ 2014; 348:g3244.
9. AL Culver et al. Statin use and risk of diabetes mellitus in
postmenopausal women in the Women’s Health Initiative. Arch
Intern Med 2012; 172:144.
10. KL Wang et al. Risk of new-onset diabetes mellitus versus
reduction in cardiovascular events with statin therapy. Am J

Cardiol 2014; 113:631.

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September 1, 2014

Drugs for Osteoarthritis
Related article(s) since publication

RECOMMENDATIONS
Acetaminophen is generally the first-line pharmacologic treatment for osteoarthritis pain. NSAIDs are
more effective, but have many more adverse effects,
especially in elderly patients. Intra-articular injection
of a corticosteroid is a reasonable alternative. Opioids
can be used as a last resort for patients with intractable osteoarthritis pain.
Many different drugs are used for treatment of osteoarthritis pain, but none of them prevent progression
of the disease. Many nonpharmacologic approaches
are available as well, including weight management,
exercise, physical therapy, assistive devices, and total
joint arthroplasty. New guidelines for the management
of osteoarthritis have recently been published.1-3
ACETAMINOPHEN
Acetaminophen is generally the first-line treatment
for mild to moderate osteoarthritis pain. It has no
clinically significant anti-inflammatory activity and
is less effective than full doses of nonsteroidal antiinflammatory drugs (NSAIDs), but has fewer adverse

effects. Mild to moderate pain generally responds to
650 mg of acetaminophen; there are no published data
showing that a dose of 1000 mg is more effective than
650 mg in treating osteoarthritis.
ADVERSE EFFECTS — Most healthy patients can take
up to 4 grams of acetaminophen daily with no adverse
effects. One gram three times daily for 2 weeks has
been shown to increase blood pressure slightly in
patients with cardiovascular disease.4 Acetaminophen
overdose can cause serious or fatal hepatotoxicity. In
some patients, such as those who are fasting, are heavy
alcohol users, or are concurrently taking isoniazid (INH),
zidovudine (Retrovir, and generics), or a barbiturate,
hepatotoxicity can develop after moderate overdosage
or even with high therapeutic doses. Continued use of
acetaminophen may increase the anticoagulant effect
of warfarin (Coumadin, and others) in some patients.5
PREGNANCY — Acetaminophen causes fetal toxicity
in animals, and controlled trials of its use in human
pregnancy are not available. Occasional use of
oral acetaminophen during pregnancy is generally
considered safe, but some reports have suggested an
association with an increased risk of attention-deficit/
hyperactivity disorder (ADHD) in the offspring.6


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NSAIDS
Full doses of NSAIDs are more effective than full doses
of acetaminophen for treatment of osteoarthritis. Some
patients may respond better to one NSAID than to another. Diclofenac is available as a topical gel or solution
for local treatment of osteoarthritis; applying the drug
topically appears to be modestly effective in reducing
pain and has a low risk of systemic side effects.7
ADVERSE EFFECTS — Bleeding – All NSAIDs except
salsalate, COX-2 selective celecoxib, and, to a lesser
extent, meloxicam and nabumetone, can interfere with
platelet function and prolong bleeding time. Unlike
aspirin, which has an irreversible inhibitory effect on
platelets that persists for the life of the platelet (up
to 10 days), the NSAID-induced antiplatelet effect is
reversed when the NSAID is cleared.
Gastrointestinal — Dyspepsia and GI ulceration,
perforation, and bleeding can occur with all NSAIDs,
including parenteral formulations. Serious GI
complications may occur without warning. High
doses, prolonged use, previous peptic ulcer disease,
concomitant use of systemic corticosteroids
or aspirin (even 81 mg/day), excessive alcohol
intake, and advanced age increase the risk of these
complications. Celecoxib is less likely than nonselective NSAIDs to cause gastric ulcers or other
GI toxicity. Diclofenac, etodolac, meloxicam, and
nabumetone are somewhat COX-2 selective in vitro.
Theoretically, these drugs may cause less GI toxicity
than less selective NSAIDs such as ibuprofen, but
there are no clinical data showing that they are less
likely to cause serious GI complications, and only

