The Family Practice Newsletter
Benzodiazepines
and Anxiety
April 2013
Inside this Issue

Benzodiazepines
and Anxiety

Community Acquired
MRSA Cellulitis (CAMRSA)

Osteoarthritis
**Updated**
Comprehensive
$4 List Available
www.doctorsfp.com
Newsletter Contact Information:
Megan Keller, PharmD
MKELLER4@OhioHealth.com
Doctors Hospital Family Practice
2030 Stringtown Road, Suite 300
Grove City, Ohio 43123
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Jessica Davis, PharmD Candidate
When treating a patient’s anxiety with
either short- or long-term therapy, there
are four major drug classes to choose
from: selective serotonin reuptake
inhibitors (SSRIs), serotoninnorepinephrine reuptake inhibitors
(SNRIs), tricyclic antidepressants, and
benzodiazepines (BZDs). Other
therapies involve controlling the
symptoms associated with anxiety
disorders (such as beta blocker). BZDs
are theorized to work through the
inhibitory neurotransmitter γaminobutyric acid (GABA) and act at
the limbic, thalamic, and hypothalamic
levels of the CNS, producing anxiolytic,
sedative, hypnotic, skeletal muscle
relaxant, and anticonvulsant effects.
They can be used to treat every type of
anxiety disorder and are the most
commonly prescribed class of agents for
treatment of anxiety. BZDs are
considered to be more effective than
barbiturates, meprobamate, or buspirone
for the treatment of anxiety symptoms
and disorder.
BZDs should be prescribed for shortterm use (4-10 wks) in generalized
anxiety disorder (GAD) or for shortterm alleviation of anxiety symptoms.
Long-term use (> 4 months) for GAD
has not yet been studied. They have,
however, been studied at periods greater
than 8 months and determined to not be
successful in treating panic disorders.
Specifically, alprazolam and
clonazepam are used for the short-term
treatment of panic disorder without
agoraphobia.
patient, lorazepam, oxazepam, and
temazepam (think “LOT”) are the safest
choices since they’re metabolized
through conjugation. Metabolism of
some BZDs (e.g., alprazolam,
clorazepate, diazepam, flurazepam, and
midazolam) is achieved through
oxidation by the cytochrome P-450
CYP3A. Use of these BZDs with
agents that inhibit (e.g., some azole
antifungals, some macrolide antibiotics,
HIV protease inhibitors, some calciumchannel blocking agents, some SSRIs,
nefazodone, grapefruit juice) this
enzyme will increase the plasma
concentrations of these drugs.
Conversely, agents that induce (e.g.,
carbamazepine, phenobarbital,
phenytoin, rifampin) this enzyme will
decrease the plasma concentrations of
these drugs.
Following the use of BZDs, a rebound
of symptoms of anxiety or panic and
withdrawal manifestations can occur.
This has been reported to occur even
after slow taper of the benzodiazepine
use for less than 8 weeks. These effects
have been shown to subside in two
weeks. In addition, seizures can also be
precipitated when discontinuing the
drug abruptly. Other side effects
associated with this class include dosedependent CNS adverse effects (such as
ataxia, somnolence, drowsiness, and
dizziness), behavioral changes,
hypotension, bradycardia, nausea,
anorexia, constipation, diplopia and
nystagmus. Most benzodiazepines are
pregnancy category X or D and should
generally be avoided.
See Table 1 for a comparison of BZDs
approved for treatment of anxiety.
