Download ANTIMICROBIAL dRug RESISTANCE

CHAPTER 1
!! Discuss the general scope of preventing
antimicrobial drug resistance.
!! Discuss and differentiate the various types of
(7 CONTACT HOURS)
isolation.
By Andrew Rosenthal, Doctor of Pharmacy, consultant
Gerson Lehman Group, Lead Medical Panel, Healthcare !! Understand the specific manner for
Advisory Board, Reckner and MD Linx.
pharmacists to prevent antimicrobial drug
resistance.
Author Disclosure: Dr Andrew Rosenthal and Elite
ANTIMICROBIAL drug Resistance
Professional Education do not have any actual or
potential conflicts of interest to this lesson.
Universal Activity Number (UAN):
0761-9999-13-191-H01-P
Activity Type: Knowledge-based
Initial Release Date: May 23, 2013
Expiration Date: May 23, 2015
Target Audience: Pharmacists in a community-based
setting.
To Obtain Credit: A minimum test score of 70 percent
is needed to obtain a statement of credit. Please submit
your answers either by mail, fax or online at
pharmacy.elitecme.com.
Questions regarding statements of credit and other
customer service issues should be directed to 1-888666-9053. This lesson is $29.00.
Educational Review Systems is accredited
by the Accreditation Council of Pharmacy
Education (ACPE) as a provider of
continuing pharmaceutical education. This
program is approved for 7 hours (0.7
CEU’s) of continuing pharmacy education credit. Proof
of participation will be posted to your NABP CPE
profile within 4 to 6 weeks to participants who have
successfully completed the post-test. Participants must
participate in the entire presentation and complete the
course evaluation to receive continuing pharmacy
education credit.
Learning objectives
!! Define and distinguish between antimicrobial
terms.
!! Understand each type of antimicrobial drug
resistance that can occur.
!! Discuss the history and discovery of
antimicrobials.
!! Compare and contrast the antimicrobial drug
classes.
!! Understand the manner in which
antimicrobial therapy can be managed
successfully.
!! List each of the hospital-acquired
antimicrobial drug resistances that can
occur (methicillin-resistant staphylococcus
aureus, vancomycin-resistant enterococci and
extended spectrum beta lactams).
!! Compare and contrast the respiratory
antimicrobial resistance noted in the hospital
and community (streptococcus pneumonia,
tuberculosis and pseudomonas aeruginosa).
!! Discuss the most common sexually
transmitted infection resistance (N.
gonorrhoreae).
!! Understand the antimicrobial resistance noted
in clostridium difficile.
!! Differentiate the antimicrobial resistance
seen in viral infections (influenza, human
immunodeficiency virus, herpes simplex
virus and hepatitis).
!! Understand the implication of agricultural
effects on antimicrobial drug resistance
globally.
Summary
It is not difficult to see that pharmacists have a
central role in the prevention and treatment of
antibiotic-resistant microbial disease. But the first
step is to understand the underlying principles of
resistance as well as the significance and impact
of specific resistant microbes. This course will
focus on understanding antimicrobial resistance.
Introduction
Pharmacists are on the front line in the battle
against antibiotic resistance. Their expertise in
the pharmacology of antimicrobial agents and
in the judicious use of these drugs has proven to
be invaluable in the treatment of various types
of infections from bacteria, fungus, viruses
and parasites. Once a bacterial infection has
developed, it is imperative that proper antibiotics
be administered to eliminate the bacteria and to
prevent it from spreading to other areas within
the body.
For the past half century, the discovery and use
of antimicrobial agents has prevented serious
complications posed by infectious diseases.
The development and success of antimicrobial
agents against diseases caused by various
microbes has been one of modern medicine’s
greatest achievements. To this day, the use of
antimicrobial agents continues to save the lives
of people who have access to health care and the
ability to complete the prescribed doses.
Although antimicrobials are wonder drugs in
fighting bacteria, viruses, fungus and parasites,
many patients have bacterial strains with a
developed resistance to the agents. Antimicrobial
resistance is an adaptive response in which
microbes tolerate the amount of medication that
previously halted the growth of the organism.
The most resistance has emerged to antibiotics,
chiefly because health care providers have
written too many prescriptions for patients
without a bacterial infection; organisms have
shed sensitivity to the prescribed antibiotic class
or dose; and patients have ingested antibiotics
incorrectly. Many physicians and researchers
have speculated that the widespread use of
antibiotics has spurred an evolutionary adaptation
that enables bacteria to survive these powerful
drugs.
The World Health Organization (WHO), Centers
for Disease Control and Prevention (CDC),
and Food and Drug Administration (FDA)
have suggested that the bacterial infections that
contribute the most to the emerging antimicrobial
resistance are diarrheal diseases, respiratory
tract infections, meningitis, sexually transmitted
diseases and hospital-acquired infections.
Elite
Antimicrobial resistance is a challenging,
frustrating problem for health care providers,
patients and the community. Unfortunately, a
patient who has bacterial strains with developed
resistance to a certain antibiotic or a class of
antibiotics may develop further complications or
die. It is important that pharmacists understand
their role in prevention of bacterial strains from
becoming resistant to antimicrobial agents,
especially antibiotics that may potentially
save patients’ lives. Unless we collaborate to
potentially eradicate and reduce the risk of
resistance, we may encounter a society faced with
previously treatable diseases that are untreatable
again, as in the days before antibiotics were
developed.
Pharmacists wear many hats in the prevention
and management of microbial resistance to
antimicrobial therapy. These include:
Subject matter expert: As experts in drugs,
their action, their chemistry, and their uses,
pharmacists should serve as consultants
for doctors, nurses, and other health care
professionals.
Educator: Pharmacists should become
active members of the facility’s education
team. Regular sessions with doctors, nurses,
and other health care professionals can go a
long way to achieving understanding of the
proper uses of antibiotics as well as how to
prevent microbial resistance. Furthermore,
pharmacists should work directly with
patients so that patients understand the
correct use of their antibiotic medications.
Policy maker: Pharmacists should be active
members of the formulary committee.
They are in the unique position of being
able to make recommendations for specific
drugs based on available data on resistance
and the potential for development of
resistance, which can be weighed against
cost effectiveness, patient compliance, and
other factors. Furthermore, pharmacists
should be able to draft policy about the use
of specific antimicrobial agents and under
which conditions they should be used as well
as recommendations on when specific agents
should not be used.
Researcher: Pharmacists are in the position
to collect and analyze data gathered at their
facilities to determine prescribing habits,
susceptibility and resistance of specific
microbes at the facility level, and to develop
guidelines for best practices based on
available evidence and data.
Networker: Pharmacists should reach out
to pharmacists at other local and regional
facilities to trade information about
susceptibility and resistance of microbes at
each facility, prescribing habits of physicians
and other prescribers, and to exchange
information about best practices at each
facility.
Advocate: Pharmacists are in the position
to advocate on behalf of specific patients,
especially those who may not be responding
to the prescribed antibiotic. Furthermore,
Page 1
For example, a patient with a long-term
indwelling urinary catheter is more likely to
develop a urinary-tract infection, and a patient
with central IV access line (either PICC or
central) is also at risk for bloodstream infections;
in cases like these, pharmacists can recommend
more frequent catheter changes or removal to
reduce the chances that such an infection will
occur.
Bactericidal agents kill bacteria.
This category includes the following
subcategories:
ŠŠ Disinfectants used to kill organisms
growing on a surface. These include
iodine (Betadine), chlorine and oxygen
compounds (e.g., bleach), and various
metal-based compounds. They have
medical value as cleaning agents
because they help prevent surface-toskin transmission of bacteria and other
microbes.
ŠŠ Antiseptics used to kill organisms on the
skin or mucosa. These include alcohol,
peroxide, phenols, and iodine. They are
typically used to prevent infection by
preventing person-to-person and personto-surface-to-person transmission; they
may also be used to prevent infection in
injuries.
ŠŠ Antibiotics used to treat infectious
disease. These include beta-lactam,
cephalosporins, metronidazole, among
others.
Bacteriostatic agents prevent bacterial
growth reproduction without killing the
organism; the bacteria die off naturally. These
include the tetracyclines, sulfonamides,
macrolides, and others.
Terminology of antimicrobial drugs
Antiviral
developing one-on-one relationships with
physicians and other prescribers, pharmacists
and other members of the health care team
can make a difference in guiding prescribing
and administration behaviors toward best
practices and away from behaviors and
habits that can cause microbial resistance to
antibiotic therapy.
Finally, although many hospital pharmacists do
not have a significant role in direct patient care,
it is still essential that they understand all of their
facility’s policies and practices on prevention
and management of diseases caused by
resistant pathogens. These include isolation and
precautions in caring for patients; environmental
precautions in maintaining the physical
environment, both of the hospital as a whole
and of the pharmacy; and in the role of hospital
equipment in the transmission of disease.
The term “antimicrobial” serves as an umbrella
term that describes any agent that controls
microbes through any means. This means that
ultraviolet light used in water purification
systems, alcohol-based hand sanitizers, and
antibiotic drugs are all examples of antimicrobial
agents because, although they work through
different mechanisms, they all control microbes
to some extent.
The overarching concept of “antimicrobial”
can be further separated into agents that
have industrial applications, such as the
aforementioned UV light, and those that have
medicinal applications, such as antibiotics.
This article will focus on antimicrobial agents
used in medicine, and specifically, those that fit
the commonly accepted definition of “drug.”
Furthermore, this course will discuss only the
drugs that are used to treat infectious disease;
anti-neoplastic antibiotics are not included here.
Antimicrobials in medicine
Suffice it to say that antimicrobials are a fairly
large category, and there are subcategories
within it. These include antibacterial, antiviral,
antifungal, and antiparasitic drugs. Each has its
own terminology, and although these terms may
not be in day-to-day usage within the health care
setting, they are important to know because they
help to explain how antimicrobial resistance
develops.
Antibacterial
As the name implies, antibacterial drugs, also
commonly called antibiotics, are used to treat
disease caused by bacteria. These drugs are
categorized by their mechanism of action.
Obviously, these drugs are used to treat viral
disease. They should not be prescribed for minor
infections, such as colds; they are reserved for
the treatment of severe acute infection, such as
influenza, and in the management of chronic
infectious diseases, such as those caused by HIV/
AIDS, hepatitis, and herpes viruses.
Antifungal
Antifungal drugs are used to treat disease caused
by fungi and yeasts.
Antiparasitic
These are used to treat infections caused by
parasites, such as malaria, amoebic dysentery,
and helminthes (worms).
Antibiotic resistance
Antibiotic resistance is one of the most serious
and pervasive problems that have emerged in
modern public health, more specifically how it
pertains to pathogenic organisms. It is important
to understand that people do not develop
resistance to antibiotics; the microorganisms
mutate or evolve to develop resistance to
antibiotics.
Antibiotic resistance is a form of drug resistance
where some or possibly all populations of
a bacterial or other microorganism species
can survive after treatment with one or more
antibiotics. These resistant pathogens are then
referred to as MDROs, (multi-drug resistant
organisms), or in the vernacular as superbugs or
gorilla bugs.
MDROs may have acquired resistance to firstline antibiotics, necessitating the need for a
second-line agent. Most commonly, first-line
Page 2
antibiotics are chosen on the basis of safety,
therapeutic efficacy and cost. The second-line
agent is more commonly broader in spectrum
and has a less favorable benefit-risk profile.
As is the case with some MDRO pathogens,
such as Staphylococcus aureus or Pseudomonas
aeruginosa, some pathogens‘ resistance to
first-, second-, and even third-line antibiotics is
sequentially developed, and possibly a significant
level of intrinsic resistance may exist.
The exposure of an organism to an antibiotic
naturally selects for the organism with the genes
for resistance. Resistance may take the form of
an induced or spontaneous mutation of genes, the
acquisition of resistance from another bacterial
species, transformation or transduction. In this
way, a gene for antibiotic resistance may quickly
spread through a population of bacteria. These
genes typically carry resistance factors for several
different types of antibiotics.
The increasing occurrence and incidence of
infections caused by MDROs is certainly noted
by the number of acronyms in use today to
identify the causative bacteria and sometimes the
cause of infection: MRSA (Methicillin resistant
staphylococcus aureus). VISA (vancomycin
intermediate S. aureus), VRSA (vancomycin
resistant S. aureus), ESBL (extended spectrum
beta-lactamase), VRE (vancomycin resistant
enterococcus) and MRAB (multi-drug resistant
Acinetobacter baumannii) are but a representative
sample. Most MDRO infections are found within
institutional settings, such as hospitals with
nosocomial infections, but the occurrence of
these is also increasing in the community.
In medicine, the major problem of the emergence
of resistant bacteria is caused by misuse and
overuse of antibiotics. In some countries,
antibiotics are sold over-the-counter without
prescription, which also aids in the formation of
resistant strains.
Other factors adding to increased occurrence
include the addition of antibiotics to cattle and
other livestock feed. In the United States in
1997, 50 percent of the antibiotics used were
fed to animals. In many institutional settings,
the procedures and clinical practice by both
physicians and pharmacists are often imperfect.
Often, no steps are taken to isolate a patient to
prevent reinfection or infection by a different
pathogen, adversely affecting the end-point goal
of total decimation of the infection.
There have been studies showing that naturally
occurring antibiotic resistance is widespread. The
bacterial genes that cause this resistance may
be transferred from non-pathogenic bacteria to
those that cause disease, resulting in clinically
significant antibiotic resistance.
An experiment in 1952 showed that penicillinresistant bacteria existed before penicillin
treatment. At the University of Wisconsin
shortly thereafter, the same effect was seen with
streptomycin. In 1962, penicillinase was shown
to exist in soil on roots of plants preserved in the
British Museum since 1689.44
Elite
The volume of antibiotics prescribed remains
one of the major factors in increasing the rate of
bacterial resistance. One dose of antibiotic may
lead to a larger risk of resistant organisms to that
drug in the patient for up to a year.
Improper prescribing of antibiotics may have
several causes, including patients who insist
on antibiotics, prescribers who prescribe them
unnecessarily, and prescribers who do not know
when to prescribe antibiotics or are excessively
cautious for medical legal reasons. Unfortunately,
the common cold remains the most common
reason antibiotics are prescribed.
Up to 44 percent of patients do not finish a course
of antibiotics, mainly because they feel better.
Conformity with once-daily dosing is much
better than with twice-daily dosing. Patients who
take less than the needed dosage or fail to take
their doses at prescribed times result in lower
than required blood levels, and in turn, cause
bacteria to be exposed to less-than-optimal drug
concentrations, resulting in increasing frequency
of antibiotic resistant organisms.
Poor hand hygiene by hospital staff and all
caregivers is associated with the spread of
resistant organisms. An increase in proper handwashing and disinfection results in decreased
rates of infection and resistant organisms.
Colonization
Infection begins when an organism successfully
colonizes by entering the body, growing and
multiplying. Most humans are not easily infected.
Those who are weak, sick, malnourished, or
have cancer or are diabetic have increased
susceptibility to chronic or persistent
infections. Individuals who have a suppressed
immune system are particularly susceptible to
opportunistic infections.
Entrance to the host generally occurs through the
mucosa in orifices such as the oral cavity, nose,
eyes, genitalia, anus, or open wounds. While
a few organisms can grow at the initial site of
entry, many migrate and cause systemic infection
in different organs. Some pathogens grow within
the host cells (intracellular), whereas others grow
freely in bodily fluids.
Wound colonization refers to nonreplicating
microorganisms within the wound, while in
infected wounds, replicating organisms exist
and tissue is injured. All multicellular organisms
are colonized to some degree by extrinsic
organisms, and the vast majority of these exist
in either a mutualistic or commensal relationship
with the host. An example of the former is the
anaerobic bacteria species, which colonizes the
mammalian colon, and an example of the latter
is various species of staphylococcus that exist
on human skin. Neither of these colonizations is
considered infections and should not be treated
with antibiotics.
The difference between an infection and
colonization is often only a matter of
circumstance. Non-pathogenic organisms can
become pathogenic given specific conditions, and
even the most virulent organism requires certain
circumstances to cause a compromising infection.
Some colonizing bacteria, such as Corynebacteria
sp. and viridans streptococci, prevent the
adhesion and colonization of pathogenic bacteria
and thus have a symbiotic relationship with the
host, preventing infection and speeding wound
healing.
For many years it was thought that
microorganisms must be in a large population to
become resistant to an antibiotic. Newer studies
have shown that it is not necessary for bacteria to
be counted in a large population to demonstrate
antibiotic resistance. We know that small colonies
of E. coli in antibiotic medium can become
resistant.
The variables involved in the outcome of a host
becoming inoculated by a pathogen and the
ultimate outcome include:
The route of entry of the pathogen and the
access to host regions that it gains.
The intrinsic virulence of the particular
organism.
The quantity or load of the initial inoculant.
The immune status of the host being
colonized.
A common mistaken belief is that a patient may
become resistant to antibiotics; in actuality, it
is the strain of microorganism that becomes
resistant, not the patient’s body.
As an example, the staphylococcus species
remains harmless on the skin, but when present
in a normally sterile space, such as in the capsule
of a joint or the peritoneum, multiplies without
resistance and creates a burden on the host.
It can be difficult to know which chronic wounds
are infected. Despite the huge number of wounds
seen in clinical practice, there are limited quality
data for evaluated symptoms and signs. A review
of chronic wounds in the Journal of the American
Medical Association’s “Rational Clinical
Examination Series” quantified the importance
of increased pain as an indicator of infection.
The review showed that the most useful finding
is that an increase in the level of pain [likelihood
ratio (LR) range, 11-20] makes infection much
more likely, but the absence of pain (negative
likelihood ratio range, 0.64-0.88) does not rule
out infection.
Mechanisms of resistance
Bacteria with a mutation that allows them to
survive to live and reproduce pass this trait to
their progeny, which leads to the creation of a
completely resistant colony.
There are four main mechanisms by
which microorganisms create resistance to
antimicrobials:
1. Drug inactivation or modification,
for example, the enzymatic splitting of
the penicillin G molecule by penicillin
resistant bacteria through the production of
β-lactamases.
2. Changing the target site, for example,
altering the binding site of penicillins,
especially in MRSA and other penicillin
resistant bacteria.
3. Changing the metabolic pathway, for
example, some sulfonamide resistant
bacteria do not need para-aminobenzoic acid
(PABA) for the synthesis of folic acid and
nucleic acids. In those strains inhibited by
sulfonamides, they use preformed folic acid.