weak data suggesting that they are less likely to
cause symptomatic ulcers.
Concurrent use of a proton pump inhibitor such as
omeprazole (Prilosec, and generics), an H2-receptor
antagonist such as ranitidine (Zantac, and generics),
or the prostaglandin analog misoprostol (Cytotec,
and generics) may decrease the incidence of GI
toxicity caused by NSAIDs. Arthrotec (diclofenac/
misoprostol), Vimovo (naproxen/esomeprazole), and
Duexis (ibuprofen/famotidine) are three commerciallyavailable combinations of an NSAID and an agent for
GI protection.8,9
Renal Toxicity – All NSAIDs, including celecoxib,
inhibit renal prostaglandins, decrease renal blood flow,
cause fluid retention, and may cause hypertension and
renal failure in some patients, particularly the elderly.
Diminished renal function or decreased effective

Vol. 56 (1450)

September 1, 2014

intravascular volume due to diuretic therapy, cirrhosis,
or heart failure increases the risk of NSAID-induced
renal toxicity.
Cardiovascular Effects – An increased risk of serious
cardiovascular events, including myocardial infarction,
stroke, and pulmonary edema, has been reported with
some NSAIDs; the risk appeared to be highest with
diclofenac and lowest with naproxen.10 The risk with
celecoxib in usual doses appears to be similar to that

with non-selective NSAIDs.
Other Effects – NSAIDs can precipitate asthma
and anaphylactoid reactions in aspirin-sensitive
patients. They frequently cause small increases in
aminotransferase activity; serious hepatotoxicity is
rare, but may occur more frequently with diclofenac.
Pancreatitis has been reported. Cholestatic hepatitis
has occurred with celecoxib, possibly related to
sulfonamide allergy; celecoxib is contraindicated in
patients allergic to sulfonamides.
NSAIDs can cause central-nervous-system effects
such as dizziness, anxiety, drowsiness, confusion,
depression, disorientation, severe headache, and
aseptic meningitis. They have been associated
with both mild and severe skin reactions, including
exfoliative dermatitis, Stevens-Johnson syndrome,
and toxic epidermal necrolysis. NSAIDs rarely cause
blood dyscrasias; aplastic anemia has been reported
with ibuprofen, fenoprofen, naproxen, indomethacin,
tolmetin, and piroxicam.
Pregnancy – Exposure to NSAIDs during pregnancy
or around the time of conception has been
associated with an increased risk of miscarriage, but
the data are weak.11 Use of NSAIDs during the third
trimester of pregnancy may cause premature closure
of the ductus arteriosus and persistent pulmonary
hypertension in the neonate, but these effects appear
to be uncommon if the drug is discontinued 6-8
weeks before delivery.
Drug Interactions – NSAIDs may decrease the

effectiveness of diuretics, beta-blockers, ACE
inhibitors, and some other antihypertensive drugs,
and may increase the toxicity of lithium and
methotrexate. If taken with warfarin, they can increase
the INR. Concomitant use of NSAIDs with warfarin
or other anticoagulants is generally discouraged.
Patients taking aspirin for cardiovascular protection
should not take NSAIDs regularly because, except
for celecoxib, they can interfere with the antiplatelet
effect of aspirin.
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September 1, 2014

Table 1. Some Nonopioid Analgesics for Osteoarthritis
Drug
Acetaminophen – generic
Tylenol (McNeil Consumer)

Some Available
Formulations

Usual Adult Dosage1

Maximum
Daily Dose

Cost2

See footnote 3

650 mg PO qid or
1000 mg tid

4000 mg

$0.90
3.60

18, 35 mg caps

18-35 mg PO tid

105 mg

52.50

1.3% patch
50 mg tabs
50 mg tabs
25 mg caps
1.5% topical soln
1.5%, 2% topical soln