When dosing BZDs, it is important to
keep in mind that the smallest effective
dose of the medication administered 3-4
times per day should be used. If the
medication will be used in an elderly
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The Family Practice Newsletter – April 2013
Drug
Alprazolam (Xanax ®and Xanax XR)
Chlordiazepoxide (Librium ®)
Clonazepam (Klonopin ®)
Clorazepate (Tranxene ®)
Table 1 – Comparison of BZDs Approved for Anxiety
Average Dose (Oral)
Max Dose
Peak Level
2.5-3mg/day in 3 x/day
4 (anxiety) and 10
1-2 hrs IR and 9
divided doses and 3-6
(panic)
hrs XR
mg daily
mg/day
15-100 mg/day in
300 mg/day
1-2 hrs
divided 2-4x/day doses
0.5-1 mg/day in divided
4 mg/day
1-4 hrs
2x/day doses (panic)
Not indicated for
anxiety
IR: 7.5-15 mg 2-4x/day
90 mg/day
1-2 hrs
Half Life*
~12 hrs
(9-20 hrs and 1016 XR hrs)
~15 hrs
(7-25 hrs)
~34 hrs
(18-50 hrs)
Equiv Doses~
0.5 mg
6-50 hrs
7.5 mg
25 mg
0.2 mg
Diazepam
2-10 mg 2-4x/day
30 mg/day
1-2 hrs
20-100 hrs
5 mg
(Valium ®)
Lorazepam
2-6 mg/day in 2-3x/day
10 mg/day
0.5-1 hr
~15 hrs
1 mg
(Ativan ®)
doses
(8-24 hrs)
Oxazepam
10-30 mg 3-4x/day
120 mg/day
2-4 hrs
~5 hrs
15 mg
(Serax ®)
(3-6 hrs)
*Half-life represents drug and metabolites
~Equivalent doses adapted from GlobalRPh’s benzodiazepine dose conversions page available at: http://www.globalrph.com/benzodiazepine_calc.cgi
Community
Acquired MRSA
Cellulitis (CAMRSA)
Ryan Hughes, PharmD Candidate
Introduction
MRSA, or methicillin-resistant
Staphylococcus aureus, is a multi-drug
resistant organism that in the past was
primarily encountered in the health care
setting. Recently, a separate strain of
the organism has spread amongst the
communities of the United States, and
MRSA is now more prevalent than
MSSA, with the number of cases
estimated to be >60% of the total
number of Staphylococcus aureus
infections. It is also estimated that
between 8-20% of the cases seen in the
hospital are CA-MRSA. The CAMRSA variant of MRSA is genetically
distinct from the hospital acquired
variant, and because of this it is more
virulent and tends to spread more
readily but is also more susceptible to
antibiotic therapy.
High-Risk Populations
In general, the groups at greatest risk of
contracting CA-MRSA cellulitis are
those that live in close proximity to each
2
other, typically under conditions that are
not completely hygienic and require the
use of shared facilities. Some examples
include military troops, athletic teams,
prisons, and college residential
dormitories. A recent study at Ohio
University looked at the prevalence of
MRSA bacteria on different surfaces
within dormitory hall bathrooms with
the following results listed on the
second table below.
These results indicate the need to
reinforce good hygiene habits, such as
the use of shower sandals, cleaning of
mirror shelves before use, regular
cleaning of utensils placed on mirror
shelves and the use of toilet seat covers.
All of these interventions will help
minimize skin contact with MRSA
surfaces and should reduce infection
rates.
Recommended Drug Therapy
There are several options available for
empiric drug therapy, but the use of the
various agents depends on the severity
of the disease. If it is a localized
abscess, then a simple drainage
procedure may be all that is required to
treat the infection. If the disease
appears to be extensive or progressing
rapidly, or if the patient has comorbid
factors such as DM II or some form of
immunosuppression, antibiotics are
indicated. The type of antibiotics used
depends on suspicion of MRSA or βhemolytic streptococci or both as the
suspected pathogen. Typically non-
purulent cellulitis will be β-hemolytic
streptococci and purulent cellulitis is
MRSA. Empiric coverage for MRSA
may be required if non-purulent
cellulitis fails to respond to therapy, and
coverage for both may be considered
with signs of systemic toxicity.
Clindamycin Resistance
The use of clindamycin to treat MRSA
has been called into question recently
with the increasing prevalence of
resistant pathogens. While there are
multiple other treatment options with
less potential resistance, clindamycin
remains a favored agent due to its
coverage of both staph and strep, its
favorable pregnancy risk category, and
its relative cost-profile compared to
linezolid. A recent study was
undertaken to determine if there were
any predictable markers for clindamycin
resistance. They found that surgery or
previous MRSA infection in the last 12
months or macrolide or clindamycin use
within 3 months were significantly
associated with clindamycin resistance.
Susceptibilities were as follows:
doxycycline (97%), TMP-SMX (99%),
clindamycin (89.6%). The sample size
was 1,026 isolates, and while these
results do not preclude the use of
clindamycin empirically, they do give
some direction for the prescribing
physician on patient selection for this
agent.
. . . . . . . . . . . . . . . . . . . . . . . .