4. Decreased drug concentration by
decreasing the permeability of the bacterial
cell to the antibiotic or increasing the
excretion of drug from the cell surface.
Elite
Antibiotic resistance is one manifestation of
an adaptation necessary for survival. Because
microbes reproduce quickly and efficiently, these
adaptations tend to happen fairly quickly. One
infection may leave enough resistant bacteria to
cause a subsequent infection that becomes that
much harder to treat. These subsequent infections
render available treatments useless, which can
cause these treatment-proof “superbugs” to
evolve.
Intrinsic resistance occurs with an alteration
in the structure and function of the microbe
based upon the genome.
ŠŠ Mutation. Microbes reproduce by
dividing every few hours, allowing
them to evolve rapidly and adapt to new
environmental conditions that may arise.
In spontaneous DNA mutation, bacterial
DNA may mutate spontaneously; drugresistant tuberculosis arises this way.
Microbes are very adaptable living
organisms with an aim to survive attack
by extrinsic factors. A key factor in the
development of antibiotic resistance is
the ability of infectious organisms to
adapt quickly to new environmental
conditions. Of all of the microbes,
bacteria are more efficient in enhancing
the effects of resistance secondary to their
ability to multiply rapidly and transfer
their resistance genes.
ŠŠ Microbes elaborate drug metabolizing
enzymes. At this time, many bacteria
have become resistant to penicillin G
because of an increased production of
penicillinase, an enzyme that converts
penicillin to an inactive product. Because
practitioners so often prescribe penicillin
products in general, resistance may
develop. Every time a patient takes
penicillin or another antibiotic for a
bacterial infection, the drug may kill most
of the bacteria present. However, a few
tenacious germs may survive by mutating
or acquiring resistance genes from
other bacteria. The surviving genes can
multiply quickly, creating drug-resistant
strains. The presence of these bacterium
strains affects the next infection because
the patient may not respond to the
prescribed antibiotics. In addition, the
resistant bacteria may be transmitted to
others in the patient’s community.
Page 3
ŠŠ Gene transfer. Microbes acquire
genes from each other, including genes
that make the microbe drug-resistant.
Chromosomal mutations or extra
chromosomal DNA are transferred from a
resistant species to a sensitive one.
ŠŠ Microbial drugs’ receptors
change. Sometimes bacteria become
resistant to certain antibacterials,
such as streptomycin. Unfortunately,
streptomycin is losing its effectiveness
because of structural changes in the
ribosomes of bacteria. According to
the Alliance for the Prudent Use of
Antibiotics (APUA), intrinsic, genetic
causes occur in about one in 10 million
cells. At any given point, there are
numerous, distinct microbes present in
any population, and a constant rate of
mutations does occur. When resistance
does occur, the end result will vary from
a slight change in microbial sensitivity,
which can be treated with larger doses
of the medication, to complete loss of
sensitivity.
Acquired resistance occurs through
random events that are increased by the
use of the drug.
ŠŠ Conjunction. Conjunction is the process
by which an extra-chromosomal DNA
is transferred from one Gram-negative
bacterium to another. For this process to
occur, the donor organism must possess
two unique DNA segments, one that
codes for drug resistance and one that
codes for “sexual” apparatus. Together,
the two codes constitute the resistance
(R) factor. A potentially dangerous
scenario to contemplate is that a single
plasmid can provide many different
types of resistance. Research has
demonstrated that plasmids encoded with
drug resistance are naturally present in
microbes before they have been exposed
to the medication. The most common
forms of bacteria that are affected by
the (R) factor include Gram-negative
bacilli, such as pseudomonas and vibrio
cholera; and Gram-positive bacteria,
such as bacillus and staphylococcus. In
1968, 12,500 people in Guatemala died
in an epidemic of shigella diarrhea. The
microbe harbored a plasmid that carried
resistances to four antibiotics.
ŠŠ Selective pressure. In the presence
of antimicrobials, microbes will cease
existing or they will survive if resistance
genes are present. To prevent selective
pressure, it is imperative that a patient
who has a bacterial infection be
prescribed an antibiotic that is sensitive
to the bacterium. Unfortunately, any
microbes that survive will replicate,
and then their progeny will become
dominant. Selective pressure becomes a
potential problem when antibiotics are
prescribed when there are no bacteria
present and the drugs provide no benefit
to the patient. Once the bacterium is
present and antibiotics are introduced, it
will create selective pressure, favoring
the overgrowth of microbes to become
resistant.
ŠŠ Spontaneous mutation. Spontaneous
mutation produces random changes
in the DNA of the microbe causing an
increase in resistance. Initially, it will
begin with a low-resistance, then with
additional mutations (use) it will become
high-resistance. The most common cause
of spontaneous mutation is overuse of
the medication due to societal pressures.
Society as a whole has a misconceived
notion that an antibiotic will improve the
symptoms and eradicate the organism that
causes a person to become ill. We must
take into account that antibiotics will not
kill 100 percent of the organisms present,
but will kill enough organisms to allow
the body’s immune system to overtake
the bacterial growth curve and finish the
destruction. It is this that puts patients
with compromised immune systems to
be at much higher risk for infection with
more serious consequences.
Unfortunately, antibiotics are too often
inappropriately prescribed, leading to
antimicrobial resistance, such as in the following
scenarios:
Incorrect diagnosis. A provider assumes an
illness is bacterial in origin when it is instead
viral. A patient may develop resistance.
Incorrect prescription. If a practitioner
speculates the source of infection is one
source of bacteria and it is another, then
the bacteria will continue to proliferate. In
addition, certain sources of bacteria require
heavier doses of antibiotics to eradicate the
infection.
Misuse of antibiotics. There are various
ways patients may abuse the use of
antibiotics.
ŠŠ Many times, patients will either not
complete their prescribed antibiotics or
they will take a leftover antibiotic for a
subsequent illness. Patients who do not
complete their prescribed antibiotics
or take a remnant dose may develop
resistance.
ŠŠ Some patients also illegally purchase
antimicrobial therapy from other
countries on the Web because their
attending provider does not prescribe
an antimicrobial; others “shop around”
to find a provider who will prescribe an
antibiotic.
Hospital use. Critically ill patients are
more susceptible to infections and thus
require heavier use of antimicrobials. Often
the complexity of the patient’s condition
and numerous, heavy doses of antibiotics
predispose the patient to potential drug
resistance. It is estimated that approximately
70 percent of the bacteria that cause
Page 4
infections in the hospitals are resistant to at
least one of the drugs most commonly used
for the treatment and eradication of that
bacteria. Even more dangerous, some forms
of bacteria are so resistant to antibiotics
that previously eradicated them that only
experimental toxic medications are being
prescribed. In addition, the complexity of
critically ill patients also predisposes other
patients in hospitals and long-term care
facilities to various bacteria and resistance.
Hospitals also provide a fertile environment
for antibiotic-resistant germs because of close
contact among sick patients and extensive use
of antibiotics.
ŠŠ Community-acquired bacteria are also
becoming resistant to bacteria at alarming
rates, especially staphylococci and
pneumococci (streptococcus pneumonia)
infections. In a recent study, 25 percent
of bacterial pneumonia cases were
shown to be resistant to penicillin, and
an additional 25 percent of cases were
resistant to more than one antibiotic.
Agricultural use. Another much-publicized
concern is the use of antibiotics in livestock,
where the drugs are used to prevent disease
in well animals that are later slaughtered
for food. For over 50 years, farmers have
administered antibiotics to their livestock
to ensure the health of animals, sometimes
placing low levels in livestock’s food to
increase the rate of weight gain and improve
the efficiency of converting animal feed to
units of animal production. Scientists fear
that certain bacteria that develop resistance
in animals can then infect people who eat
meat or other animal products. It is difficult
to precisely measure the impact on human
health, but experts believe that resistant
strains of salmonella, campylobacter,
enterococcus, and Escherichia coli (E.coli)
have been transmitted from animals to
people. (See the section on the impact of
agriculture on antimicrobial resistance).
As noted, there is a plethora of reasons that
antimicrobial resistance occurs. Antibiotics are
designed to eradicate specific bacteria; they are
not mutagenic and do not directly cause the
genetic changes that underlie drug sensitivity.
However, with continuous use, spontaneous
mutation and conjunction will occur.
The CDC reiterates the concept and estimates that
the major factor in the emergence of antibiotic
resistance bacteria is attributed to the overuse and
misuse of antibiotics. The more antibiotics are
used, the faster drug resistance will emerge in our
society.
Antibiotics may be a double-edged sword when
they are overused; although they can heal,
they also can promote emergence of resistant
pathogens and the overgrowth of normal flora
that possess the ability to develop resistance. It is
important to understand this concept and to avoid
prescribing antibiotics when they are not needed,
because normal flora can transfer resistance to
potential pathogens.
Elite
Because of the complexity and importance of
certain contributing factors to the development of
antimicrobial drug resistance, some causes will
be further elaborated throughout this chapter.
Remember, anytime antibiotics are used, one
or more microorganisms may survive. As these
bacteria reproduce, they pass this antibiotic
resistance to subsequent generations. Stronger
antibiotics are then used, which can escalate
the cycle of antibiotic resistance. It is more
likely to occur when antibiotics are stopped
prematurely (before all bacteria are killed), or
when prescribed inappropriately. Therefore,
people must understand that if it is not bacterial
in nature, they must let the viral infection run its
course.
The CDC speculates that many providers are
sometimes quick to prescribe antibiotics for all
sorts of symptoms, even though antibiotics work
only against bacterial infections – not viruses
such as those that cause the flu or the common
cold. Most biologists do not consider viruses
to be living things, but instead as infectious
particles. More than 50 million of the 150 million
antibiotic prescriptions written each year for
patients outside of hospitals are unnecessary,
according to a recent CDC study.
Respiratory antimicrobial drug resistance
Pneumonia is the second-most common
nosocomial infection in the U.S. and is associated
with substantial morbidity and mortality. The
majority of patients who have nosocomial
pneumonia include:
Infants.
Young children.
Persons older than 65 years of age.
Persons who have severe underlying disease,
immunosuppression, depressed sensorium,
cardiopulmonary disease.
Persons who have had thoraco-abdominal
surgery.
Another potential risk factor includes patients
receiving mechanically assisted ventilation.
Although they do not represent the majority of
patients who have nosocomial pneumonia, they
are among the highest risk for acquiring the
infection. Most bacterial nosocomial pneumonias
occur by aspiration of bacteria colonizing the
oropharynx or upper gastrointestinal tract of
the patient. Since intubation and mechanical
ventilation alter first-line patient defenses, they
greatly increase the risk for nosocomial bacterial
pneumonia.
Traditional preventive measures for nosocomial
pneumonia include decreasing aspiration by
the patient, preventing cross-contamination or
colonization via hands of personnel, appropriate
disinfection or sterilization of respiratory-therapy
devices, use of available vaccines to protect
against particular infections, and education of
hospital staff and patients. New measures being
investigated involve reducing oropharyngeal
and gastric colonization by pathogenic
microorganisms.
Several large studies have examined the potential
risk factors for nosocomial-acquired bacterial
pneumonia related to mechanically assisted
ventilation and endotracheal intubation:
In many studies, the administration of
antacids and H-2 blockers for prevention of
stress bleeding in critically ill, postoperative,
and mechanically ventilated patients has been
associated with gastric bacterial overgrowth.
Sucralfate, a cytoprotective agent that has
little effect on gastric power of Hydrogen
(pH) and may have bactericidal properties
of its own, has been suggested as a potential
substitute for antacids and H-2 blockers.
In most randomized trials, intensive care
unit (ICU) patients receiving mechanically
assisted ventilation who were treated either
with only antacids or with antacids and
H-2 blockers had increased gastric pH,
high bacteria counts in the gastric fluid and
increased risk for pneumonia in comparison
with patients treated with sucralfate.
Patients receiving continuous, mechanically
assisted ventilation have six to 21 times the
risk for acquiring nosocomial pneumonia
compared with patients not receiving
ventilator support. One study indicated
that the risk for developing ventilatorassociated pneumonia increased by 1 percent
per day. The rationale for the increased
risk was attributed partially to carriage of
oropharyngeal organisms upon passage of
the endotracheal tube into the trachea during
intubation, as well as to depressed host
defenses secondary to the patient’s severe
underlying illness.
In addition, bacteria can aggregate on the
surface of the tube over time and form a
glycocalyx (i.e., a biofilm) that protects the
bacteria from the action of antimicrobial
agents or host defenses. Some researchers
believe that these bacterial aggregates can
become dislodged by ventilation flow, tube
manipulation, or suctioning and subsequently
embolize into the lower respiratory tract
and cause focal pneumonia. Removing
tracheal secretions by gentle suctioning
and using aseptic techniques to reduce
cross-contamination to patients from
contaminated respiratory therapy equipment
or contaminated or colonized hands of
health care workers (HCWs) have been used
traditionally to help prevent pneumonia in
patients receiving mechanically assisted
ventilation.
Another risk for pneumonia also is increased
by the direct access of bacteria to the lower
respiratory tract, which often occurs because
of leakage around the endotracheal cuff,
thus enabling pooled secretions above the
cuff to enter the trachea. In one study, the
occurrence of nosocomial pneumonia was
delayed and decreased in intubated patients
whose endotracheal tubes had a separate
dorsal lumen that allowed drainage (i.e.,
by suctioning) of secretions in the space
Elite
above the endotracheal tube cuff and below
the glottis. However, additional studies are
needed to determine the cost-benefit ratio of
using this device.
Another factor to contemplate are the devices
we use in the hospital that may be potential
reservoirs and vehicles for harboring
infectious microbes, such as:
ŠŠ Nebulizers. They can allow the growth
of hydrophilic bacteria that subsequently
can be aerosolized during use of the
device. Gram-negative bacilli (e.g.,
pseudomonas sp., xanthomonas sp.,
flavobacterium sp., legionella sp., and
nontuberculous mycobacteria) can
multiply to substantial concentrations in
nebulizer fluid and increase the risk for
pneumonia in patients using such devices.
ŠŠ Diagnostic examinations
(bronchoscopes and spirometers).
ŠŠ Administration of anesthesia. The
internal components of anesthesia
machines, which include the gas
sources and outlets, gas valves, pressure
regulators, flow meters and vaporizers,
are not considered an important source of
bacterial contamination of inhaled gases.
Thus, routine sterilization or high-level
disinfection of the internal machinery is
unnecessary.
ŠŠ Mechanical ventilators. The potential
risk for pneumonia in patients using
mechanical ventilators that have heated
bubble-through humidifiers stems
primarily from the condensate that
forms in the inspiratory-phase tubing
of the ventilator circuit as a result of
the difference in the temperatures of
the inspiratory-phase gas and ambient
air; condensate formation increases
if the tubing is unheated. The tubing
and condensate can rapidly become
contaminated, usually with bacteria that
originate in the patient’s oropharynx.
In one study, 33 percent of inspiratory
circuits were colonized with bacteria
via this route within two hours, and 80
percent within 24 hours, after initiation of
mechanical ventilation.
Spillage of the contaminated condensate
into the patient’s tracheobronchial tree,
as can occur during procedures in which
the tubing is moved (e.g., for suctioning,
adjusting the ventilator setting, or
feeding or caring for the patient), may
increase the risk for pneumonia in the
patient. Thus, in many hospitals, health
care professionals are trained to prevent
such spillage and to drain the fluid
periodically.
Resistant pathogens
Staphylococcus aureus
Staphylococcus aureus, more commonly known
as “Staph aureus” is one of the most resistant
of pathogenic bacterium, commonly found on
mucous membranes and skin in about 30 percent
Page 5
of the population. It was one of the first bacteria
in which penicillin resistance was found, in 1947,
just four years after the drug was commercially
available.
limited recent data available on penicillinresistant S. pneumonia. The majority of the
literature is based upon data from the 1990s to the
early turn of the century. It is speculated that the
majority of health care professionals are aware
of the risk of drug-resistant S. pneumonia with
penicillins, perhaps abating the notion that they
over-write prescriptions for high-risk patients.
meningitis die of the infection. While one of
four children will survive, they will suffer from
neurologic damage, including hearing loss after
“getting over” the infection. Pneumococci are the
most common cause of ear infections and sinus
Methicillin-resistant Staph aureus (MRSA) was
infections, as well as the most common bacteria
first identified in England in 1961, and is now one
found in the blood of children under 2 years old
of the more prevalent pathogens found mainly in
with fevers, many of whom have no obvious site
hospitals. Methicillin was the antibiotic of choice
of infection. Many people have pneumococci in
in the “early penicillin” years but has since been
Researchers have discovered that the resistance
their noses and throats but have no symptoms.
replaced by oxacillin, which demonstrates far
of pneumococcus to penicillin and cephalosporins
The bacteria are transmitted from one person to
less renal toxicity. Retrospectively, MRSA was
is through alteration in the cell wall penicillinanother, usually by droplets.
responsible for 37 percent of fatal cases of sepsis binding proteins (PBPs). By altering these
in 1999, up from 4 percent in 1991. Currently,
sites (where the antibiotics bind), the antibiotic
Like viral upper respiratory infections,
half of all Staph aureus infections in the United
affinity is decreased, subsequently decreasing
pneumococcal infections are more common in
States are resistant to penicillin, methicillin,
the susceptibilities. This type of resistance
winter. Infection can begin as little as one to three
tetracyclines and erythromycin.
can be overcome if the serum or site levels of
days after exposure. Studies of ear fluid cultures
the antibiotic exceed the minimum inhibitory
suggest that anywhere from 20 to 40 percent of
This left vancomycin as the only alternative
concentration (MIC) of the organism for 40-50
ear infections are caused by pneumococcus. The
available at the time; however vancomycinpercent of the dosing interval.
signs of pneumococcal meningitis and sepsis
intermediate Staph aureus (VISA) (4-8µcg/ml)
can be the same as those of meningococcal
showed in the late 1990s. The first documented
According to the CDC, for more than 25
meningitis. Often, however, pneumococcal
strain with complete (>16µcg/ml) resistance
years, isolates of S. pneumoniae were initially
infection can appear first as a high fever with a
to vancomycin, termed VRSA (vancomycinsusceptible to penicillin. However, since 1967,
very high white blood cell count (where almost
resistant Staph aureus) surfaced in the United
there has been a gradual increase in penicillinall of the white cells are neutrophils or bacteriaStates in 2002.
resistant S. pneumoniae, on average a 25 percent
fighting cells) and no obvious site of infection.
risk. In certain areas of the U.S., PRSP strains
A new class of antibiotics, the oxazolidinones,
become widespread during the 1990s; Alaska had There are also some people who are more
became available in the 1990s, with linezolid
the highest reported prevalence at 26 percent.
susceptible to pneumococcal infections than
being comparable to vancomycin in effectiveness
According to the CDC and New England Journal others. The risk factors include:
against MRSA, depending on the infection site.
of Medicine (NEJM), a study conducted in
Lack of a spleen due to injury or disease.