180 mg (1 patch) bid
50 mg PO bid or tid
50 mg PO bid or tid
25 mg PO qid
40 drops per knee qid
40 mg (2 pump actuations)
per knee bid6
2-4 g qid8
100 mg PO once/d

360 mg
200 mg

104.20
9.80
74.80
128.20
208.60
241.40

Some Non-Selective NSAIDs
Diclofenac – Zorvolex4 (Iroko)
Diclofenac epolamine –
Flector4 (Pfizer)
Diclofenac potassium – generic
Cataflam (Novartis)
Zipsor 4 (Depomed)
Diclofenac sodium – generic
Pennsaid 5 (Mallinckrodt)

Voltaren Gel 7 (Endo/Novartis)
extended-release – generic
Voltaren-XR (Novartis)
Duloxetine – generic
Cymbalta (Lilly)
Etodolac – generic
Fenoprofen – generic
Nalfon (Xspire)
Flurbiprofen – generic
Ansaid (Pfizer)
Ibuprofen – generic
Caldolor  4,10 (Cumberland)
Advil (Pfizer)
Ketoprofen – generic
Ketorolac12 – generic
Sprix (Regency Therapeutics)

Meclofenamate – generic
Mefenamic acid4 – generic
Ponstel (Shionogi)
Meloxicam – generic
Mobic (Boehringer Ingelheim)
Nabumetone – generic
Naproxen – generic
Naprosyn, EC-Naprosyn
(Genentech)
Naproxen sodium – generic
Anaprox, Anaprox DS (Genentech)
Naproxen sodium OTC – generic
Aleve (Bayer)

Salsalate – generic
Selective COX-2 Inhibitor
Celecoxib – generic
Celebrex (Pfizer)

1% gel
100 mg ER tabs
20, 30, 60 mg delayedrelease caps
200, 300 mg caps;
400, 500 mg tabs;
400, 500, 600 mg ER tabs
400 mg caps; 600 mg tabs
400 mg caps
50, 100 mg tabs
100 mg tabs
See footnote 3
100 mg/mL IV soln
50, 75 mg caps;
200 mg ER caps
10 mg tabs
15 mg/mL, 30 mg/mL,
60 mg/2 mL injection
15.75 mg/intranasal spray

50, 100 mg caps
250 mg caps
7.5, 15 mg tabs; 7.5 mg/5mL
PO susp
500, 750 mg tabs
250, 375, 500 mg tabs;

375, 500 mg enteric-coated
tabs; 25 mg/mL PO susp15
275, 550 mg tabs

30 mg PO once/d for 7d,
then 60 mg once/d
300 mg PO bid or tid or
400-500 mg bid
400-1000 mg PO once/d
400-600 mg PO tid or qid
100 mg PO bid or tid
200-400 mg PO q4-6h
IV : 400-800 mg qid
50 mg PO qid or 75 mg tid or
200 mg once/d (ER caps)
PO: 10 mg q4-6h
IM or IV: <65 yrs: 30 mg qid
>65 yrs: 15 mg qid
<65 yrs: 1 spray tid or qid
in each nostril
>65 yrs: 1 spray tid or qid
in only one nostril
50-100 mg PO qid
500 mg PO x1, then 250 mg qid14
7.5-15 mg PO once/d

160 mg
32 g9
200 mg
120 mg

1000 mg

42.00
15.70
65.80
44.00
50.90
10.30

1200 mg
3200 mg

14.00
53.80
55.90
300 mg
3.70
29.40
2400 mg (1200 mg OTC) 1.30
3200 mg
205.80
6.5011
300 mg
8.80
40 mg
120 mg
60 mg
126 mg