The Family Practice Newsletter – April 2013
Drug
TMP-SMX
Coverage
MRSA
Adult
1-2 DS tabs BID
Pediatric
TMP 4-6 mg/kg/dose, SMX 2030 mg/kg/dose BID
Notes
Preg C/D, not
recommended for <2 YO
Doxycycline
MRSA
100 mg BID
≤45 kg 2 mg/kg/dose BID, >45
kg adult dose
Preg D, not recommended
for < 8 YO
Minocycline
MRSA
200 mg x1 then
100 mg BID
4 mg/kg x1 then 2 mg/kg/dose
BID
Preg D, not recommended
for <8 YO
Dicloxacillin or
Cephalexin
Streptococci
500 mg QID
Diclox: not for newborns
Cephal: not for <1 YO,
>15 YO refer to adult
dosing
Amoxicillin + TMPSMX or tetracycline
MRSA +
Streptococci
Amoxicillin 500
mg TID
Diclox: <40 kg 12.5-25
mg/kg/day in four doses, >40 kg
125-250 mg Q6H
Cephal: 12.5-25 mg/kg/day Q
12H
≤3 months: 20-30 mg/kg/day in
2 doses >3 months <40 kg: 20100 mg/kg/day in 2-3 doses
Clindamycin
MRSA +
Streptococci
300-450 mg TID
10-13 mg/kg/dose Q6-8H, max
40 mg/kg/day
Linezolid
MRSA +
Streptococci
600 mg BID
10 mg/kg/dose Q8H, max
600mg/dose
Higher risk of
Clostridium dificile
infection
>12 YO use adult dosing
Osteoarthritis
Layomi Fakunmoju, PharmD Candidate
Osteoarthritis (OA) is a progressive
disorder and, its contributory factors
include increasing age, obesity, joint
trauma and instability and repetitive
joint overuse. The most successful
treatment programs for patients with
OA comprise of a combination of
treatments tailored to the patient’s
needs, health and lifestyle and the goal
of therapy for OA is to improve quality
of life, reduce and control pain. These
can include exercise, weight control,
pain relief techniques, rest, medications,
alternative treatments and surgery.
These methods are described below.



Non-Pharmacological therapy
 Low impact aerobic exercise
programs to lose weight (if
overweight)

Children >3 months and
≥40 kg, use adult dosing
Physical therapy: Range of
motion exercises for flexibility
and strength training exercise
for muscle tone.
Occupational therapy: the
provision of assistive devices
for ambulation such as
crutches, cane and other
walking aids
Use of local heat or cold to the
affected joint
Manual therapy: Manipulation
and stretching joints
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The Family Practice Newsletter – April 2013


Appropriate footwear and
assistance devices for mobility
Supports and braces
Pharmacological therapy
See the table below for a summary of
treatment options.
Patients who fail Pharmacological and
Non-pharmacological therapy:
Arthroscopic lavage, debridement and
joint replacements.
In conclusion, the combination of
patient education, exercise, and
pharmacologic treatment improves
patient outcomes more considerably
when compared to pharmacologic
treatment alone especially in patients at
increased risk, such as, elderly patients,
women and patient with previous joint
surgery or trauma. Early interventions
would improve treatment outcomes and
also, better quality of life with patient
with OA. Therefore, It is recommended
that health care providers provide a
treatment combination approach to
patients with OA and the method of
treatment should also be based on
individual preference giving patients the
opportunity to make informed decision
about their treatment.
Drug
Acetaminophen (APAP)
(Tylenol®)
Oral NSAIDs
Ibuprofen (Motrin, Advil)
Naproxen (Aleve OTC or
Naprosyn ®) Meloxicam
(Mobic), etc.
Celecoxib (Celebrex)selective COX-2
Topical NSAIDs
Diclofenac (Voltaren)
Efficacy
Good
Limitation
Inferior to NSAIDs in efficacy
Oral NSAIDS >
APAP
GI bleed risk
Myocardial infarction risk (high dose)
except naproxen
Comparable to Oral
Dermatological side effects
More expensive than oral NSAIDS
Less side effects than oral NSAIDs
Topical (Capsaicin or
salicylates)
Good efficacy
*Salicylatesineffective
Good efficacy
Burning skin reaction
Start with low dose and titrate up
Abuse & addiction
Opiate-like analgesic
Tramadol (Ultram)
Glucosamine
Good efficacy
Abuse & addiction
Good efficacy in
some patients
Conflicting data for efficacy
Caution- elderly
For patient with severe pain or whom other
analgesic are CI
Relief of moderate to moderately severe pain.
Cause dizziness and somnolence.
Adjunctive therapy
Use sulfate salt slow onset (2months)
Chondroitin
Moderate efficacy
Mild GI side effects
Intra-articular Hyaluronate
injectable
(Synvisc, hyaluronic acid
Hyalgan
Intra-articular
glucocorticoids inj.