Resistance to linezolid by Staph aureus has been
Atlanta found a 25 percent prevalence of PRSP
Sickle-cell anemia because repeated sicklereported since 2003.
in the community. In 2004, 21.4 percent of all
cell crises cause damage to the red blood cells
CA-MRSA (community-acquired methicillin
isolates obtained showed intermediate or resistant
and destruction of the spleen tissue. Most
resistant Staph aureus) has become epidemic,
susceptibility patterns to penicillin (up from 20
doctors assume that the spleen of patients
mainly responsible for rapidly progressing, fatal
percent in 2003). Outside the United States, an
with sickle-cell disease will not be working
diseases, including necrotizing pneumonia, severe even higher (33 to 58 percent) prevalence of
by the time they are in their 20s, at the latest.
sepsis, and necrotizing fasciitis. MRSA has
PRSP has been reported.
So sickle-cell patients are usually vaccinated
become the most often identified antimicrobial
against bacteria, such as pneumococcus and
Pneumococcal infections are a leading cause
drug-resistant pathogen in the United States.
meningococcal strains, which the spleens of
of morbidity and mortality in the U.S.; S.
Outbreaks of CA-MRSA have been reported
healthy people help kill.
pneumoniae causes more than 500,000 cases of
in correctional facilities, among athletic teams,
Immunodeficiencies, such as AIDS,
pneumonia, 55,000 cases of bacteremia and 6,000
among military recruits, in newborn nurseries,
decreased production of white blood cells,
cases of meningitis annually, which result in
and among homosexual men. These outbreaks
and chronic illnesses.
40,000 deaths. The death rate from pneumococcal
have usually been associated with skin and soft
bacteremia approaches 30 percent, despite
S. pneumonia is prevalent in various bacterial
tissue infections.
the use of appropriate antimicrobial therapy.
infections (upper, lower respiratory infections,
Reports of refractory illness due to resistant
meningitis, etc.) and a leading cause of death.
Streptococcus and Enterococcus
pneumococci demonstrate the clinical relevance
It is highly resistant to not only penicillins, but
Streptococcus pyogenes (Group A strep: GAS)
of these strains. Identifying risk factors in the
also cephalosporins, sulfonamides, trimethopriminfections are treatable with many different
development of these infections is important
sulfamethoxazole (through amino acid changes),
antibiotics. Early diagnosis and treatment
for both the prevention and treatment of these
macrolides (through methylation or via an
may reduce mortality from invasive group A
infections.
efflux pump), quinolones (through decreased
streptococcal infections. Some strains have
permeability, efflux pumps, and alteration
emerged demonstrating resistance to macrolide
Streptococcus pneumoniae, or pneumococcus, is
of enzymes), and chloramphenicol (through
antibiotics, but all strains remain sensitive to
a bacterium that causes many different kinds of
inactivating enzymes).
penicillins.
infections in people, ranging from ear infections
Resistance rates of pneumococcal isolates
and sinus infections to pneumonia, meningitis
Streptococcus pneumoniae, however, is showing
in the United States to trimethoprimand sepsis. Up to 30 percent of the strains of
resistance to penicillins and beta-lactam
sulfamethoxazole, doxycycline and the
the bacterium are at least partially resistant to
antibiotics (cephalosporins and carbapenems)
macrolides are relatively high. Some isolates
antibiotics in the penicillin family. Although
on a worldwide scale. The mechanism for this
(less than 10 percent in the United States)
the names (and bacterial genuses) are similar,
resistance involves gene mutation, and the use
that are resistant to macrolides are also
S. pneumoniae is quite different from group
of beta-lactam antibiotics has been identified
resistant to clindamycin.
A streptococcus (the bacteria that causes strep
as a major risk factor leading to resistance. S.
No vancomycin-resistant pneumococcal
throat and rheumatic fever).
pneumoniae is a causative agent for pneumonia,
isolates have been reported to date. The
S. pneumoniae infections are on average much
bacteremia, otitis media, meningitis, sinusitis,
phenomenon of tolerance (survival but not
more serious; pneumococcus is the most common
peritonitis and septic arthritis.
growth in the presence of a given antibiotic)
cause of bacterial meningitis in the U.S., and
Although streptococcus pneumonia (S.
has been observed, but its clinical relevance
about 8 percent of children with pneumococcal
pneumonia) is prevalent, in general, there is
is unknown.
Page 6
Elite
Fortunately, in the U.S., most pneumococcal
isolates remain susceptible to fluoroquinolones,
but in certain countries and specific populations
in whom the use of fluoroquinolones is more
prevalent (e.g., nursing homes), an increase in
resistance has been seen. Although there is a 25
percent risk of penicillin drug resistance noted
in streptococcus pneumonia, penicillin is still
the mainstay drug of choice because 75 percent
of the time it will work. Therefore, each patient
is customized based upon his or her history and
other risk factors.
Depending upon the site and patient, the
following guidelines are recommended:
Otitis media/sinusitis – Amoxicillin 80-90
mg/kg/day. If no improvement in 48-72
hours, re-evaluate the patient and switch
to amoxicillin-clavulanate or a second- or
third-generation oral cephalosporin, although
highly resistant pneumococci may require
treatment with parenteral ceftriaxone to
achieve adequate serum levels of antibiotics.
Pneumonia
ŠŠ Children – Amoxicillin or amoxicillinclavulanate at dosages used for
the treatment of otitis media is
recommended. In school-aged children
(older than 5 years), the addition of
a macrolide for coverage of atypical
organisms is advised.
In 2000, a new vaccine (Prevnar)
became available for children in
the United States, and CDC began
tracking the vaccine’s impact on
resistant pneumococcal infections.
Since the vaccine was introduced
into the routine childhood
immunization program in the
United States, penicillin-resistant
pneumococcal infections declined
by 35 percent. Not only has the
vaccine been shown to prevent
antibiotic-resistant infections, it has
been shown to reduce the need for
prescribing antibiotics for children
with pneumococcal infection in the
first place. CDC data also show that
adults are getting fewer resistant
pneumococcal infections because
the vaccine is preventing spread of
pneumococci from infected children
to adult populations.
Since 2001, it is estimated from
CDC data that 170,000 severe
pneumococcal infections and
10,000 deaths have been prevented
by vaccine use. According to data
published in the Archives of Pediatric
Adolescent Medicine, the vaccine
is highly cost-effective, saving an
estimated $310 million in direct
medical costs each year.
ŠŠ Adults – Macrolide (or doxycycline) for
outpatient therapy of previously healthy
adults with no specific risk factors for
resistant S. pneumoniae infection.
Meningitis – The recommended initial
therapy of presumed bacterial meningitis in
children is with vancomycin and ceftriaxone
or cefotaxime at increased doses. If S.
pneumoniae is isolated from the blood or
cerebral spinal fluid (CSF) and is susceptible
to penicillin or ceftriaxone/cefotaxime,
vancomycin should be stopped and therapy
completed with penicillin G, ceftriaxone
or cefotaxime as indicated. If the isolate is
resistant to penicillin and cephalosporins, the
regimen started initially should be continued
through the completion of therapy, usually 10
days in uncomplicated cases.
Most pneumococcal isolates in the United States
remain susceptible to certain fluoroquinolones,
including moxifloxacin (most effective)
and levofloxacin. Ciprofloxacin has limited
activity against pneumococcal infections.
Fluoroquinolones provide broad-spectrum
treatment for CAP and achieve excellent serum
drug levels and tissue penetration. Specific
populations in whom the use of fluoroquinolones
is traditionally increased (e.g., residents of
nursing homes) have shown increased levels of
pneumococcal resistance to fluoroquinolones,
and their empiric use in respiratory infections
should also be tempered by the concern for rapid
development of resistance to this class by many
organisms.
Multidrug-resistant Enterococcus faecalis and
Enterococcus faecium are most commonly
associated with nosocomial infections, and in
a number of other infections from urinary tract
to heart valve. Among these strains, penicillinresistant enterococcus was seen in 1983,
vancomycin-resistant enterococcus in 1987, and
linezolid-resistant enterococcus in the late 1990s.
Vancomycin-resistant enterococcus is a particular
problem because of vancomycin’s status as a
first-line therapy for drug-resistant pathogens.
Some patients are at higher risk for VRE because
of several factors. These factors include:
Previous vancomycin therapy, or therapy
with other microbes.
Severe underlying disease or
immunosuppression.
Long-term use of intravenous or urinary
catheters.
Utilization of third-generation
cephalosporins.
Utilization of anti-anaerobic antibiotics, such
as clindamycin.
Use of fluoroquinolones.
Intra-abdominal surgery.
Because enterococcus is typically found in
the normal gastrointestinal and female genital
tracts, most infections have been attributed
to endogenous sources within the individual
patient. However, recent reports of outbreaks
and endemic infections caused by enterococcus,
including VRE, have indicated that patient-topatient transmission of the causative organism
can occur either through direct contact or through
Elite
indirect contact via the hands of health care
workers and contaminated patient care equipment
and environmental surfaces.
Therefore, the CDC recommends that health care
facilities screen for vancomycin-enterococcus
(VRE) with all new admitted or high-risk
patients, such as oncology and surgical patients,
and those receiving intensive care. If the
patient tests positive for VRE, the physician
and infection control team need to be notified
immediately.
Vancomycin-resistant enterococcus infection is
currently treated with linezolid, daptomycin, or a
combination of quinopristin and daptomycin.
Preventing and controlling VRE transmission in
all hospitals requires the following:
Initiate the following isolation precautions
to prevent patient-to-patient transmission of
VRE:
ŠŠ Place VRE-infected or colonized patients
in private rooms or in the same room as
other patients who have VRE.
ŠŠ Wear gloves (clean, nonsterile gloves
are adequate) when entering the
room of a VRE-infected or colonized
patient because VRE can extensively
contaminate such an environment.
When caring for a patient, a change of
gloves might be necessary after contact
with material that could contain high
concentrations of VRE (e.g., stool).
ŠŠ Wear a non-permeable gown (a clean,
nonsterile gown is adequate) when
entering the room of a VRE-infected
or colonized patient a) if substantial
contact with the patient or with
environmental surfaces in the patient’s
room is anticipated, b) if the patient is
incontinent, or c) if the patient has had an
ileostomy or colostomy, has diarrhea, or
has a wound drainage not contained by a
dressing.
ŠŠ Remove gloves and gown before leaving
the patient’s room and immediately
wash hands with an antiseptic soap or a
waterless antiseptic agent. Hands can be
contaminated via glove leaks or during
glove removal, and bland soap does not
always completely remove VRE from the
hands.
ŠŠ Ensure that after glove and gown removal
and hand washing that clothing and hands
do not contact environmental surfaces
in the patient’s room that are potentially
contaminated with VRE (e.g., a doorknob
or curtain).
Dedicate the use of noncritical items (e.g.,
a stethoscope, sphygmomanometer, or
thermometers) to a single patient or cohort of
patients infected or colonized with VRE. If
such devices are to be used on other patients,
adequately clean and disinfect these devices
first.
Obtain a stool culture or rectal swab from
roommates of patients newly found to be
infected or colonized with VRE to determine
Page 7
their colonization status, and apply isolation
precautions as necessary. Perform additional
screening of patients on the ward at the
discretion of the infection-control staff.
Adopt a policy for deciding when patients
infected or colonized with VRE can be
removed from isolation precautions. The
optimal requirements remain unknown;
however, because VRE colonization can
persist indefinitely, stringent criteria might be
appropriate, such as VRE-negative results on
at least three consecutive occasions (greater
than or equal to one week apart) for all
cultures from multiple body sites (including
stool or rectal swab, perineal area, axilla or
umbilicus, and wound, Foley catheter and
colostomy sites, if present).
Because patients with VRE can remain
colonized for long periods after discharge
from the hospital, establish a system for
highlighting the records of infected or
colonized patients so they can be promptly
identified and placed on isolation precautions
upon readmission to the hospital. This
information should be computerized so that
placement of colonized patients on isolation
precautions will not be delayed because the
patients’ medical records are unavailable.
Local and state health departments should
be consulted when developing a plan for
the discharge of VRE-infected or colonized
patients to nursing homes, other hospitals,
or home-health care. This plan should be
part of a larger strategy for handling patients
who have resolving infections and patients
colonized with antimicrobial-resistant
microorganisms.
Acinetobacter baumanii
The CDC has reported (2004) an increase in
the number of bloodstream infections from
Acinetobacter spp. Most of these show MDRO
characteristics with some isolates resistant to all
drugs tested.
Acinetobacter baumanii has been linked to
nosocomial infections in both hospitals and
nursing homes, and in soldiers returning from
Iraq and Afghanistan.
Salmonella and E. coli
Pathogenic Salmonella spp. and Escherichia coli
are responsible for most foodborne illnesses.
Because they thrive in feces, they are often found
in raw food, in raw and undercooked ground
meat, in shell eggs, and in contaminated bodies
of fresh water such as rivers and lakes; people
who swim in these may contract E. coli-caused
diarrhea.
It is generally not recommended that mild
salmonellosis or E. coli-caused diarrhea be
treated with antibiotics; the diarrhea itself is often
enough to rid the body of the causative organism.
However, although resistance rates have
increased overall, third-generation cephalosporins
are still effective.
Pseudomonas aeruginosa
Pseudomonas aeruginosa is an extremely
opportunistic pathogen with low antibiotic
susceptibility. It is responsible for urinary
tract infections and pneumonia. It is an
anaerobe that is also responsible for causing
pneumonia in patients with cystic fibrosis;
the mucus that forms in the lungs of patients
with cystic fibrosis limit the diffusion of
oxygen, allowing the P. aeruginosa bacteria to
thrive. Furthermore, it is frequently a cause of
nosocomial infection because it colonizes on
catheters and in ventilators; patients who are
immunocompromised are especially vulnerable
to P. aeruginosa infection. Finally, it is linked to
dermatitis caused by poor water quality in hot
tubs; to postoperative infections after LASIK
surgery; to osteomyelitis resulting from puncture
wounds of the foot; and to infection in burn
victims.
The bacterium is capable of utilizing a wide
range of organic compounds as food sources,
thus giving it an exceptional ability to colonize
ecological niches where nutrients are limited.
P. aeruginosa can produce a number of toxic
proteins that not only cause extensive tissue
damage, but also interfere with the human
immune system’s defense mechanisms. These
proteins range from potent toxins that enter and
kill host cells at or near the site of colonization to
degradative enzymes that permanently disrupt the
cell membranes and connective tissues in various
organs.
with immune system deficiencies. Unlike
many environmental bacteria, P. aeruginosa
has a remarkable capacity to cause disease in
susceptible hosts. It has the ability to adapt
to and thrive in many ecological niches, from
water and soil to plant and animal tissues.
Elderly patients with vertebral osteomyelitis
resulting from a pseudomonal infection.
Young people who experiment with
intravenous (IV) drug abuse.
Clostridium difficile
Clostridium difficile is a nosocomial pathogen
that causes diarrheal disease. Selective strains
of C. diff. have been shown to be resistant to
clindamycin and fluoroquinolones.
Clostridium difficile (C. diff) is an anaerobic,
spore-forming rod typically found in the gut flora
in approximately 2-5 percent of the population.
It is typically transmitted via the oral-fecal route
and, because it forms spores that are heat- and
acid-resistant, is able to survive in the gut. The
organism releases toxins that cause diarrhea,
bloating, and pseudomembranous colitis, a
severe inflammation of the colon. C. diff presents
significant challenges both because of the nature
of its biology and because of antibiotic resistance.
It is nosocomially acquired, although it may be
acquired in the community as well.
The first challenge is that C. diff forms large
numbers of spores. Spores are difficult to kill
and can survive for very long periods of time
P. aeruginosa is an opportunistic pathogen.
on surfaces that most bacteria find inhospitable,
It rarely causes disease in healthy persons.
such as countertops and floors. Furthermore, most
In most cases of infection, the integrity of a
disinfectants are ineffective against them; the
physical barrier to infection (i.e., skin, mucous
most effective is dilute bleach. Likewise, alcoholmembranes) is lost or an underlying immune
based hand sanitizers are also ineffective, so
deficiency (i.e., neutropenia, immunosuppression)
when the person touches the surface, the spores
is present. Pseudomonas is both invasive and
are transferred to the skin.
toxigenic. The three stages include:
1. Bacterial attachment and colonization.
Consequently, the C. diff spores are able to
2. Local infection.
enter the body fairly easily. This underscores a
3. Bloodstream dissemination and systemic
major reason why hand-washing is so critical;
disease. The importance of colonization and
the mechanical scrubbing helps to remove the
adherence is most evident when studied in
bacteria that sanitizers will not kill.
the context of respiratory tract infection in
Once they enter the body, they are heat- and acidpatients with cystic fibrosis and in those
resistant, which means they are able to survive in
that complicate mechanical ventilation.
the human digestive tract. Upon being exposed
Production of extracellular proteases adds
to bile acids in the colon, they enter a vegetative
to the organism’s virulence by assisting in
state, and once they are established, the spores
bacterial adherence and invasion.
release toxins, such as enterotoxin (Clostridium
According to CDC data collected from 1990difficile toxin A) and cytotoxin (Clostridium
1996, P. aeruginosa was the second-most
difficile toxin B), that cause the diarrhea and
common cause of nosocomial pneumonia (17
inflammation symptomatic of C. diff infection
percent of the isolates), the third-most common
(CDI).
cause of UTI (11 percent), the fourth-most
When infection is suspected, the stool must be
common cause of surgical site infections (8
cultured to rule it in. Previously, some caregivers
percent), the seventh-most common isolated
would look for a characteristic C. diff smell,
pathogen from the bloodstream (3 percent),
and some dogs have been trained to detect that
and the fifth-most common isolate overall (9
odor with some accuracy. Most hospitals will
percent) obtained from all sites. Internationally,
test for toxin A, although toxin B is becoming
P. aeruginosa is common in patients with diabetes
increasingly widespread in the hospital setting.
who are immunocompromised.