11.3013

28.1613
185.0013

63 mg
400 mg
1250 mg first day,
then 1000 mg
15 mg

77.80
426.90
571.70
0.50
40.30
7.70
1.30
36.30

500-750 mg PO bid or tid
250-500 mg PO bid

2000 mg
1250 mg first day,
then 1000 mg

275-550 mg PO bid

1375 mg first day,
then 1100 mg
660 mg

3.00
57.60
5.0011
7.8011
10.10

600 mg

N.A.16
49.10

220 mg tabs and caps

220 mg PO bid or tid

500, 750 mg tabs

1500 mg PO bid or 1000 mg tid

50, 100, 200, 400 mg caps

200 mg PO once/d or 100 mg bid

ER = extended-release
1. Dosage adjustment may be needed for hepatic or renal impairment.
2. Approximate wholesale acquisition cost of 1 weeks' treatment with the lowest dose and/or longest dosing interval, or smallest size bottle available. Source:
Analy$ource® Monthly (Selected from FDB MedKnowledge™) August 5, 2014. Reprinted with permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/
policies/drug-pricing-policy. Actual retail prices may be higher.
3. Available in multiple strengths and dosage forms, alone and in combination with other drugs, both over the counter and by prescription.

4. Not FDA-approved for treatment of osteoarthritis.
5. FDA-approved only for knee osteoarthritis.
6. Dosage for 1.5% topical soln is 40 drops per knee qid.
7. FDA-approved only for hand and knee osteoarthritis.
8. The dose for lower extremities is 4 g and for upper extremities is 2 g.
9. The maximum dose is 16 g/day to one joint of the lower extremeties and 8 g/day to one joint of the upper extremities.
10. FDA-approved as an adjunct to opioids.
11. Cost according to cvs.com. Accessed August 12, 2014.
12. FDA-approved only for short-term treatment (≤5 days) of moderate to severe pain that requires analgesia at the opioid level.
13. Cost of 5 days’ treatment.
14. Treatment should not exceed 7 days.
15. The suspension is not available as a generic drug.
16. The generic formulation has been approved by the FDA, but will not be marketed until later this year.

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OTHER DRUGS
DULOXETINE — The selective serotonin and norepinephrine reuptake inhibitor duloxetine (Cymbalta, and
generics) has been approved by the FDA for treatment
of chronic musculoskeletal pain. Its superiority over
placebo for treatment of osteoarthritis pain appears
to be modest at best.12 Adverse effects of duloxetine
include nausea, fatigue, dry mouth, constipation, insomnia, dizziness, and sexual dysfunction. Like other
drugs that inhibit reuptake of serotonin, duloxetine can
also increase the risk of bleeding.

TRAMADOL — An opioid agonist that also inhibits
reuptake of serotonin and norepinephrine, tramadol
(Ultram, and others) is approved by the FDA for
treatment of moderate to moderately severe chronic
pain in adults.13 In clinical trials in patients with
moderate to severe osteoarthritis knee pain, extendedrelease tramadol was modestly more effective than
placebo in reducing pain, but a substantial minority
of patients discontinued it because of adverse
effects that included nausea, vomiting, constipation,
dizziness, and somnolence. Seizures have occurred
with tramadol, and physical dependence has been
reported. It has recently been classified as a schedule
IV controlled substance by the DEA.
DIETARY SUPPLEMENTS — Glucosamine stimulates
cartilage cells in vitro to synthesize glycosaminoglycans
and proteoglycans. Given orally to animals, it has
a modest anti-inflammatory effect. Chondroitin
sulfate, a glycosaminoglycan sometimes combined
with glucosamine, has been reported in animals to
maintain viscosity in joints, stimulate cartilage repair
mechanisms, and inhibit enzymes that break down
cartilage.14 Neither glucosamine nor chondroitin sulfate
has been approved by the FDA for any indication, but
both are widely available as dietary supplements and
heavily promoted for treatment of "joint health".
Several randomized trials have reported beneficial
structural effects or moderate symptomatic efficacy
with glucosamine and/or chondroitin sulfate, but
the effectiveness of these agents remains to be
established.1-3 They appear to be safe, but as with

other dietary supplements, the potency and purity of
the ingredients may vary.
OPIOIDS — Long-term use of opioids to treat chronic
pain is problematic, but they can be used as a last
resort for treatment of intractable osteoarthritis pain.15
With continued use, patients become tolerant to both
the analgesic and adverse effects of opioids, except
for constipation.