Methylprednisolon
(Medrol)
Triamcinolone (Kenalog10 and 40)
Acupuncture
Comparable to Oral
NSAIDs
Very Expensive
Mix clinical trial data due to
synthesis/formulation
Acute knee pain with
inflammation
Short term relief
Adjunctive therapy
Can use up to 40mg triamcinolone
hexacetonide, injections should not be
administered to a single joint more often then
once every 3 months
No conclusive
evidence regarding its
effectiveness
Can be beneficial to
patient with lower
bone density because
they are at higher risk
for OA
Short term relief
Adjunctive therapy
May cause temporary changes in appetite,
sleep, and GI
Adjunctive therapy
Hypercalcemia, malabsorption syndrome, and
evidence of vitamin D toxicity
Opioids
Codeine
Vitamin D supplementation
4
All NSAIDs - equal
in efficacy
Hypercalcemia resulting in HA, N/V,
confusion. Bone pain
Clinical Pearls
Max = 4g for adults and 3g in elderly (liver tox)
1st line
High GI bleed risk - PPI or double dose H2
Caution- DM, HTN & CHF
Second line. Used in Pts who fails to respond to
APAP, conservative tx and who has no
Contraindication for use
Adjunctive therapy
Lack as much evidence as glucosamine
Adjunctive therapy
Two different formulations approved by FDA
. . . . . . . . . . . . . . . . . . . . . . . .
The Family Practice Newsletter – April 2013
References:
Benzodiazepines and Anxiety
1. Munjack DJ, Crocker B, Cabe D et al. Alprazolam, propranolol, and placebo in the treatment of panic disorder and agoraphobia with panic attacks. J Clin
Psychopharmacol. 1989; 9:22-7. [IDIS 251932] [PubMed 2651490]
2. Davidson JR. Continuation treatment of panic disorder with high-potency benzodiazepines. J Clin Psychiatry. 1990; 51(Suppl A):31-7. [IDIS 275894]
[PubMed 2258375]
3. Pollack MH. Long-term management of panic disorder. J Clin Psychiatry. 1990; 51(Suppl):11-3. [IDIS 266882] [PubMed 1970813]
4. Pecknold JC, Swinson RP, Kuch K et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial: III. Discontinuation effects. Arch
Gen Psychiatry. 1988; 45:429-36. [IDIS 241071] [PubMed 3282479]
5. Anxiety and Depression Association of America. “Finding Help/ Treatment/ Medications”. Last Updated Unknown. Accessed on 3/12/13. Available online
from http://www.adaa.org/finding-help/treatment/medication
6. Lexi-Comp OnlineTM , AHFS DI (Adult and Pediatric) OnlineTM , Hudson, Ohio: Lexi-Comp, Inc.; March 14, 2013
7. Lexi-Comp OnlineTM , Lexi-Drugs OnlineTM , Hudson, Ohio: Lexi-Comp, Inc.; March 14, 2013
Community Acquired MRSA Cellulitis (CA-MRSA)
1. Cadena J, Sreeramoju P, Nair S, Henao-Martinez A, Jorgensen J, Patterson J. Clindamycin-resistant methicillin-resistant Staphylococcus aureus:
epidemiologic and molecular characteristics and associated clinical factors. Diagnostic Microbiology And Infectious Disease [serial online]. September
2012;74(1):1621. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed March 17, 2013.
2. IDSA Guidelines: Catherine Liu, Arnold Bayer, Sara E. Cosgrove, Robert S. Daum, Scott K. Fridkin, Rachel J. Gorwitz, Sheldon L. Kaplan, Adolf W.
Karchmer, Donald P. Levine, Barbara E. Murray, Michael J. Rybak, David A. Talan, and Henry F.Chambers Clinical Practice Guidelines by the Infectious
Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children Clin Infect Dis. first
published online January 4, 2011. Accessed March 17, 2013.
3. Tonn K, Ryan T. Community-associated methicillin-resistant Staphylococcus aureus in college residential halls. Journal Of Environmental Health [serial
online]. January 2013;75(6):44-49. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed March 17, 2013.
Osteoarthritis References
1. National Institute for Health and Clinical Excellence: The care and management of osteoarthritis in adults
2. American college of Rheumatology Osteoarthritis management guidelines: www.rheumatology.org
3. Arthritis Foundation: www.arthritis .org
4. American Geriatrics Society: www.americangeriatrics.org
5. Brasington R, Hsia EC, O’Hanlon KM, Murray JL eds. Osteoarthritis. Maryland Heights, Missiouri, 2010. MD Consult. 14 March. 2013. Retrieved
from<http: //www.mdconsult.com>.
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