To ensure that treatment will be successful, tests
Others at risk for P. aeruginosa include:
for both toxins should be ordered. A newer test
Cancer and burn patients, who also
involving PCR technology (based on bacterial
commonly suffer serious infections by this
DNA) is becoming the gold standard in testing
organism, as do certain other individuals
for C. difficile.
Page 8
Elite
The second challenge is that C. diff has become
resistant to a number of antibiotics, especially
the fluoroquinolones, like ciprofloxacin (Cipro)
and levofloxacin (Levaquin). This resistance has
led to an increased virulence, producing more
toxin, which causes more severe disease that
can be fatal. In addition to the fluoroquinolones,
C. diff may be resistant to other antibiotics, as
well; some strains may produce as much as 10
times the amount of toxin and may be resistant
to metronidazole, one of the two drugs currently
recommended as treatment.
Furthermore, the use of H2-receptor antagonists
such as ranitidine (Zantac) and cimetidine
(Tagamet) as well as proton pump inhibitors may
cause an increase in the risk of C. diff infection
because, although the spores are able to survive
the acidic environment of the stomach, the
reduction in stomach acid leaves an environment
that is that much more hospitable.
As noted above, the spores produce two types of
toxins that cause diarrhea and bloating that can
be quite painful. If the infection is not treated
quickly and aggressively, it may advance to
pseudomembranous colitis, an inflammation
of the colon characterized by the presence of
inflammatory cells, fibrin, and necrotic cells. If
the infection advances, it can be fatal.
The risk factors for developing TB include:
Living in close proximity (i.e., incarcerated,
group homes).
Poverty (poor living conditions).
Exposure to another with TB.
HIV or acquired immunodeficiency diseases
(AIDS). The risk of developing TB disease is
much greater for those infected with HIV and
living with AIDS. Because HIV infection so
severely weakens the immune system, people
dually infected with HIV and TB have a 100
times greater risk of developing active TB
disease and becoming infectious compared to
people not infected with HIV. CDC estimates
that 10 to 15 percent of all TB cases and
nearly 30 percent of cases among people
ages 25 to 44 are occurring in HIV-infected
individuals.
Another problem with TB is the enormous
resistance that has developed in multidrugresistant tuberculosis. MDR-TB is resistant to
two or more of the primary drugs used for the
treatment of tuberculosis.
Resistance to one or several forms of treatment
occurs when the bacteria develop the ability to
withstand antibiotic attack and relay that ability
to their progeny. Because that entire strain of
bacteria inherits this capacity to resist the effects
of the various treatments, resistance can spread
Treatment must be aggressive and quick to have
from one person to another.
the greatest chance of success. This may involve
On an individual basis, however, inadequate
metronidazole (Flagyl) or oral vancomycin
treatment or improper use of anti-tuberculosis
(Vancocin). However, some strains may be
medications remains an important cause of drugbecoming resistant to metronidazole, which is
resistant tuberculosis:
presenting a challenge.
In 2003, the CDC reported that 7.7 percent of
A recently released drug,, fidaxomicin (Dificid)
tuberculosis cases in the U.S. were resistant
has shown promise in treating resistant C.
to isoniazid, the first-line drug used to treat
difficile, but its cost limits widespread use. It
TB.
is considered a third-line agent in the treatment
The CDC also reported that 1.3 percent of
of C. difficile. Probiotics may be helpful in
tuberculosis cases in the U.S. were resistant
preventing C. diff infection because they maintain
to both isoniazid and rifampin. Rifampin is
gut flora levels that encourage competition, and
the drug most commonly used with isoniazid.
doxycycline may have a protective effect when
The World Health Organization estimates
prescribed with other antibiotics.
that up to 50 million persons worldwide may
be infected with drug-resistant strains of TB.
Finally, because diarrhea is effective at removing
Also, 300,000 new cases of MDR-TB are
the spores and toxins from the colon, antimotility
diagnosed around the world each year, and
drugs such as diphenoxylate/atropine (Lomotil)
79 percent of the MDR-TB cases now show
or loperamide (Imodium) are more likely to
resistance to three or more drugs.
increase the severity of the disease, and patients
A strain of MDR-TB originally develops
with C. diff infection should be discouraged from
when a case of drug-susceptible tuberculosis
using either of these.
is improperly or incompletely treated. This
The best way to prevent C. diff infection is the
occurs when a physician does not prescribe
judicious use of antibiotics, both in humans and
proper treatment regimens or when a patient
in agriculture.
is unable to adhere to therapy. Improper
treatment allows individual TB bacilli that
Mycobacterium tuberculosis
have natural resistance to a drug to multiply.
Tuberculosis is increasing throughout the world,
Eventually the majority of bacilli in the body
especially in developing countries. This rise of
are resistant.
HIV and AIDS epidemics has contributed to
Once a strain of MDR-TB develops, it can be
TB becoming resistant to antibiotics, termed
transmitted to others just like a normal drugMDR-TB (multidrug-resistant TB). The fact that
susceptible strain. Airborne transmission has
treatment can last for several months contributes
been the cause of several well-publicized
to MDR-TB because patient compliance may
cases of nosocomial (hospital-based)
dwindle after such lengthy treatment.
outbreaks of MDR-TB in New York City and
Florida. These outbreaks were responsible
for the deaths of several patients and health
Elite
care workers, a majority of whom were coinfected with HIV.
MDR-TB has been a particular concern
among HIV-infected persons. Some of the
factors that have contributed to the number
of cases of MDR-TB, both in general and
among HIV-infected individuals, are:
ŠŠ Delayed diagnosis and delayed
determination of drug susceptibility,
which may take several weeks.
ŠŠ Susceptibility of immunosuppressed
individuals for not only acquiring MDRTB but also for rapid disease progression,
which may result in rapid transmission of
the disease to other immunosuppressed
patients.
ŠŠ Inadequate respiratory isolation
procedures and other environmental
safety conditions, especially in confined
areas such as prisons.
ŠŠ Noncompliance or intermittent
compliance with anti-tuberculosis drug
therapy.
MDR-TB is more difficult to treat than
drug-susceptible strains of TB. The success
of treatment depends upon how quickly a
case of TB is identified as drug resistant
and whether an effective drug therapy is
available. The second-line drugs used in
cases of MDR-TB are often less effective and
more likely to cause side effects.
FDA has approved rifater, a medication that
combines the three main drugs (isoniazid,
rifampin and pyrazinamide) used to treat
tuberculosis into one tablet. This reduces the
number of pills a patient has to take each day
and makes it impossible for the patient to take
only one of the three medications, a common
path to the development of MDR-TB.
In June 1998, the FDA approved the first new
drug for pulmonary tuberculosis in 25 years.
The drug, rifapentine (Priftin), has been
approved for use with other drugs to fight
TB. One potential advantage of rifapentine is
that it can be taken less often in the final four
months of treatment – once a week compared
with twice a week for the standard regimen.
Overall, the CDC’s message is that resistance can
be slowed if patients take medications correctly.
Resistance of Mycobacterium tuberculosis to
isoniazid, rifampin, ehtambutol and pyrazinamide
has become an increasing clinical challenge.
M. tuberculosis develops resistance to drugs
by spontaneous mutations in its core genetic
structure. Resistance to one drug is common; this
is the main reason for using as many as four or
five drugs simultaneously to treat TB.
Alternatives
Prevention
Rational use of antibiotics may reduce the
chances of development of opportunistic
infections by antibiotic resistant bacteria; for
example, extended use of fluoroquinolones is
clearly associated with Clostridium difficile
infection, the leading cause of nosocomial
diarrhea in hospitals, and a major cause of death
worldwide.
Page 9
Antimicrobial stewardship programs in hospitals
seek to optimize antimicrobial prescribing
to improve individual patient care as well as
reduce hospital costs and slow the spread of
antimicrobial resistance. With antimicrobial
resistance on the increase worldwide and few
new agents in development, antimicrobial
stewardship programs are more important than
ever in ensuring continued efficacy of available
antimicrobials.
The design of antimicrobial management
programs should be based on the best current
understanding of the relationship between
antimicrobial use and resistance. Such programs
should be administered by multidisciplinary
teams composed of ID physicians, clinical
pharmacists, clinical microbiologists and
infection control practitioners, and should be
actively supported by hospital administrators.
Strategies for changing antimicrobial prescribing
behavior include educating prescribers on proper
antimicrobial usage, creation of an antimicrobial
formulary with restricted prescribing of targeted
agents and review of antimicrobial prescribing
with feedback to prescribers. Clinical computer
systems can aid in the implementation of each of
these strategies, especially as expert systems able
to provide patient-specific data and suggestions at
the point of care.
Antibiotic rotation strategies control the
prescribing process by scheduled changes of
antimicrobial classes used for empirical therapy.
When instituting an antimicrobial stewardship
program, a hospital should tailor its choice of
strategies and its needs and available resources.
Vaccines in development do not have the problem
of resistance because vaccines enhance the
body’s natural defenses through the immune
system, while antibiotics operate separately from
the body’s normal defenses. New strains that may
evolve, however, may require updated “boosters”
similar to influenza vaccines that are updated
each year with new strains.
Because of the prevalence of antimicrobial drug
resistance, the CDC and various other prestigious
organizations have been collaborating to work
to eradicate antimicrobial resistance. The public
health task force committee is co-chaired by
the CDC, FDA, National Institute of Health
(NIH) and Agency for Healthcare Research and
Quality (AHRQ), Centers for Medicare Medicaid
Services (CMS), the Health Resources and
Services Administration (HRSA), Department of
Agriculture (USDA), the Department of Defense
(DOD), Department of Veterans Affairs (VA) and
the Environmental Protection Agency (EPA).
The CDC’s Campaign to Prevent Antimicrobial
Resistance aims to prevent antimicrobial
resistance in health care settings. The campaign
centers on four main strategies: prevent infection,
diagnose and treat infection, use antimicrobials
wisely, and prevent transmission. Within the
context of these strategies, multiple 12-step
programs are being developed targeting clinicians
who treat specialty-specific patient populations,
including hospitalized adults, dialysis patients,
surgical patients, hospitalized children and longterm care patients.
Educational tools and materials are being
developed for each patient population. The 12step program is available customized for various
kinds of patients: those who are hospitalized,
undergoing dialysis or surgeries, long-term
patients, and children.
The CDC’s 12-step goals for hospitalized
patients
Step 1. Vaccinate staff and patients.
ŠŠ Get the influenza vaccine.
ŠŠ Give influenza and pneumococcal
vaccine to patients in addition to routine
vaccines (e.g., hepatitis B).
Step 2. Get the catheters out.
Hemodialysis
ŠŠ Use catheters only when essential.
ŠŠ Maximize use of fistulas/grafts.
ŠŠ Remove catheters when they are no
longer essential.
Peritoneal dialysis
ŠŠ Remove/replace infected catheters.
Step 3. Optimize access care.
ŠŠ Follow established KDOQI and CDC
guidelines for access care.
ŠŠ Use proper insertion and catheter-care
protocols.
ŠŠ Use the correct catheter.
Step 4. Target the pathogen.
ŠŠ Obtain appropriate cultures.
ŠŠ Target empiric therapy to likely
pathogens.
ŠŠ Target definitive therapy to known
pathogens.
ŠŠ Optimize timing, regimen, dose, route
and duration.
Step 5. Access the experts.
ŠŠ Consult the appropriate expert for
complicated infections.
Step 6. Use local data.
ŠŠ Know your local antibiogram (most
common microbes and resistance in your
area).
ŠŠ Get previous microbiology results when
patients transfer to your facility.
Step 7. Know when to say “no” to vancomycin.
ŠŠ Follow CDC guidelines for vancomycin
use.
ŠŠ Consider first-generation cephalosporins
instead of vancomycin.
Step 8. Treat infection, not contamination or
colonization.
ŠŠ Use proper antisepsis for drawing blood
cultures.
ŠŠ Get one peripheral vein blood culture, if
possible.
ŠŠ Avoid culturing vascular catheter tips.
ŠŠ Treat bacteremia, not the catheter tip.
Step 9. Stop antimicrobial treatment.
ŠŠ When infection is treated.
ŠŠ When infection is not diagnosed.
Step 10. Follow infection control precautions.
ŠŠ Use standard infection control
precautions for dialysis centers.
ŠŠ Consult local infection control expert.
Step 11. Practice hand hygiene.
ŠŠ Wash your hands with soap and water or
use an alcohol-based hand rub.
ŠŠ Set an example.
Step 12. Partner with your patients.
ŠŠ Educate on access care and infection
control measures.
ŠŠ Re-educate regularly.
Antibiotic resistance in the pediatric
patient
Common infections, such as ear infections,
tonsillitis and strep throat, and urinary tract
infections seem to be part and parcel of
childhood. When children present with these
problems, they are often prescribed antibiotics
as a routine treatment. Compounding the issue is
that some of these problems recur either because
the problem is caused not by a bacterium but
by a virus or developing respiratory allergies,
or in a scenario that is becoming increasingly
more likely, the causative organism has become
resistant to the antibiotics used to treat them. For
this reason, children may be prescribed different
antibiotics; when one does not work, another
is tried. As we have seen, this leads to bacterial
resistance formation.
In addition to the challenge of drug resistance,
there are other factors at play. First, hygiene is
essential in the prevention of the transmission
of disease; we are bombarded with reminders to
wash our hands, use hand sanitizers, and sneeze
into either the crook of the elbow, or at least a
tissue.
On the other hand, children have not yet gotten
into the habit of hand-washing, period, let alone
the habit of correct hand-washing. Furthermore,
children tend to rely on tactile stimulation to
make sense of their world; virtually any object
that fits will go into an infant’s mouth, and older
children touch everything, often without washing
their hands afterwards. Finally, kids share. This
is not necessarily a bad thing, but one child may
touch an object with dirty hands, then hand the
object over to another child, along with whatever
germs have found their way to that object.
Another issue is that children are not always able
to clearly communicate their physical needs.
All they know is that something hurts, and they
want the pain to go away. Furthermore, they do
not always understand that when their ear hurts,
the problem may really be in the throat; referred
pain is not a concept for them. The prescriber
may not see any signs of an ear infection but
may decide to treat for it anyway on the theory
that the physical signs have not yet manifested
themselves. Therefore, an antibiotic may be
prescribed for a problem that does not exist.
Finally, children must rely on their parents and
other adults for compliance to drug and other
treatment regimens. The adult must be the one to
administer the drug, so the adult must understand
the instructions on the bottle, be available at
dosing time, and monitor the child for signs of
improvement. The adult may decide that because
the child feels well enough to return to his usual
routine, the antibiotic is no longer necessary. A
Page 10
Elite
parent may request an antibiotic as a “quick fix”
because she is unable to take time off from work
to stay home with a sick child. Teachers may
forget to send the child to the nurse’s office for
the next dose, or the parent may forget to send the
medicine to school. And so forth.
There are vaccines that stimulate the child’s
immune system to fight off bacterial infection
before it takes hold. Pneumonococcal conjugate
vaccines are those that prevent S. pneumoniae.
Tuberculosis is prevented with BCG vaccine
in children who live in communities where TB
is prevalent. And, of course, the old standby
Physiologically, neonates and infants are more
is the diphtheria-tetanus-pertussis shot (DTP,
susceptible to bacterial infection, and this is
DTaP), a component of the standard childhood
including an ever-increasing population of
vaccine series. More vaccines to prevent bacterial
premature infants. Their immunity has not yet
infection are in development, and many of them
developed to the point where they are able to fend
show promise and may help guide efforts toward
off infection by themselves, and they are exposed
prevention, rather than treatment.
to hospital-acquired (HA) pathogens just as older
patients are, many of them resistant to antibiotics. Resistance to vaccination
Some of these children require a great deal of
The efficacy and power of vaccination to
invasive treatments, such as surgeries and tube
eliminate or significantly reduce disease has been
insertions among others, and these create access
known for centuries, ever since Jenner developed
points for bacteria to invade the body.
the smallpox vaccine in the mid-18th century.
Unfortunately, there are social and political
These access points continue in older childhood.
Some children, especially athletes, are susceptible forces involved in vaccine campaigns, both in the
United States.
to methicillin resistant Staphylococcus aureus
(MRSA) because these bacteria grow in gyms
and locker rooms that are often warm and moist,
and the focus of disinfection may be fungus, not
bacteria. Other children may have diseases such
as asthma, cystic fibrosis, urinary tract defects
that tend to make them susceptible to UTIs, and
other problems that tend to lead to infection.
These kids may be treated with multiple courses
of different antibiotics over the course of their
lifetimes in an effort to control the infection.
This repeated exposure to antibiotics can lead to
resistance that makes future infections difficult
to treat. One study found that recent exposure
to antibiotics before a UTI made the UTI more
likely to be resistant to ampicillin, ampicillinclavulanate (Augmentin), and amoxicillin.
Another study confirmed this and added that
prophylactic antibiotics given in the hospital may
create bacterial resistance to third-generation
cephalosporins, which are among the most
prescribed antibiotics. Given that urinary tract
infections are fairly common in children, this
resistance is frightening.
Furthermore, there are new strains of
Streptococcus pneumoniae that cause ear
infections and that are resistant to virtually every
drug but levofloxacin (Levaquin), which is not
approved for children. Ear infections, if left
untreated or are untreatable, can cause scarring
on the eardrum and in the ear canal, and in
infants, can lead to significant hearing loss and
speech delays. If the infections are recurrent
or are caused by resistant bacteria, it may be
necessary for the child to have tubes placed in
the ears to drain the fluid and keep them open to
allow drainage to continue until the ear canals
are completely clear. This exposes the child to
hospital-acquired pathogens as well. The same
pathogen also can cause meningitis.
Additionally, drug and multidrug-resistant
Mycobacterium tuberculosis is starting to be
seen in children, although this may simply be
a function of drug-resistant TB bacteria in the
community.
Some parents are reluctant to vaccinate their
children against any disease, bacterial or viral,
out of fear that either the active pathogen in
the vaccine or one or more of the adjuvants or
preservatives can create other problems, such as
autism. Although this notion has its champions
that run organized anti-vaccination publicity
campaigns, much of the misinformation is spread
from parent to parent through face-to-face and
online social networks. Formal anti-vaccination
campaigners often claim conspiracies, such
as “Big Pharma’s” perceived profit motive,
or they cite anecdotal data and studies of
questionable quality, such as the research of
Andrew Wakefield, to raise doubts in the minds
of parents. Finally, they encourage parents to “do
their own research,” pointing them to websites
run by “experts” with dubious credentials.