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September 1, 2014

CAPSAICIN — FDA-approved as Qutenza for treatment of neuropathic pain and available over the
counter as Zostrix and other brands, the vanillyl
alkaloid capsaicin found in hot peppers and
related plants has also been used topically to treat
osteoarthritis. It appears to be effective for some
patients in reducing osteoarthritis pain, but it can
cause severe skin burns and nerve damage at the
site of application, and the dried residue can cause
coughing, sneezing, and eye irritation.16
INTRA-ARTICULAR INJECTIONS
Many patients with osteoarthritis have inadequate
responses or relative contraindications to systemic
anti-inflammatory or analgesic drugs. Injectable
intra-articular agents, particularly corticosteroid and
hyaluronic acid preparations, have been used as alternatives in such patients.
CORTICOSTEROIDS — Corticosteroid injections can
be effective in relieving osteoarthritis pain, even in

joints that are not obviously inflamed.17
Efficacy – About 80% of patients with symptomatic
osteoarthritis of the knee have a therapeutic response
to intra-articular injections of a corticosteroid.
Pain relief usually lasts for at least one month; by 2
months, the effect tends to wane. Most clinicians wait
a minimum of 3 months between injections. Mixing
a local anesthetic such as lidocaine 1% with the
corticosteroid can provide immediate pain relief and
ensure the accuracy of the injection.
Adverse Effects – Intra-articular corticosteroid
injections are generally safe. Some patients may
develop a local post-injection inflammatory reaction.
Septic arthritis is rare. Other uncommon local adverse
effects include bleeding, tendinopathy, tendon rupture,
lipoatrophy, skin atrophy, and avascular necrosis.
Systemic effects are also rare. Flushing can occur
several hours after injection. Adverse effects
commonly associated with systemic steroid use
such as osteoporosis and gastric ulcers have
not been reported with intra-articular injection of
corticosteroids.
HYALURONIC ACID — In osteoarthritis, the viscoelasticity of synovial fluid is reduced, in part due to
decreases in the molecular weight and concentration
of endogenous hyaluronic acid. Commercially
available hyaluronic acid preparations injected into
the joint space are claimed to increase the viscoelasticity of synovial fluid and possibly prevent
83

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degradation of articular cartilage. Although FDAapproved for treatment of osteoarthritis of the knee,
hyaluronic acid preparations have had only modest
beneficial effects. In one randomized, open-label
trial in 200 patients with osteoarthritis of the knee,
intra-articular hyaluronic acid was non-inferior to
oral NSAIDs in effectiveness and superior in safety.18
There are no reliable data showing that hyaluronic
acid injections slow progression of osteoarthritis. ■

1. MC Hochberg et al. American College of Rheumatology
2012 recommendations for the use of nonpharmacologic
and pharmacologic therapies in osteoarthritis of the
hand, hip, and knee. Arthritis Care Res (Hoboken) 2012;
64:465.
2. American Academy of Orthopaedic Surgeons. Treatment
of osteoarthritis of the knee. Evidence-based guideline 2nd
edition. Available at: www.aaos.org/Research/guidelines/
Treatmentof OsteoarthritisofthekneeGuideline.pdf. Accessed
August 21, 2014.
3. TE McAlindon et al. OARSI guidelines for the non-surgical
management of knee osteoarthritis. Osteoarthritis Cartilage 2014;
22:363.
4. In brief: does acetaminophen increase blood pressure? Med
Lett Drugs Ther 2011; 53:29.
5. Addendum: warfarin-acetaminophen interaction. Med Lett Drugs
Ther 2008; 50:45.