Others cite political or religious philosophies as
reasons not to vaccinate or treat their children.
Some have claimed that universal, mandatory
vaccination is simply a government conspiracy to
deny parents the right to make decisions on their
children’s behalf. Some parents claim religious
belief as a reason, saying antibiotics and vaccines
interfere with God’s plan, or that disease is a test
of their faith and that treatment or vaccination
amounts to failing that test.
The role of the pharmacist
The pharmacist has a significant role to play
as an educator. As with the treatment of adults,
prescribers should be made aware of the benefits
of the judicious use of antibiotics in the treatment
of minor infections, such as ear infections or
tonsillitis, that are likely to be self-limiting even
without treatment, and that antibiotics should be
reserved for more serious infections and against
susceptible pathogenic organisms.
Furthermore, although this is changing as older
doctors are retiring and newer ones are taking
their place, it should emphasized that antibiotics
are useless against viral infections, such as colds
and other upper-respiratory infections, and that
Elite
symptomatic treatment is more likely to be
appropriate.
Pharmacists can also educate parents as well,
teaching that antibiotics have a role in the
treatment of infectious disease, but they must
be used correctly and until the prescription is
finished. Pharmacists can also teach appropriate
symptomatic relief, such as management of
pain and fever. Finally, pharmacists can give
scientifically accurate information about the
benefits of antibiotics and vaccines to hesitant
parents. In the case of parents with religious
objections, a referral to the hospital chaplain may
be beneficial.
Finally, pharmacists can track drug resistance and
community-acquired infectious disease in their
communities, make suitable recommendations for
antibiotics and regimens that will work against
susceptible organisms, and develop evidencebased policies for their facilities based on the
available data. They can also work closely with
the infection-control team to develop policies
designed to reduce the likelihood of exposure of
children to hospital-acquired infectious disease.
Antibiotic resistance and the geriatric
and long-term care facility patient
Like children, the older patient’s health needs
present significant challenges from infection
and the use of antibiotics to manage them.
Unlike children, however, this is not because
of an immature immune system but rather to
an immune system that is winding down. Older
patients are, as a general rule, more susceptible to
infection for a number of reasons. These include:
Depressed immunity as the number of
T-cells, which fight pathogenic organisms,
are reduced.
Other health problems that can affect
immunity, such as diabetes and heart disease.
Increased risk of malnutrition because of
poor dentition, poor diet because of economic
factors (e.g., being on a fixed income), or
poor appetite.
Polypharmacy because of multiple
medications prescribed by multiple
physicians to manage multiple problems; the
patient may not be able to follow instructions,
or the drugs themselves may reduce the
body’s immune response.
Cognitive impairment, especially if the
patient is unable to communicate well.
Loss of mobility, which can create sites
for cutaneous infections to develop, cause
circulation to be impaired, and make it
difficult for the patient to achieve postural
drainage.
Emotional stresses, such as those caused by
loss of independence or the loss of a spouse
or close friends.
Inability to engage in activities of daily living
(ADLs), such as bathing, dressing, oral care,
and so on.
Furthermore, the elderly are also more likely
to have indwelling devices, such as urinary
catheters, central IV lines, dialysis shunts, and
ventilator tubes that can be sources of infection,
Page 11
as well as artificial joints and other body parts.
Geriatric patients are also more likely to suffer
from pneumonia, urinary tract infections (UTIs),
herpes zoster (shingles), infected pressure ulcers,
and intra-abdominal infections than are younger
patients.
Infections in this population also tend to be more
severe than those in younger populations; a case
of pneumonia that may cause a week’s worth
of bed rest and a few days’ recovery time in a
younger person may be fatal in an elderly person.
Finally, the elderly are far more likely to spend
time in a hospital, long-term care facility, or
some other care facility (e.g., a personal care
home), where they are exposed to hospitalacquired infections such as methicillin-resistant
Staphylococcus aureus (MRSA), vancomycinresistant enterococcus (VRE), Haemophilus
influenzae and other pathogenic organisms. The
problem of hospital-acquired infection and the
need for judicious use of antibiotics have been
covered elsewhere in this course. There is also
little need to discuss at length the needs of the
healthy, independent older patients because they
have the same community-acquired infections.
Therefore, this section will focus on the needs of
geriatric patients who resides in a long-term care
facility.
However, there is a significant problem with
antibiotic resistance in nursing home-acquired
infections, especially those caused by bacteria
that would be susceptible if the infection were
acquired in the community. For example, strains
of Gram-negative ampicillin-resistant E. coli are
found in urine cultures of nursing home residents;
this same infection would likely be susceptible to
ampicillin in the community.
Another study found Providencia, which tends to
be resistant to beta lactam and aminoglycoside
antibiotics, in a long-term care facility; this
is a fairly rare bacterium in other settings.
Methicillin-resistant Staphylococcus aureus
(MRSA) is another significant problem in longterm care settings.
The origins of antibiotic resistant
pathogens in the long-term care facility
Ultimately, there are three possible origins for
resistant pathogens in long-term care facilities.
The first occurs when a resident is first
admitted to the facility, or if a patient is
re-admitted after a hospital stay. The new
resident brings new species and strains
of bacteria with him; these may cause an
infection in susceptible patients, and some
of these new bacteria may be resistant to
available antibiotics.
The second occurs when the bacteria mutates
as a response to antibacterial therapy, either
in an individual patient or in a group of
patients who are prescribed antibiotics. For
example, if a resident is on a long-term
antibiotic because of an indwelling catheter,
any once-susceptible bacteria may soon
become resistant.
The third is caused by the transfer of genes
from one species of bacteria to another,
conferring resistance.
The prevalence and significance of each of these
is not known at present.
The persistence of antibiotic resistant pathogens
in nursing homes is caused by a number of
factors:
Close sleeping quarters and shared spaces
provide excellent opportunities for residentto-resident and person-to-surface-to-person
contact.
The hands-on nature of nursing home care
means that nursing staff and aides can spread
pathogens from one resident to another. This
is especially problematic in facilities where
hand-washing facilities are minimal and
where infection control policies are minimal.
High patient-to-staff ratios often create
situations where nurses are too busy to be
able to follow proper standard precautions.
High turnover among nonprofessional staff
means that new people must be trained and
that training must be reinforced.
Low turnover of residents may make
housekeeping a lower priority. Furthermore,
housekeeping staff may be told not to move
residents’ belongings, which makes it difficult
to properly clean and disinfect surfaces.
Residents may transfer from hospital to
rehabilitation center to nursing home, picking
up new pathogens along the way.
Challenges of long-term care facilities vs.
hospitals
Obviously, there are some fundamental
differences between hospitals and long-term care
facilities. Hospitals are generally intended for
acute care lasting, at most, a period of weeks.
They are capable of taking care of very medically
complex patients and have laboratory, imaging,
and other diagnostic facilities; fully stocked and
staffed pharmacies and other ancillary services;
and tend to be staffed with more professionals.
Long-term care facilities, on the other hand, are
intended more for routine care lasting months or
years. They are intended more for people who are
no longer able to live independently, but who do
not require much in the way of acute care, at least
not on a day-to-day basis. There are typically no
diagnostic services available on-site, although
there may be an arrangement with a local lab
for pick-ups of specimens, and a mobile x-ray
service may be available.
Finally, there may be a basic dispensary for
medications, but it will probably have only
the most commonly prescribed medications.
Long-term care facilities tend to be staffed
with a combination of professional registered
and licensed practical/vocational nurses and
nonprofessional nursing aides.
The long-term nature of nursing homes creates a
number of challenges to a successful infectioncontrol program. First, residents must have some
means of socialization. This means communal
spaces, such as dining rooms and dayrooms; at a
hospital, most patients stay in their rooms most
of the day. Second, bed space in long-term care
facilities is often at a premium; there may simply
not be enough private rooms to accommodate
patients who are colonized with an antibioticresistant pathogenic organism; private rooms
for such patients is standard protocol at most
hospitals. Finally, the patient turnover at longterm care facilities is much, much lower, giving
more residents the opportunity to be exposed to
more pathogens.
Sociocultural factors
Any discussion of long-term care necessarily
has to include a discussion of end-of-life issues.
Many infections that are, at best, a minor
inconvenience to a younger, healthier person
may be fatal to a frail, elderly nursing home
resident, and antibiotics may be of dubious
benefit to such a person. There is, of course, the
risk that the organism will be resistant to the
prescribed antibiotic and place additional strain
on the person’s body for no clear benefit. But
the decision of whether to treat these infections
is often a difficult one and not one to be made
lightly.
These decisions should be centered on what is
best for the patient. For example, the family
may request a prescription for an antibiotic
because they may feel guilty if they have not
tried all available treatment options, even though
antibiotics may be futile. However, if the patient
does not want treatment or if the prescriber
believes that treatment would be detrimental
to the patient, then antibiotics should not be
prescribed. The palliative use of antibiotics, such
as to control the pain of a kidney infection, may
be a possibility, however.
Common infections in long-term care
facilities
Pneumonia
Pneumonia is often seen in residents who have
dysphagia, who have cognitive impairment,
who are taking a sedative or a hypnotic drug,
or who have had at least one witnessed episode
of aspiration. It has a high mortality rate, and is
a frequent cause of admission to an acute-care
hospital. However, there are precautions that can
be taken to prevent the disease. These include:
Ensuring adequate staff to make sure that
residents, especially those on mechanically
altered diets for dysphagia, are able to eat
safely.
Ensuring that residents and staff are
vaccinated against pneumococcus.
Ensuring that the causative organism is
susceptible to the prescribed antibiotic.
Urinary tract infections (UTIs)
Urinary tract infections are the single largest
cause of infection in the long-term care setting.
In addition to the classic symptoms of flank
pain, burning on urination, low-grade fever, and
foul-smelling urine, elders with a UTI may have
an altered mental status and possibly experience
sudden incontinence.
Page 12
Elite
To determine to which antibiotics the causative
organism is susceptible, a pre-treatment culture
should be performed. If empiric therapy is
required before the results of the culture are
available, then it should be re-evaluated when the
culture results come back. Otherwise, there is a
significant risk that an ineffective antibiotic may
be used, leading to resistance.
Infected pressure ulcers
These may be difficult to diagnose in elders,
but the criteria for diagnosis are either pus in
the wound or other classical signs of infection,
such as increased temperature, redness, swelling,
altered mental status, serous drainage, and pain.
They should be treated with systemic antibiotics.
The role of the pharmacist
It is essential to develop a positive relationship
with the long-term care facility.
History of antibiotic development and
current challenges
Although microbes would not be visualized
until van Leeuwenhoek in the 17th and 28th
centuries, and although germ theory would not
be fully developed until the 19th with Koch and
Pasteur, the idea that specific substances could
cure infection was known in ancient times. Beer
brewed by the Egyptians probably had traces of
natural tetracycline formed during fermentation.
More recently, a Russian folk remedy for wounds
involved applying cobwebs that were probably
laced with Penicillium molds grown in musty
basements.
And although Semmelweis and Lister in mid19th century advocated in favor of the use
of antiseptics to reduce the transmission of
infectious disease in childbirth and surgery, and
although their efforts were successful in reducing
deaths caused by infection, their approach had
one major problem. Antiseptics are effective in
killing pathogens, but they damage healthy tissue
in the process. What was needed was a way to
kill pathogens while preserving healthy human
cells.
Ehrlich considered this problem and, in the first
decade of the 20th century, developed Salvarsan
(arsphenamine), the first drug specifically
intended to treat infectious disease, specifically
syphilis and trypanosomiasis. This laid the
groundwork for antibiotic chemotherapy, or
the idea that infectious disease could be cured
through drugs; before this, the prevailing theory
was that immunotherapy, which involved
injections of agents to stimulate the body’s own
immunity, was the better treatment. (The specific
word “chemotherapy” refers to any treatment
that involves the use of drugs to kill foreign
cells. This applies not only to pathogens but to
cancerous cells as well.)
Since the 1920s, the development of
chemotherapeutic agents has grown rapidly.
The first three types of antibiotics – penicillin,
initially discovered by Fleming but further
developed by Chain, Florey, and Heatley;
sulfonamides, developed by Domagk; and
Penicillins
Penicillins are a large and diverse group
of antibiotics that consist of three parts: a
thiazolidine ring, a beta-lactam ring, and a
variable side chain that dictates its specific
bactericidal activity. Recall that bacteria are
enveloped within a cell membrane, and that
osmotic pressure within the cell is extremely
high. Penicillins weaken the cell membrane
The success of antibiotics is now contributing
of susceptible bacteria, causing the organism
to their ultimate failure. They would often be
to absorb excess water and swell, which in
prescribed for viral infections, against which
turn, causes the bacteria to rupture, killing it.
they are ineffective, and for minor, selfŠŠ Penicillins are considered the drug of
limiting infections, such as most otitis media
choice for infections caused by sensitive
and tonsillitis in children. Patients would often
Gram-positive cocci, such as streptococci
shorten their prescribed course either because
and Gram-negative meningococci and
they felt better or because they wanted to reserve
spirochetes.
some medication “just in case.” Finally, it was not
ŠŠ Synthetic penicillins, such as ampicillin,
uncommon to take antibiotics prophylactically,
amoxicillin, and carbenicillin are
such as when soldiers received shots of penicillin
broader-spectrum; they can be used to
to prevent sexually transmitted diseases before
treat infections caused by Gram-negative
leaving on liberty. All of these contributed to
enteric rods such as Haemophilus
widespread resistance to such an extent that
influenzae, Escherichia coli, and
there are organisms that require massive doses of
Salmonella and Shigella spp. because
strong antibiotics to control.
they are able to penetrate the outer
Unfortunately, there are very few new antibiotics
membrane.
in the pipeline and, at this point, it appears that
ŠŠ Extended-spectrum penicillins consist of
the age of antibiotic chemotherapy may be
three drugs: ticarcillin, mezlocillin, and
closing. The primary reasons for this include
piperacillin. They are ineffective against
lack of economic incentive because of the cost
Staphylococcus aureus because they
involved in developing new drugs; regulatory
are susceptible to beta-lactamase, but
hurdles in getting new antibiotics approved;
they are effective against Pseudomonas
and the pure science involved in finding novel
aeruginosa and Bacteroides fragilis,
antibiotics.
as well as Enterobacter, Proteus, and
Current research focuses on immunotherapies
Klebsiella spp.
such as vaccines and phage therapy, and these
ŠŠ Penicillinase-resistant penicillins, such
may be effective against resistant bacteria,
as methicillin, nafcillin, and cloxacillin,
but they are far on the horizon.4 For now, the
are useful in treating infections caused by
best strategy seems to be the prudent use of
some penicillinase-producing bacteria.
antibiotics.
The major problems with penicillins include:
Allergic reactions that may appear as a mild
Classification of antibiotics
rash or escalate to anaphylaxis. To date,
Regardless of the venue or specialty of practice,
however, there has been no direct relationship
pharmacists will be responsible for dispensing
between the dosage and the intensity of the
antimicrobials. Therefore, the pharmacist needs
allergic response.
to be familiar with the classification, action, and
Resistant strains of pathogens, especially
purpose of the drug.
bacteria encapsulated by a beta-lactamase
Broadly speaking, antibiotics are chemical
ring. Beta-lactamase activity can occur in:
compounds that interfere with the biological
ŠŠ Gram-positive organisms, such
processes of bacteria, either inducing death or
as Staphylococcus aureus and
damage, thus curing the infection. They are
Staphylococcus epidermidis.
chemically complex and their chemistry is
ŠŠ Gram-negative organisms, such as
responsible for the bacteria they affect. Some are
Haemophilus influenzae, Neisseria
intended to treat a broad range of microbes; these
gonorrhea, Moraxella catarrhalis,
are termed broad-spectrum antibiotics. Others are
Escherichia coli, and Proteus, Serratia,
intended to treat a much narrower range; these
Pseudomonas and Klebsiella spp.
are termed narrow-spectrum. Furthermore, there
ŠŠ Anaerobic organisms, such as
are more than 260 antimicrobial drugs that are
Bacteroides spp.
categorized into 20 families.
Bacteria encapsulated by a beta-lactamase ring
This course will discuss the most commonly used
are eliminated by combining a penicillin with
classes of drugs as they relate to antimicrobial
a beta-lactamase inhibitor, such as Unasyn
resistance of pathogenic organisms.
(ampicillin plus sulbactam), Augmentin
(amoxicillin plus clavulanic acid), Timentin
Antibacterial drugs that weaken the
(ticarcillin plus clavulanic acid), and Zosyn
bacterial cell membrane
(piperacillin plus tazobactam).
This drug class is comprised of the penicillins,
cephalosporins, carbapenems and vancomycin.
streptomycin, developed by Waksman – have
proven to be a boon to medicine in that they
help to cure diseases that were previously fatal.
Once the efficacy and utility of these drugs were
established by their widespread use in World
War II, discovery and development skyrocketed.
Many other types of antibiotics found their way
from the test tube to the marketplace.
Elite
Page 13
Clavulanic acid is a beta-lactamase inhibitor
that increases the longevity of beta-lactam
antibiotics in the presence of penicillinaseproducing bacteria. Beta-lactamase inhibitors
have a minimal risk of toxicity, and any adverse
reactions that may occur with combination drugs
are related to the penicillin component.
Cell biology and the penicillins
Bacterial resistance to the penicillins develops
from two factors:
1. Inability of the drug to reach its target.
2. Inactivation of the drug by bacterial enzymes.
It is important to note that all bacteria are
surrounded by a cell envelope, but the envelope
differs in Gram-positive and Gram-negative
bacteria.
The cell envelope of Gram-positive bacteria
has only two layers: the cytoplasmic
membrane, plus a relatively thick cell wall.
Although the membrane is fairly thick,
penicillins can easily penetrate it.
The cell envelope of Gram-negative bacteria
has three layers: the cytoplasmic membrane,
a thin cell wall, and an additional outer
membrane. The penicillins can penetrate
the inner two walls, but are unable to break
through the outer layer. Therefore, penicillins
are generally inactive against Gram-negative
organisms.
Cephalosporins
These are a newer group of antibiotics that are
very commonly prescribed. Similar to penicillins,
cephalosporins bind to receptors and activate
enzymes that cleave to the cell wall, causing the
cell’s death.
Cephalosporins are versatile drugs that are
relatively broad-spectrum and resistant to
most penicillinase. They typically have fewer
and less severe adverse reactions compared
to the penicillins. That said, there is a risk of
cross-sensitivity in patients who are allergic to
penicillin. If the patient has ever had an allergic
reaction to penicillin, a cephalosporin should
never be administered.
There are five groups of cephalosporins, called
“generations.”
First-generation cephalosporins, such as
cephalothin and cefazolin, are most effective
against Gram-positive cocci but few Gramnegative bacteria. They are destroyed by
beta-lactamase.
Second-generation cephalosporins, such as
cefaclor and cefotetan, are more effective
against Gram-negative bacteria.
Third-generation cephalosporins, such as
ceftriaxone and cefotaxime, are broadspectrum antibiotics that are stable in the
presence of bacteria with a beta-lactamase
ring. These are commonly prescribed for a
number of conditions, but they should be
used prudently to avoid resistance.
Fourth-generation cephalosporins, such as
cefepime, are prescribed for both Grampositive and Gram-negative bacterial
pathogens.
Fifth-generation cephalosporins, such as
ceftaroline, are somewhat effective against
MRSA.
Carbapenems
These are beta-lactam antibiotics that are very
broad-spectrum. They are only administered
parenterally because of poor oral bioavailability5
and are used more commonly to avoid
development of resistance. Nevertheless, there is
some concern that at least some resistance may
be forming because carbapenem-resistant strains
have been found in the United States, the United
Kingdom, India, Pakistan, and Bangladesh. This
may be due to the presence of a gene that creates
a metallo-beta-lactamase that hydrolyzes the
carbapenem6.
Drugs in this category include:
Imipenem (combined with cilastatin in
Primaxin).
Meropenem (Merrem).
Ertapenem (Invanz).
Doripenem (Doribax).
Vancomycin (Vancocin, Vancoled)
This is a potentially toxic drug that is reserved
most commonly for serious Gram-positive
bacterial infections, such as Clostridium
difficile-caused pseudomembranous colitis,
methicillin-resistant Staphylococcus aureus
(MRSA) infections, and serious Gram-positive
infections in patients allergic to penicillin (e.g.,
Staphylococcus epidermidis). The most common
complications associated with vancomycin
include reversible ototoxicity, flushing,
tachycardia, hypotension, and thrombophlebitis.
Situations in which the use of vancomycin is
appropriate or acceptable include:
For treatment of serious infections caused
by beta-lactam-resistant Gram-positive
microorganisms. Vancomycin may be
less rapidly bactericidal than are betalactam agents for beta-lactam-susceptible
staphylococci.
For treatment of infections caused by Grampositive microbes in patients who have
serious allergies to beta-lactam antibacterials.
When antibiotic-associated colitis fails to
respond to metronidazole therapy or that is
severe and potentially life-threatening.
Prophylaxis as recommended by the
American Heart Association (AHA) for
endocarditis following certain procedures in
patients at high risk for endocarditis.
Prophylaxis for major surgical procedures
involving implantation of prosthetic materials
or devices (e.g., cardiac and vascular
procedures and total hip replacement) at
institutions that have a high rate of infections
caused by MRSA or methicillin-resistant S.
epidermidis. A single dose of vancomycin
administered immediately before surgery is
sufficient unless the procedure lasts greater
than six hours, in which case the dose
should be repeated. Prophylaxis should be
discontinued after a maximum of two doses.
Situations in which the use of vancomycin should
be discouraged:
Routine surgical prophylaxis other than in a
patient who has a life-threatening allergy to
beta-lactam antibiotics.
Empiric antimicrobial therapy for a febrile
neutropenic patient, unless initial evidence
indicates that the patient has an infection
caused by Gram-positive microbes (i.e., at an
inflamed exit site of a Hickman catheter) and
when the prevalence of infections caused by
MRSA in the hospital is substantial.
Treatment in response to a single blood
culture positive for coagulase-negative
staphylococcus, if other blood cultures taken
during the same time frame are negative
(i.e., if contamination of the blood culture
is likely). Because contamination of blood
cultures with skin flora (i.e., S. epidermidis)
could result in inappropriate administration
of vancomycin, phlebotomists and other
personnel who obtain blood cultures
should be trained to minimize microbial
contamination of specimens.
Continued empiric use for presumed
infections in patients whose cultures are
negative for beta-lactam-resistant grampositive microbes.
Systemic or local (i.e., antibiotic lock)
prophylaxis for infection or colonization of
indwelling central or peripheral intravascular
catheters.
Selective decontamination of the digestive
tract.
Eradication of MRSA colonization.
Primary treatment of antibiotic-associated
colitis.
Routine prophylaxis for very low birthweight infants (i.e., infants who weigh less
than 1,500 grams, which is equivalent to 3
pounds, 4 ounces).
Routine prophylaxis for patients on
continuous ambulatory peritoneal dialysis or
hemodialysis.
Treatment (chosen for dosing convenience)
of infections caused by beta-lactam-sensitive,
Gram-positive microbes in patients who have
renal failure.
Use of vancomycin solution for topical
application or irrigation.
Enhancing compliance with recommendations:
Although several techniques may be useful,
further study is required to determine the
most effective methods for influencing the
prescribing practices of physicians.
Key parameters of vancomycin use can be
monitored through the hospital’s quality
assurance/improvement process or as part of
the drug-utilization review of the pharmacy
and therapeutics committee and the medical
staff.
Antibacterial drugs that inhibit protein
synthesis
Rather than kill bacteria, these drugs suppress
the ability of the bacteria to grow and reproduce.
Because of increasing bacterial resistance, these
are now considered second-line drugs.
Page 14
Elite
Tetracyclines
These are broad-spectrum antibiotics that
suppress bacterial growth by binding to the
30S subunit, thereby inhibiting the ability of
amino acids to be added to peptide chains.
Consequently, the inability of the bacterium to
synthesize proteins causes retardation of growth.
Although once first-line treatment against
virtually all medically-relevant pathogens,
increasing bacterial resistance has relegated
this drug to second-line status. However, it is
still used in the treatment against Chlamydia,
Mycoplasma, and Rickettsia infection, as well as
diseases caused by spirochetes, such as syphilis,
leptospirosis and Lyme disease. Finally, they are
effective against relatively rare diseases, such as
plague, anthrax, and brucellosis.
Macrolides
These are broad-spectrum antibiotics that also act
by suppression of protein synthesis. They include
erythromycin, azithromycin, and clarithromycin.
They are commonly used in Streptococcus
pneumoniae, group A Streptococcus pyogenes,
Legionella, Bordetella pertussis (whooping
cough), and chlamydial infections. Azithromycin,
in particular, has gained favor because its long
duration of action means that patients do not
have to take many doses over a period of weeks;
consequently, compliance is greater, meaning that
the course of treatment will be finished. (Recall
that incomplete treatment can lead to resistance.)
Aminoglycosides
These drugs have two or more amino-modified
sugars. They are relatively broad-spectrum in
their action because of their inhibitory action on
the bacterium, specifically because they bind to
the 30S ribosomal subunit. However, they may
also cause cell death because they apparently
cause errors in cellular reproduction, and they
may compromise the cell wall.
Drugs in this category include:
Streptomycin.
Amikacin.
Gentamicin.
Neomycin.
Tobramycin.
Others.
Other drugs that inhibit protein synthesis
Clindamycin (Cleocin) is active against
most Gram-positive and Gram-negative
organisms, although Gram-negative bacteria
are showing increasing resistance. However,
it remains a preferred treatment for pelvic and
abdominal infections and is often substituted
for the penicillin component in the prevention
of group B strep infection during labor. It has
been linked to pseudomembranous colitis.
Linezolid (Zyvox) is a relatively new
antibiotic. Currently, it has excellent activity
against multiple drug-resistant Gram-positive
pathogens, including vancomycin-resistant
Enterococcus (VRE) and MRSA. Therefore,
its use should be restricted to the treatment of
either of these infections.
Other antimicrobials
Antimycobacterial
Mycobacteria are slow-growing microbes that
require prolonged treatments. Because of the
prolonged therapy, patients typically develop
drug toxicity, non-compliance or drug resistance.
(See tuberculosis under “respiratory.”)
Antifungal drugs
Fungal cells are eukaryotic, and there are
currently four main drug classifications to treat
fungal infections. Systemic antifungals are used
to treat opportunistic infections (candidiasis,
aspergillosis, cryptococcosis and mucormycosis)
and non-opportunistic infections that can occur in
any host (sporotrichosis).
Mycoses are common and a variety of
environmental and physiological conditions
can contribute to the development of fungal
diseases. Inhalation of fungal spores or localized
colonization of the skin may initiate persistent
infections; therefore, mycoses often start in the
lungs or on the skin.
People are at risk of fungal infections when
they are taking broad spectrum antibiotics for
an extended period of time because antibiotics
kill not only pathogenic bacteria, but healthy
bacteria as well. This alters the balance of
microorganisms in the mouth, vagina, and
intestines and may result in an overgrowth of
fungus.
Individuals with compromised immune systems
are at greater risk of developing fungal infections.
This is the case of patients with HIV/AIDS and
those undergoing chemotherapy or corticosteroid
treatments.
Azole antifungals include ketoconazole,
itraconazole, fluconazole, posaconazole,
clotrimazole, miconazole, and voriconazole.
A drug may be classified by the chemical type
of the active ingredient or by the way it is used
to treat a particular condition. Each drug can be
classified into one or more drug classes.
Azole antifungals are a group of fungistatic
agents with broad spectrum activity. They are
classified into two groups: the triazloles and
imidazoles.
The azole antifungals inhibit the cytochrome
P450 dependent enzyme lanosterol
14-α-demethylase, which converts lanosterol
to ergosterol the main sterol in fungal cell
membrane. Depletion of ergosterol damages the
cell membrane resulting in cell death.
Azole antifungal agents can be used to treat
systemic and topical (athletes foot, ringworm,
etc.) fungal infections.
Echinocandins are antifungal drugs that inhibit
the synthesis of glucan in the cell wall via
noncompetitive inhibition of the enzyme 1.3-β
glucan synthase and thus called the “penicillin”
of antifungals. They are used in candidiasis and
aspergillosis.
They are fungicidal against some yeasts (most
species of candida, but not against Cryptococcus,
Elite
trichosporon and rhodotorula), fungistatic
against some molds (aspergillis but not fuserium
and rhizopus), and minimally active against
dimorphic fungi (blastomyces and histoplasma).
These have some activity against the spores of
the fungus pneumocystis carinii.
Advantages of echinocandins include:
Broad range (especially against all candida),
thus can be given empirically in febrile
neutropenia and stem cell transplant.
Can be used in cases of azole resistant
candida or used as a second line agent for
refractory aspergillosis.
Long half-life polyphasic elimination: α
phase 1-2 hours + β phase 9-11 hours + γ
phase 40-50 hours.
Low toxicity: only histamine release (3
percent), fever (2.9 percent), nausea and
vomiting (2.9 percent), and phlebitis at the
injection site (2.9 percent), very rarely allergy
and anaphylaxis.
Not an inhibitor, inducer, or substrate of the
cytochrome P450 system or p-glycoprotein,
thus minimal drug-drug interactions.
Lack of interference from renal failure and
hemodialysis.
No dose adjustment is necessary based on
age, gender, race.
Better than amphotericin B and fluconazole
against yeast infections.
The echinocandins include caspofungin,
micafungin, and anidulafungin.
Antiparasitic drugs
Because of the enormous diversity among
protozoan and parasites, there are numerous
approved drugs on the market.
Antimalarial drugs. For over a hundred
years, quinine has been utilized as the
principle treatment for malaria. In past
years, quinine was extracted from the bark
of cinchona tree, but later replaced by the
synthesized quinolones.
Chemotherapy for other protozoan
infections. The most common amebicide is
metronidazole (flagyl), which is effective in
treating mild and severe intestinal infections
and hepatic disease.
Quinicrine (a quinine-based drug),
sulfonamides and tetracyclines also have
antiprotozoan activities.
Anti-helminthic drug therapy. Treating
helminthic infections, such as flukes,
tapeworms and roundworms, is accomplished
by blocking the reproduction and inhibiting
the metabolism of various stages of the life
cycle.
Antiviral drugs
Viruses are unique because the infectious agent
relies on the host cell for the majority of its
metabolic functions. Therefore, to eradicate
infections induced by certain viruses, the drug
needs to disrupt the metabolism of the host cell.
It should be noted that not all viruses are treated
with antiviral agents; many resulting ailments
typically run their course, such as colds, measles,
Page 15
and mumps. The majority of viral compounds
need to exert their effects on the completion of
the virus cycle by barring complete penetration
of the virus into the host cell, blocking the
transcription and translation of viral molecules
and preventing the maturation of viral particles.
The most common antiviral medications
prescribed include:
Acyclovir (Zovirax), which blocks DNA
synthesis in a small group of viruses,
especially the herpes virus. The herpes virus
has developed resistance to acyclovir because
of:
ŠŠ Decreased production of thymidine
kinase.
ŠŠ Alteration of the thymidine kinase.
ŠŠ Alteration of viral DNA polymerase that
is less sensitive to inhibition.
AZT (zidovudine) and others are
administered for human immunodeficiency
virus (HIV). (See HIV under the section on
antimicrobial drug resistance and antiviral
agents)
Amantadine (Symmetrel) and rimantadine
(Flumadine) are used for the treatment
of viruses restricted exclusively to the
influenza A virus (flu). Relenza (zanamivir)
and Tamiflu (oseltamivir) are effective
prophylactic and standard treatments against
influenzas A and B, but for the medication to
be effective, it needs to be administered early
in the virus infection to ensure that it can
inhibit the fusion and uncoat the virus.
There are a number of other virals. Refer to the
Sanford Guide or another drug reference for more
information about these.
Managing the success of antimicrobial
therapy
To prescribe the most appropriate antimicrobial
agent, the prescriber must consider a number of
factors. These include the patient’s age, allergies,
the likely causative organism, risk of drug
resistance, and whether the bacterium has a betalactamase ring.
Patient’s age: It is important to consider
the body’s ability to absorb, distribute,
metabolize, and excrete the medication.
ŠŠ Young children, such as infants and
neonates, have a difficult time absorbing
drugs in their gastrointestinal tract
because of a variable and prolonged
gastric emptying time, prolonged transit
time, and peristalsis. Gastric acidity
reaches adult levels between 1 to 2
years of age, and the gastric emptying
time reaches adult levels between
6 to 8 months of age. Furthermore,
their peripheral circulation is poorly
developed, which causes vasoconstriction
and decreased absorption. They also
have less muscle mass, which makes
intramuscular and subcutaneous routes
poor choices for neonates. Finally,
their kidneys are not as developed as
adults’, resulting in a longer half-life
and increased absorption of certain
drugs, especially penicillins and
aminoglycosides.
ŠŠ Similar to the young, elderly patients
have difficulty absorbing, distributing,
metabolizing, and excreting their
medication. Absorption may be
affected by poor nutritional status,
bowel problems such as constipation
or diarrhea, or reduced metabolism.
They also have a decrease in liver mass,
volume, and blood flow, which affects
the ability of the liver to eliminate
medication. Finally, they may be on a
number of other medications that can
interfere with the overall effectiveness of
an antimicrobial drug.
Pregnancy: In pregnancy, certain
medications pass through the placenta,
posing a risk to the developing fetus
due to teratogenicity. Therefore, careful
consideration must be given to the need for
the medication weighed against the risk for
the fetus. Furthermore, some antibiotics,
such as tetracycline and chloramphenicol,
cause problems that are not necessarily lifethreatening to the fetus but can still cause
problems. In the case of pregnant women, an
obstetrician should be consulted.
Drug allergies: The most common, most
severe drug allergy is with the penicillins,
although allergies may develop from any
antibiotic. When discussing medication
with the patient, it is important to ask
about previous reactions to the prescribed
medication, especially those that can be
indicative of an anaphylactic reaction. It is
also essential to remember that a relatively
mild reaction previously may worsen during a
subsequent round of antibiotic treatment, and
that dose alone is not indicative of the risk
of anaphylaxis. Symptoms of anaphylactic
reaction include:
ŠŠ Difficulty breathing and wheezing.
ŠŠ Tachycardia.
ŠŠ Urticaria or rash.
ŠŠ Edema of the tongue, lips, or face.
Drug sensitivity: Optimal antimicrobial
therapy is based upon the identified infecting
organism and sensitivity of the medications.
To assess drug sensitivity, a culture and
sensitivity (C & S) should be done if
applicable. There are certain conditions in
which a culture may not be feasible because
of the location of the infecting organism,
cost, and decreased risk of drug resistance.
At that time, the patient is treated empirically,
based on the best guess and experience of the
prescriber considering the patient’s subjective
complaints and the clinician’s objective
findings. However, a C & S should still be
performed to make sure that the causative
organism is sensitive to the antibiotic
prescribed.
ŠŠ The current C & S tests include the
disk diffusion test, which is performed
by inoculating an agar plate with the
infecting organism and then placing
on that plate several small disks that
have each been impregnated with a
different antibiotic. The other test, the
broth dilution test, is similar to the
disk diffusion test, but the bacteria are
grown in tubes containing different
concentrations of antibiotics. Either
way, sensitivity is determined by
which antibiotic kills the bacteria and
the concentration needed to achieve
successful treatment.
ŠŠ Drug sensitivity is assessed in two
clinical values. The first is minimum
inhibitory concentration (MIC), which
is defined as the lowest concentration
of antibiotic that produces complete
inhibition of bacterial growth, but
that does not kill the bacteria. The
other is the minimum bactericidal
concentration (MBC), defined as the
lowest concentration that produces a 99.9
percent decline in the number of bacterial
colonies, indicating a bacterial kill.
Host factors: In addition to matching the
drug with the infecting bug and determining
the drug sensitivity, the host factors (host
defenses and site of infection) must be
considered.
ŠŠ Host defenses consist primarily of the
immune system and phagocytic cells
(macrophages and neutrophils). For
antimicrobial therapy to be successful, it
requires collaboration of the host defense
system to subdue the infection.
ŠŠ To be effective, the antibiotic must be
present at the site of the infection in a
concentration greater than the MIC. It
may pose a challenge if the bacteria are
in a difficult area to reach, such as the
brain, joint, or sinuses.
Bacteria with a beta-lactamase ring: Betalactamases are enzymes that cleave to a betalactam ring, thus rendering the prescribed
antibiotic inactive. Beta-lactam antibiotics
include penicillins, cephalosporins,
monobactams, and carbapenems.