6. Z Liew et al. Acetaminophen use during pregnancy, behavioral
problems, and hyperkinetic disorders. JAMA Pediatr 2014;
168:313.
7. Diclofenac gel for osteoarthritis. Med Lett Drugs Ther 2008;
50:31.
8. Naproxen/esomeprazole (Vimovo). Med Lett Drugs Ther 2010;
52:74.
9. A fixed-dose combination of ibuprofen and famotidine (Duexis).
Med Lett Drugs Ther 2011; 53:85.
10. S Trelle et al. Cardiovascular safety of non-steroidal antiinflammatory drugs: network meta-analysis. BMJ 2011;
342:c7086.
11. R Antonucci et al. Use of non-steroidal anti-inflammatory
drugs in pregnancy: impact on the fetus and newborn. Curr
Drug Metab 2012; 13:474.
12. Duloxetine (Cymbalta) for chronic musculoskeletal pain. Med
Lett Drugs Ther 2011; 53:33.
13. Another once-daily formulation of tramadol (Ryzolt). Med Lett
Drugs Ther 2010; 52:39.
14. Y Henrotin and C Lambert. Chondroitin and glucosamine in the
management of osteoarthritis: an update. Curr Rheumatol Rep
2013; 15:361.
15. Drugs for pain. Treat Guidel Med Lett 2013; 11:31.
16. RD Altman and HR Barthel. Topical therapies for osteoarthritis.
Drugs 2011; 71:1259.
17. CT Hepper et al. The efficacy and duration of intra-articular
corticosteroid injection for knee osteoarthritis: a systematic
review of level I studies. J Am Acad Orthop Surg 2009;
17:638.
18. M Ishijima et al. Intra-articular hyaluronic acid injection
versus oral non-steroidal anti-inflammatory drug for the

treatment of knee osteoarthritis: a multi-center, randomized,
open-label, non-inferiority trial. Arthritis Res Ther 2014;
16:R18.

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IN BRIEF

New Polio Vaccination Guidance for
Travelers
Wild poliovirus has circulated during the previous
12 months in Cameroon, Equatorial Guinea, Ethiopia,
Iraq, Israel (also the West Bank and Gaza), Somalia,
and Syria, as well as in those countries where polio
is still endemic (Afghanistan, Nigeria, and Pakistan).
The World Health Organization (WHO) has declared
a public health emergency related to the possible
spread of polio from affected countries. In response,
the Centers for Disease Control and Prevention
(CDC) has issued interim guidance for US residents
planning travel to and from these countries.
Vaccine Recommendations – All travelers to countries
with wild poliovirus circulation during the last 12
months should have completed a primary series of
inactivated polio vaccine (IPV; IPOL – Sanofi-Pasteur)
before departure. Adults who have not previously been

immunized against polio should receive a 3-dose
primary series of IPV (2 doses 4-8 weeks apart; third
dose 6-12 months after the second). If protection is
needed sooner, 2 or 3 doses ≥4 weeks apart can be
given; if <4 weeks are available before protection is
needed, a single dose is recommended. Adults who
previously completed a primary series and have never
had a booster should receive a single booster dose of
IPV. Previously unimmunized children should receive
a 4-dose primary series of IPV. The first dose can
be given at age ≥6 weeks; the minimum interval is 4
weeks between doses 1 and 2 and 2 and 3, and is 6
months between doses 3 and 4. A child who received
4 doses before age 4 should be given a fifth dose.1
Interim Guidance – Travelers planning to stay for >4
weeks in a polio-infected country may be required to
present proof of polio vaccination when departing
that country. The CDC is now recommending that all
polio vaccine administration for travelers be documented on an International Certificate of Vaccination
or Prophylaxis (“yellow card”). Children and adults
who will be in a polio-infected country for >4 weeks,
and whose last dose of polio vaccine was administered >12 months before the date they will be leaving that country should receive an additional dose of
IPV before leaving the US. Those who plan to reside
in a polio-infected country for >12 months may be required to receive a dose of the polio vaccine that is
available in that country (either IPV or oral polio vaccine) between 4 weeks and 12 months before their
departure from the polio-infected country.2 ■
1. Advice for Travelers. Treat Guidel Med Lett 2012; 10:45.
2. GS Wallace et al. Interim CDC guidance for polio vaccination for
travel to and from countries affected by wild poliovirus. MMWR
Morb Mortal Wkly Rep 2014; 63:591.