Risk of drug resistance: Unfortunately,
antimicrobial drug resistance is prevailing
on a global level. Every pathogen is at risk
of developing resistance to antimicrobial
drugs. However, there are certain factors that
increase the risk:
ŠŠ Overuse of antibiotics.
ŠŠ Overuse of broad-spectrum antibiotics.
ŠŠ Use of higher doses of antibiotics,
especially in combination with overuse
of antibiotics; the faster drug-resistant
organisms will emerge. Not only
do antibiotics eliminate the targeted
pathogenic organism, they also affect
normal flora that possess mechanisms for
resistance.
ŠŠ Method of administration most
commonly determines the concentration
of the antibiotic at the site of infection.
Β-lactam antibiotics should be infused
Page 16
Elite
over an extended period of time,
preferably four hours to increase the
concentration and AUC (area under the
curve).
However, all antimicrobial drugs are at risk
of becoming resistant as they promote the
emergence of drug-resistant organisms. Over
time, organisms become less susceptible to
previously effective prescribed antimicrobials.
However, broad-spectrum antibiotics are more
prone to induce this phenomenon because they
kill off more organisms than narrow-spectrum
antibiotics do. At this time, the organisms for
which drug resistance has the most serious
clinical problem include:
1. VRE – Vancomycin-resistant enterococci.
2. MRSA – Methicillin/oxacillin-resistant
Staphylococcus aureus.
3. ESBLs – Extended-spectrum beta-lactamases,
which are resistant to cephalosporins and
monobactams.
4. PRSP – Penicillin-resistant Streptococcus
pneumonia.
According to the National Institute of Allergy and
Infectious Disease, the most dangerous emerging
microbes affecting the community at large
include vancomycin-resistant enterococci (VRE)
and methicillin/oxacillin-resistant Staphylococcus
aureus (MRSA). Because each organism can
increase the patient’s risk of complications and
death, each will be explored in depth.
In June 2008, the United States Department of
Health and Human Services provided testimony
based on unpublished data from the CDC’s
National Nosocomial Infection Surveillance
System indicating that:
More than 90 percent of Staphylococcus
aureus strains are no longer treatable with
penicillins.
One-third of Streptococcus pneumoniae
isolates, a common cause of ear infections,
pneumonia, and meningitis, are also no
longer treatable with penicillin. In fact, there
are many strains that are resistant to penicillin
that are also becoming resistant to other
commonly used drugs such as ceftriaxone
(Rocephin), erythromycin, and trimethoprimsulfamethoxazole (Bactrim and Septra).
Other strains that are showing increasing
resistance include:
Strains of Salmonella Newport, which cause
infection in food animals such as dairy cows,
have shown to be resistant to as many as
seven antibiotics.
Although still small, there is a growing subset
of Gram-negative bacterial strains that cause
health care-associated infections such as
Acinetobacter baumanii and Pseudomonas
aeruginosa, which have become resistant to
all available antimicrobial agents.
Worldwide, tuberculosis caused by strains
of mycobacteria resistant to the two most
commonly used anti-tuberculosis agents,
isoniazid and rifampin, was recently
estimated to affect approximately half a
million people annually.
Recently, the first ciprofloxacin-resistant
strains of Neisseria meningitides were
reported in the upper Midwestern United
States.
Hospital-acquired antimicrobial drug
resistance
According to the CDC, antibiotic-resistant
infections are becoming a prevalent problem for
hospitals and nursing homes because they can
spread from one patient to another from open
wounds and impaired immune systems. In 2007,
the Journal of the American Medical Association
estimated that 94,360 patients in the United
States developed an invasive infection from
MRSA in 2005; nearly one in five, or 18,650,
died. Failure to control MRSA leads to prolonged
hospital stays and the possible risk of death.
Also according to the CDC, health careassociated infections account for an estimated 1.7
million infections and 99,000 associated deaths
each year. Of these infections:
Urinary tract infections comprise 32 percent
of all health care-associated infections.
Surgical site infections comprise 22 percent.
Pneumonia and lung infections comprise 15
percent.
Bloodstream infections make up 14 percent.
Anyone can be colonized with drug-resistant
microorganisms. Environmental cultures have
shown vancomycin-resistant enterococci (VRE)
and methicillin-resistant Staphylococcus aureus
(MRSA) on linens as well as hard surfaces such
as counters and medical devices.
Postoperative wound infections may be the
result of the contamination of the surgical wound
during the procedure or migration of an infection
from another site. It could also be a reactivation
of an infection that occurred previously. For
example, a common site of hospital-acquired
infection is the urinary tract, secondary to a
procedure or catheterization. Infection can occur
when a microbe migrates to a location where it is
typically not found.
Some people are more susceptible to infection
because of various risk factors. These groups
include:
The elderly.
Individuals with suppressed immune systems.
Individuals with orthopedic implants, such as
artificial joints, or hardware, such as plates or
screws after fracture repair surgery.
Individuals with other sites of infection.
The morbidly obese.
Those using IVs, catheters, feeding tubes,
central lines, or other invasive lines.
A history of long-term or frequent use of
antibiotics, multiple hospitalizations, and
long-term inpatient care.
Antibiotic-resistant Neisseria gonorrhea
Gonorrhea is a sexually transmitted infection
(STI) that is marked by pelvic pain, burning
on urination, purulent discharge, and if left
untreated, pelvic inflammatory disease and
infertility in women. If a woman with untreated
Elite
gonorrhea gives birth, the baby may develop
gonorrheal conjunctivitis with symptoms
that include eye pain, redness, and purulent
discharge; babies are now routinely treated
with silver nitrate or erythromycin ointment
immediately after birth to prevent infection. Men
may also suffer burning on urination, urethritis,
epididymitis, discharge, urethral strictures, and
rectal pain.
The bacterium responsible for the infection,
Neisseria gonorrhea, may travel to the rest of the
body and cause septic arthritis and dermatitis.
Finally, patients with gonorrhea may be comorbid with Chlamydia trachomatis, requiring
treatment for that infection as well.
Gonorrhea was often a serious problem in
wartime when soldiers sought the services
of prostitutes who had STIs. These diseases
were debilitating to armies, often causing tens,
if not hundreds, of thousands of casualties.7
Penicillin, first widely introduced during World
War II, cured most, if not all, of the major STIs,
generally with fairly low doses, and it was not
uncommon for soldiers to receive prophylactic
injections of the drug before going on liberty. By
the time of the Vietnam War, however, military
physicians noted increasing antibiotic resistance
in STIs, with cases requiring higher doses to cure
them.7
Over time, N. gonorrhea has developed
reduced susceptibility or frank resistance to
just about every antibiotic class available.
In 2006, the CDC updated its guidelines to
eliminate fluoroquinolones as a treatment option
and to restrict treatment to cephalosporins,8
specifically ceftriaxone (Rocephin). The current
recommendation for treatment is as follows:9
250 mg ceftriaxone (Rocephin) IM as a
single dose (400 mg cefixime if ceftriaxone is
unavailable) AND
1 g azithromycin as a single dose OR
100 mg doxycycline BID for 10 days.
The single-dose nature of this regimen guarantees
patient compliance as well as doses high enough
to eliminate the infection before permanent
scarring and infertility can result.
Given the increasing virulence of antibioticresistant N. gonorrhea, all sexually active patients
should be advised to follow safer-sex procedures,
including the use of barriers such as condoms, to
prevent the transmission of pathogens.
Viral resistance
Through the use of three- and four-drug
combinations for HIV, the course of the disease
has changed over the past few years for many
people. The inception of these new therapeutic
approaches has also created further challenges for
the clinician.
Of concern is viral resistance to the currently
available drugs and how it may affect future
treatment options for HIV patients using drug
combinations. This may become a major concern
for all those afflicted with HIV, but especially
those who were previously prescribed monoPage 17
therapy or double-nucleoside therapy, as well
as those failing regimens that included protease
inhibitors.
The HIV virus is one that replicates at a very high
rate and produces mutations at a rate of one new
mutation for each replication cycle. A mutation
is just a change in the proteins or the amino acids
that form the genetic materials of the virus. What
does this mean?
The type of virus the patient has will mutate
regardless of whether the patient is taking
medications.
Triple and quadruple combinations may reduce
viral replication to very low levels. At present, it
is not known how high the drug levels must be to
keep the mutations at the lowest possible level.
The more mutations the virus develops, the more
chances it has to produce ones that are resistant
to medications. Obedience to the medication
schedule prescribed is the basis for successful
antiviral therapy. Taking the medication as
prescribed will prevent the peaks of viral
replication between doses, which, in turn, will
lead to the prevention of mutant virus that can
overcome the antiviral action of the drug.
Drug resistance and treatment options
Substantial and sustained viral increase during
combination therapy is mostly the result of drug
resistance, but substantial and sustained are not
clearly defined. A variation of the viral load from
the lower level achieved by 0.5 log (an increase
from ~ 32,000 to ~ 100,000 organisms/gm) is
considered a biological variation of the virus and
does not always mean the appearance of viral
resistance. If the viral load increases by this
factor, it is important not to stop the treatment
but to repeat the test within two weeks to verify
whether the increase was due to the appearance to
resistant virus.
If the increase of viral load is higher than 0.5
log, federal guidelines suggest changing the
combination to a new set of drugs not previously
used. This is easier said than done because
in many cases, the person has used a variety
of medications before, and the virus may be
resistant to one or all drugs that were used
previously. Even though we now have several
approved antiviral drugs and the number of
combinations is high, in practice, the options are
limited because of drug interactions, previous
treatment and side effects.
Antiviral drug resistance occurs because of a
decrease in the susceptibility of the drug in a
laboratory culture (a phenotype), change in the
genetic makeup (genotype), and evolutionary
changes over time (virus replicating over time).
The specific cause of antiviral drug resistance can
be tested in the laboratory.
At this time, the most prevalent antiviral
resistance noted in the U.S. occurs with the
following:
Influenzae. According to the CDC (2008),
amantadine and rimantadine were NOT
recommended for use in the United States
during the 2008-09 influenza season because
many influenza viruses are resistant to these
drugs.
HIV. The primary reasons HIV
treatment fails are poor drug compliance,
pharmacological factors and drug resistance,
but in many cases, failure occurs with
resistant virus [46]. It is estimated that some
HIV patients may be prescribed up to 30
tablets a day. Because of the significant
prevalence of HIV-antiviral drug resistance,
the National Institute of Health (NIH) (2007)
recommends the following guidelines [30]:
ŠŠ HIV drug-resistance testing is
recommended for persons with HIV
infection when they enter into care,
regardless of whether therapy will be
initiated immediately. If therapy is
deferred, repeat testing at the time of
anti-retroviral therapy initiation should be
considered.
ŠŠ A genotypic assay is generally preferred
for anti-retroviral-naïve persons.
ŠŠ HIV drug-resistance testing should be
performed to help select active drugs
when changing anti-retroviral regimens
in cases of virologic failure.
ŠŠ Drug-resistance testing should also be
performed when managing suboptimal
viral load reduction.
ŠŠ Drug-resistance testing in the setting of
virologic failure should be performed
while the patient is taking his or her
anti-retroviral drugs, or immediately (i.e.,
within four weeks) after discontinuing
therapy.
ŠŠ Genotypic-resistance testing is
recommended for all pregnant women
before initiation of therapy and for those
entering pregnancy with detectable HIV
RNA levels while on therapy.
ŠŠ Drug-resistance testing is not advised
for persons with HIV RNA less than
1,000 copies/ per milliliter (ml) because
amplification of the virus is unreliable.
Herpes virus. More than 45 million people
nationwide have been infected by the genital
herpes virus. The typical treatment for genital
herpes includes drugs such as acyclovir,
valaciclovir and famciclovir, which are
widely used to treat infections with herpes
simplex and varicella zoster. Researchers
have noted drug resistance with acyclovir
(5 to 10 percent), especially among patients
with other immunocompromised disorders,
such as AIDS, and recipients of bone marrow
transplant].
Hepatitis virus. Although there are more
than five types of hepatitis, researchers say
hepatitis B has superseded as the one with
the most antiviral drug resistance. Drug
resistance to lamivudine and famciclovir
showed staggering increases over one year,
10 to 20 percent in patients with chronic
hepatitis B [11]. It is speculated that the
resistance occurs much like HIV because the
viral polymerase catalytic site targeted by the
drug is homologous between the two viruses.
Antibiotic use in agriculture
Another source of concern in the area of
antibiotic resistance is the routine use of lowdose antibiotics in animal feed with the goal of
increasing the animal’s weight and, therefore,
the available amount of meat, or in the case of
chickens, their eggs. They are also used to treat
disease and lower the mortality rate in animals
produced for meat and eggs.
The process by which resistant bacteria pass
from animal to human is fairly straightforward.
The animal is fed antibiotics, which in turn,
create resistance in some bacteria. These bacteria
find their way to the animal’s feces, which are
handled by humans. The bacteria are then spread
through person-to-person and person-to-surfaceto-person contact, where they colonize. Most
healthy people have few, if any, issues with these
bacteria, but some humans are more vulnerable to
these bacteria, such as children, the elderly, and
immunocompromised patients, and consequently
face severe illness or death.
Occasionally, a strain of so-called “superbugs”
emerges, such as methicillin-resistant
Staphylococcus aureus CC398, which has been
traced back to swine.10 There is a very real
concern that more resistant bacteria will develop
if the use of antibiotics continues. That said,
the Food and Drug Administration is moving
toward a program of judicious use of antibiotics
in animals and is working toward requiring
that antibiotic use be supervised by a licensed
veterinarian and be for the health of the animal,
not to increase weight for production.11
New guidelines aside, the underlying debate
is complex. On the one hand, antibiotics are
necessary to protect the health of animals raised
for food as well as to maintain the overall
economic viability of large-scale meat production
and keep meat and eggs affordable for the
consumer. On the other hand, the increase in
antibiotic-resistant pathogens is a significant
concern as well. Clearly, stakeholders must find
some middle ground.
Isolation and precautions
As pharmacists move more into the area of
direct patient care, they should be aware of the
various precautions in place to protect them from
antibiotic-resistant disease, as well as to slow
or stop the spread of these pathogens into the
hospital or community setting.
Standard precautions
These synthesize the major features of universal
precautions (UP) that are designed to reduce the
risk of transmission of blood-borne pathogens
and body substance isolation (BSI), which are
those precautions in place to reduce transmission
of pathogens from moist body substances.
Standard precautions apply to:
Blood.
All body fluids, secretions, and excretions
except sweat, regardless of whether they
contain visible blood.
Non-intact skin.
Mucous membranes.
Page 18
Elite
The following are recommendations for standard
precautions. Although many of them are geared
more for patients and pharmacists in the hospital
setting, some are appropriate in the outpatient or
retail setting as well.
Hand-washing.
Wash hands after touching blood, body fluids,
secretions, excretions and contaminated
items, regardless of whether gloves are
worn. Wash hands immediately after gloves
are removed, between patient contacts, and
when otherwise indicated to avoid transfer
of microorganisms to other patients or
environments.
Gloves.
Wear gloves (e.g., nonsterile exam gloves)
when touching blood, body fluids, secretions,
excretions, and contaminated items. Put on
clean gloves just before touching mucous
membranes and nonintact skin. Change
gloves between tasks and procedures on
the same patient after contact with material
that may contain a high concentration of
microorganisms. Remove gloves promptly
after use before touching noncontaminated
items and environmental surfaces and
before going to another patient, and wash
hands immediately to avoid transfer to other
patients or environments.
Mask, eye protection, face shield.
Wear a mask and eye protection or a face
shield to protect mucous membranes of the
nose, eyes, and mouth during procedures
and patient care activities that are likely to
generate splashes or sprays of blood or other
body fluids.
Gown.
Wear a non-permeable gown to protect skin
and to prevent soiling of clothing. Select a
gown that is appropriate for the activity and
amount of fluid likely to be encountered.
Remove a soiled gown as promptly as
possible and wash hands to avoid transfer
of microorganisms to other patients or
environments.
Patient care equipment.
Handle used patient care equipment soiled
with blood and body fluids in a manner
that prevents skin and mucous membrane
exposure, contamination of clothing, and
transfer of microorganisms to other patients
and environment. Ensure that reusable
equipment is not used for the care of
another patient until it has been cleaned and
reprocessed appropriately. Ensure that singleuse items are discarded properly.
Environmental control.
Ensure that the facility has adequate
procedures for routine care, cleaning, and
disinfection of environmental surfaces,
such as counters, drug-preparation areas,
refrigerators, and other frequently-touched
surfaces, and that these procedures are being
followed.
Occupational health and blood-borne
pathogens.
Take care to prevent injuries when using
needles and other sharp instruments or
devices, especially when handling them after
procedures; when cleaning used instruments;
and when disposing of used sharps. Never
recap used needles or otherwise manipulate
them using both hands or use any other
technique that involves directing the point
of the needle toward any part of the body;
instead, use either a one-handed “scoop”
technique or a mechanical device designed
for holding the needle sheath. Do not remove
used needles from disposable syringes by
hand, and do not bend, break or manipulate
used needles by hand. Place used disposable
needles and other sharps in a punctureresistant container placed as close as possible
to the work area, and place reusable syringes
and needles in a puncture-resistant container
for transport to the reprocessing area. Use
mouthpieces, resuscitation bags, or other
ventilation devices as an alternative to
mouth-to-mouth resuscitation.
Transmission-based precautions
These are designed for patients documented or
suspected to be infected with highly transmissible
or epidemiologically important pathogens
for which additional precautions beyond
standard precautions are needed to interrupt
transmission in hospitals. There are three types
of transmission-based precautions that may be
combined for diseases that have multiple routes
of transmission. Whether they are used separately
or in combination, they are to be used in addition
to standard precautions.
Airborne precautions
Airborne precautions are designed to reduce the
risk of airborne transmission of infectious agents.
Airborne transmission occurs by dissemination
of either airborne droplets or dust particles
containing the infectious agent. Microorganisms
can be dispersed widely by air currents and may
become inhaled or deposited on a susceptible host
within the same room or a longer distance from
the source patient, depending on environmental
factors. Therefore, special air handling and
ventilation are required to prevent airborne
transmission.
Pharmacists who must enter the room of a
patient under airborne precautions should wear
respiratory protection if the patient has known
or suspected infectious pulmonary tuberculosis.
They should also receive regular booster
immunizations against other airborne diseases,
such as varicella, rubeola (measles), and rubella,
to avoid contracting these diseases.