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Explain the new label changes for HMG-CoA reductase inhibitors (statins) and why the FDA recommended them.
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Discuss the pharmacologic options available for management of osteoarthritis and compare them based on their efficacy and potential adverse effects.
Determine the most appropriate therapy for various clinical presentations of osteoarthritis.
Explain the recent polio vaccination guidance for US residents planning travel to and from countries with circulating wild poliovirus.

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Issue 1450 Questions

(Correspond to questions #41-50 in Comprehensive Exam #71, available January 2015)
Statins and Diabetes Risk
1. Which of the following has been associated with an increased

risk of new-onset diabetes?
a. use of higher-intensity statin therapy
b. use of statins in patients with major risk factors for diabetes
c. higher statin adherence rate
d. all of the above
2. Which of the following statin doses is considered high-intensity?
a. lovastatin 40 mg
b. fluvastatin 80 mg
c. pravastatin 80 mg
d. rosuvastatin 20 mg
Drugs for Osteoarthritis
3. An otherwise healthy 65-year-old woman presents to the walkin clinic with mild osteoarthritis knee pain and asks you for a
recommendation for her pain. Which of the following drugs would
generally be the first-line treatment for this patient?
a. aspirin
b. acetaminophen
c. ibuprofen
d. celecoxib
4. How much acetaminophen can most healthy patients take per
day without adverse effects?
a. 1 gram
b. 2 grams
c. 4 grams
d. 6 grams
5. Which of the following statements about NSAIDs is true?
a. full doses of NSAIDs are more effective than full doses of
acetaminophen for treatment of osteoarthritis pain
b. all NSAIDs interfere with platelet function
c. NSAIDs do not increase the risk of serious cardiovascular
events

d. all NSAIDs, except celecoxib, can cause renal toxicity

6. Which of the following selective norepinephrine reuptake
inhibitors has also been used for treatment of osteoarthritis?
a. duloxetine
b. venlafaxine
c. desvenlafaxine
d. all of the above
7. Adverse effects of tramadol include:
a. seizures
b. constipation
c. dizziness
d. all of the above
8. Which of the following statements about glucosamine and
chondroitin sulfate are true ?
a. they are both approved by the FDA for treatment of
osteoarthritis
b. they are heavily promoted for treatment of “joint health”
c. they can slow progression of osteoarthritis
d. all of the above
9. A 55-year-old woman with osteoarthritis recently saw an
advertisement for Qutenza and asks you whether it would help
her knee pain. You could tell her that:
a. in some patients it appears to be effective in reducing pain
b. it can cause severe burns at the site of application
c. the dried residue can cause coughing and sneezing
d. all of the above
10. Intra-articular corticosteroid injections:
a. are generally safe
b. can cause a local post-injection inflammatory reaction

c. are generally given at least 3 months apart
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-14-450-H01-P; Release: September 1, 2014, Expire: September 1, 2015
Comprehensive Exam 71: 0379-0000-15-071-H01-P; Release: January 2015, Expire: January 2016

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical
School; Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P, Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
Copenhagen; Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H.,
Harvard Medical School; F. Estelle R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R.,
Weill Medical College of Cornell University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. Valentino;
VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by
Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter,
Inc. is supported solely by subscription fees and accepts no advertising, grants, or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without
prior permission in writing. The editors do not warrant that all the material in this publication is accurate and complete in every respect. The editors shall not be held responsible for any damage
resulting from any error, inaccuracy, or omission.

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