Droplet precautions
Transmission via these large-particle droplets
requires close contact between source and
recipient because the weight of the droplets is
heavy enough that they can only travel distances
of a few feet before falling. For this reason,
special ventilation and air handling are usually
not needed. However, it may be advisable to wear
a mask and gloves if it is necessary to be in close
proximity to the patient.
Contact precautions
Unlike transmission-based precautions, which
are designed to prevent the spread of pathogens
through the air, contact precautions are intended
to prevent transmission through direct or indirect
contact. Direct contact occurs when an infected
or susceptible person touches the skin of another
person, such as when shaking hands. Indirect
contact occurs when an infected or susceptible
person touches a surface, such as a kitchen or
bathroom fixture, which another person then
touches.
The principle precautions to be followed to avoid
direct and indirect contact are:
Wear gloves and follow proper hand-washing
protocol, and use alcohol-based hand
sanitizer as appropriate, i.e., if the hands are
not visibly soiled.
Wear a non-permeable gown if there is a risk
of clothing having contact with the patient,
environmental conditions, or if the patient
is incontinent, has diarrhea, an ostomy, or
an undressed wound. The gown should be
removed before leaving the patient’s room.
Make sure that surfaces, such as pharmacy
med carts, are kept clean.
Environmental precautions within the
pharmacy
Given that many pharmacists spend most of their
workday within the pharmacy itself, it is critical
that special attention be given to that area.
The pharmacy area should be surveyed
regularly to ensure that it is easy to clean
and to determine whether there are any
improvements that can be made.
All surfaces, such as counters, should be kept
clean. Spills should be wiped up as soon as
possible to avoid attracting pests.
Food should not be kept in refrigerators
reserved for drug storage, and food should
not be consumed within medication
preparation areas.12
Pharmacists who are ill should practice
good hand hygiene by washing frequently
and using hand sanitizer when appropriate.
Furthermore, sneezes should be directed into
the crook of the elbow and tissues should be
discarded after one use. Finally, pharmacists
who are ill should avoid working in areas
where they are likely to spread pathogens,
such as sterile compounding rooms. It is also
advisable to stay current on immunizations
and to get a flu shot every year.
These are designed to reduce the risk of droplet
transmission of infectious agents. Droplet
transmission involves contact of the conjunctivae
or the mucous membranes of the nose and
mouth of a susceptible person with large-particle
droplets (larger than 5 μm in size) containing
microorganisms. These droplets are generated
The role of pharmacists in the prevention
from a source person primarily during coughing,
of antibiotic resistance
sneezing, or talking and during certain procedures As the subject matter expert in the area of drugs
such as suctioning or bronchoscopy.
Elite
Page 19
and pharmacological treatment, pharmacists have
a considerable role in the prevention of antibiotic
resistance.
First and foremost, however, pharmacists must
educate themselves about antibiotics and their
appropriate use. Two especially remarkable
resources available are:
The Sanford Guide, which is the goldstandard reference for antimicrobial therapy
in infectious disease. It is available both
in book form, as a mobile app, and online.
(http://www.sanfordguide.com/index.html)
Dr. Mark Crislip, an infectious disease
specialist, has a number of resources about
infectious disease available, including a
daily podcast featuring a notable case, a
semi-monthly review podcast of pertinent
ID literature, and a reference guide that is
available both online and as a mobile app.
(http://pusware.com/testpus/Table_of_
Contents.html)
Education
Pharmacists can help prevent the development
of drug-resistant microorganisms by explaining
antibiotic misuse to physicians, pharmacists,
and patients in the hospital, outpatient, and retail
settings. When involved in the provision of
prescriptions for antibiotics, pharmacists should:
Provide both the generic and trade name of
the drug.
Explain the purpose of the medication.
Explain the dosage.
Give the pertinent instructions in clear
language. This information should include:
ŠŠ The dosing schedule (how often and
when).
ŠŠ Whether it can be taken with food or on
an empty stomach.
ŠŠ Any drug/drug or drug/food interactions.
Emphasize that the prescription must be
finished, even after the patient feels better,
and that medication should not be reserved
“just in case.”
In addition, pharmacists need to do the following
when caring for a patient who has been
prescribed antimicrobial therapy:
Carefully monitor antibiotic therapy,
checking the peak and trough levels, and
reviewing the data and recommendations
based on the cultures.
Encourage the use of appropriate antibiotics
until culture results are available.
Always check the culture results before
antibiotics are started and make suitable
recommendations to prescribers based on
cultures and other lab results.
Advocate for restrictions on the empirical use
of certain antibiotics, such as vancomycin,
for preoperative prophylaxis to ensure that it
remains effective against resistant organisms.
Finally, pharmacists should assume the role of
subject matter experts in the use of antimicrobial
drugs. To this end, they should:
Make recommendations for inclusion and
exclusion to the formulary based on evidence
and data.
Monitor adherence to medical staff guidelines
for antibiotic use.
Advocate for restrictions on the empirical use
of certain antibiotics, such as vancomycin,
for preoperative prophylaxis to ensure that it
remains effective against resistant organisms.
Become an active participant on the infection
control team.
Research has demonstrated that although there
are stringent guidelines in place to prevent the
spread of microorganisms, the phenomenon
is still occurring. Therefore, it is important to
realize that each one of us can make a difference
at all levels. If in doubt, ask the infection control
team at the hospital. Never hesitate, as it is
imperative that pharmacists diligently work
together with all members of the health care team
to prevent the spread of microorganisms that can
further exacerbate the resistance to antimicrobial
therapy.
References
1.“Antibiotic Resistance Questions & Answers”. Get Smart: Know When Antibiotics
Work. Centers for Disease Control and Prevention, USA. 30. Retrieved 20 March 2013.
2.a b USA (2013-01-30). “Does Mycobacterium tuberculosis have plasmids? [Tubercle.
1990] - PubMed — NCBI”. Ncbi.nlm.nih.gov. Retrieved 2013-03-12.
3.“A Balancing Act: Efflux/Influx in Mycobacterial Drug Resistance”. Aac.asm.org.
2009-05-18. Retrieved 2013-03-12.
4.D’Costa et al. 2011, pp. 457–461.
5.Donadio et al. 2010, pp. 423–430.
6.Caldwell & Lindberg 2011.
7.Nelson 2009, p. 294.
8.Hawkey & Jones 2009, pp. i3-i10.
9.WHO (January 2002). “Use of antimicrobials outside human medicine and resultant
antimicrobial resistance in humans”. World Health Organization. Archived from the
original on 13 May 2004.
10. Ferber, Dan (4 January 2002). “Livestock Feed Ban Preserves Drugs’ Power”.
Science 295 (5552): 27–28. doi:10.1126/science.295.5552.27a. PMID 11778017.
11. a b Mathew, AG; Cissell, R; Liamthong, S (2007). “Antibiotic resistance in bacteria
associated with food animals: a United States perspective of livestock production”.
Foodborne Pathog. Dis. 4 (2): 115–33. doi:10.1089/fpd.2006.0066. PMID 17600481.
12. CDC. “Antibiotic Resistance Questions & Answers” [Are antibacterial-containing
products (soaps, household cleaners, etc.) better for preventing the spread of infection?
Does their use add to the problem of resistance?]. Atlanta, Georgia, USA.: Centers
for Disease Control and Prevention. Archived from the original on 8 November 2009.
Retrieved November 17, 2009.
13. Larsson, DG.; Fick, J. (Jan 2009). “Transparency throughout the production chain -a way to reduce pollution from the manufacturing of pharmaceuticals?”. Regul Toxicol
Pharmacol 53 (3): 161–3. doi:10.1016/j.yrtph.2009.01.008. PMID 19545507.
14. Tacconelli, E; De Angelis, G; Cataldo, MA; Pozzi, E; Cauda, R (January 2008).
“Does antibiotic exposure increase the risk of methicillin-resistant Staphylococcus
aureus (MRSA) isolation? A systematic review and meta-analysis”. J. Antimicrob.
Chemother. 61 (1): 26–38. doi:10.1093/jac/dkm416. PMID 17986491.
15. Muto, CA.; Jernigan, JA.; Ostrowsky, BE.; Richet, HM.; Jarvis, WR.; Boyce, JM.;
Farr, BM. (May 2003). “SHEA guideline for preventing nosocomial transmission of
multidrug-resistant strains of Staphylococcus aureus and enterococcus”. Infect Control
Hosp Epidemiol 24 (5): 362–86. doi:10.1086/502213. PMID 12785411.
16. Vonberg, Dr Ralf-Peter. “Clostridium difficile: a challenge for hospitals”. European
Center for Disease Prevention and Control. Institute for Medical Microbiology and
Hospital Epidemiology: IHE. Archived from the original on 11 June 2009. Retrieved
27 July 2009.
17. Kuijper, EJ; van Dissel, J.; Wilcox, MH (Aug 2007). “Clostridium difficile: changing
epidemiology and new treatment options”. Curr Opin Infect Dis 20 (4): 376–83.
doi:10.1097/QCO.0b013e32818be71d. PMID 17609596.
18. editors, Ronald Eccles, Olaf Weber, (2009). Common cold (Online-Ausg. ed.). Basel:
Birkhäuser. p. 240. ISBN 978-3-7643-9894-1.
19. a b c Wright, GD (2010 Oct). “Antibiotic resistance in the environment: a link
to the clinic?”. Current opinion in microbiology 13 (5): 589–94. doi:10.1016/j.
mib.2010.08.005. PMID 20850375.
20. “Mutations are random”. University of California. Retrieved Aug 14, 2011.
21. Richard William Nelson. Darwin, Then and Now: The Most Amazing Story in the
History of Science, iUniverse, 2009, p. 294
22. Wayne W. Umbreit, Advances in Applied Microbiology, vol. 11, Academic Press,
1970, p. 80
23. M. R. Pollock. “Origin and Function of Penicillinase: a Problem in Biochemical
Evolution”,British Medical Journal, 14 Oct 1967, p. 76
24. a b New Scientist, Jun 8, 1972, p. 546
25. a b New Scientist, Feb 11, 1989, p. 34
26. Pollock, p. 77
27. Abigail A. Salyers, Dixie D. Whitt. Revenge of the microbes: how bacterial
resistance is undermining the antibiotic miracle, ASM Press, 2005, p. 34
28. Pechère, JC (September 2001). “Patients’ interviews and misuse of antibiotics”. Clin.
Infect. Dis. 33 Suppl 3: S170–3. doi:10.1086/321844. PMID 11524715.
29. Costelloe, Ceire; Metcalfe, Chris; Lovering, Andrew; Mant, David; Hay, Alastair
D (May 18 2010). “Effect of antibiotic prescribing in primary care on antimicrobial
resistance in individual patients: systematic review and meta-analysis”. BMJ (BMJ)
340: c2096. doi:10.1136/bmj.c2096. Retrieved 2011-11-03.
30. Arnold, SR; Straus, SE (2005). “Interventions to improve antibiotic prescribing
practices in ambulatory care”. In Arnold, Sandra R. Cochrane Database Syst Rev (4):
CD003539. doi:10.1002/14651858.CD003539.pub2. PMID 16235325.
31. McNulty, CA; Boyle, P; Nichols, T; Clappison, P; Davey, P (August 2007). “The
public’s attitudes to and compliance with antibiotics”. J. Antimicrob. Chemother. 60
Suppl 1: i63–8. doi:10.1093/jac/dkm161. PMID 17656386.
32. editors, Ronald Eccles, Olaf Weber, (2009). Common cold (Online-Ausg. ed.). Basel:
Birkhäuser. p. 234. ISBN 978-3-7643-9894-1.
33. Li, JZ; Winston, LG; Moore, DH; Bent, S (September 2007). “Efficacy of shortcourse antibiotic regimens for community-acquired pneumonia: a meta-analysis”. Am.
J. Med. 120 (9): 783–90. doi:10.1016/j.amjmed.2007.04.023. PMID 17765048.
34. Bignardi, G.E. (31 August 1998). “Risk factors for Clostridium difficile infection”.
Journal of Hospital Infection 40 (1): 1–15. doi:10.1016/S0195-6701(98)90019-6.
PMID 9777516. Retrieved 6 November 2012.
35. Runyon, BA; McHutchison, JG; Antillon, MR; Akriviadis, EA; Montano, AA (1991
Jun). “Short-course versus long-course antibiotic treatment of spontaneous bacterial
peritonitis. A randomized controlled study of 100 patients”. Gastroenterology 100 (6):
1737–42. PMID 2019378.
36. Singh, Nina; PAUL ROGERS, CHARLES W. ATWOOD, MARILYN M.
WAGENER and VICTOR L. YU (1). “Short-course Empiric Antibiotic Therapy for
Patients with Pulmonary Infiltrates in the Intensive Care Unit A Proposed Solution
for Indiscriminate Antibiotic Prescription”. Am. J. Respir. Crit. Care Med. 162 (2):
505–511. PMID 10934078.
37. Gleisner, Ana L.M; Argenta, Rodrigo; Pimentel, Marcelo; Simon, Tatiana K;
Jungblut, Carlos F; Petteffi, Leonardo; de Souza, Rafael M; Sauerssig, Mauricio; Kruel,
Cleber D.P; Machado, Adão R.L (30 April 2004). “Infective complications according to
duration of antibiotic treatment in acute abdomen”. International Journal of Infectious
Diseases 8 (3): 155–162. doi:10.1016/j.ijid.2003.06.003. PMID 15109590.
38. PICHICHERO, MICHAEL E.; COHEN, ROBERT (July 1997). “Shortened course
of antibiotic therapy for acute otitis media, sinusitis and tonsillopharyngitis.[Review]”.
Pediatric Infectious Disease Journal 16 (7): 680–695. doi:10.1097/00006454199707000-00011. PMID 9239773.[dead link]
39. Dellinger, E. P.; Wertz, M. J.; Lennard, E. S.; Oreskovich, M. R. (1 January 1986).
“Efficacy of Short-Course Antibiotic Prophylaxis After Penetrating Intestinal Injury:
A Prospective Randomized Trial”. Archives of Surgery 121 (1): 23–30. doi:10.1001/
archsurg.1986.01400010029002. PMID 3942496.
40. Perez-Gorricho, B; Ripoll, M (1 March 2003). “Does short-course antibiotic therapy
better meet patient expectations?”. International Journal of Antimicrobial Agents 21
(3): 222–228. doi:10.1016/S0924-8579(02)00360-6. PMID 12636982.
41. Keren, R.; Chan, E. (1 May 2002). “A Meta-analysis of Randomized, Controlled
Trials Comparing Short- and Long-Course Antibiotic Therapy for Urinary Tract
Infections in Children”. Pediatrics 109 (5): e70–e70. doi:10.1542/peds.109.5.e70.
PMID 11986476.
42. Casey, Janet R.; Pichichero, Michael E (October 2005). Metaanalysis of Short
Course Antibiotic Treatment for Group A Streptococcal Tonsillopharyngitis 24 (10).
pp. 909–917.
43. McCormack, J; Allan, GM (2012 Feb 2). “A prescription for improving antibiotic
prescribing in primary care”. BMJ (Clinical research ed.) 344: d7955. doi:10.1136/bmj.
d7955. PMID 22302779.
44. “Should you stop an antibiotic course early?” (PDF). Retrieved 2013-03-12.
45. Marc Bonten, MD; Eijkman-Winkler Institute for Medical Microbiology, Infectious
Diseases, and Inflammation; Utrecht, the Netherlands. | http://hicsigwiki.asid.net.au/
images/4/41/Should_you_stop_an_antibiotic_course_early_if_you_feel_better_R._
Everts.pdf
46. Pechère, JC; Hughes, D; Kardas, P; Cornaglia, G (March 2007). “Non-compliance
with antibiotic therapy for acute community infections: a global survey”. Int. J.
Antimicrob. Agents 29 (3): 245–53. doi:10.1016/j.ijantimicag.2006.09.026. PMID
17229552.
47. Kardas, P (March 2007). “Comparison of patient compliance with once-daily and
twice-daily antibiotic regimens in respiratory tract infections: results of a randomized
trial”. J. Antimicrob. Chemother. 59 (3): 531–6. doi:10.1093/jac/dkl528. PMID
17289766.
48. Thomas, JK; Forrest, A; Bhavnani, SM; Hyatt, JM; Cheng, A; Ballow, CH;
Schentag, JJ (March 1998). “Pharmacodynamic Evaluation of Factors Associated
with the Development of Bacterial Resistance in Acutely Ill Patients during Therapy”.
Antimicrob. Agents Chemother. 42 (3): 521–7. PMC 105492. PMID 9517926.
49. Girou, E; Legrand, P; Soing-Altrach, S; Lemire, Astrid; Poulain, Celine;
Allaire, Alexandra; TkoubScheirlinck, Latifa; Chai, Steeve Ho Tam et al. (October
2006). “Association between hand hygiene compliance and methicillin-resistant
Staphylococcus aureus prevalence in a French rehabilitation hospital”. Infect Control
Hosp Epidemiol 27 (10): 1128–30. doi:10.1086/507967. PMID 17006822.
50. Swoboda, SM; Earsing, K; Strauss, K; Lane, S; Lipsett, PA (February 2004).
“Electronic monitoring and voice prompts improve hand hygiene and decrease
nosocomial infections in an intermediate care unit”. Crit. Care Med. 32 (2): 358–63.
doi:10.1097/01.CCM.0000108866.48795.0F. PMID 14758148.
51. Farmer, Paul E., Bruce Nizeye, Sara Stulac, and Salmaan Keshavjee. 2006. Structural
Violence and Clinical Medicine. PLoS Medicine, 1686-1691.
52. Hersom, Matt. “Application of Ionophores in Cattle Diets”. AN285 Department of
Animal Sciences. University of Florida IFAS Extension. Retrieved 14 March 2013.
53. American Veterinary Association. “MRSA: Methicillin-Resistant Staphylococcus
Aureus and Animals (FAQ)”. Retrieved 14 March 2013.
54. http://www.efsa.europa.eu/EFSA/Report/biohaz_report_301_joint_mrsa_en,0.pdf
55. Schneider, K; Garrett, L (June 19, 2009). “Non-therapeutic Use of Antibiotics in
Animal Agriculture, Corresponding Resistance Rates, and What Can be Done About
It”. Center for Global Development.
56. Castanon, J.I. (2007). “History of the use of antibiotic as growth promoters in
European poultry feeds”. Poult. Sci. 86 (11): 2466–71. doi:10.3382/ps.2007-00249.
PMID 17954599.
57. Bengtsson, B.; Wierup, M. (2006). “Antimicrobial resistance in Scandinavia
after ban of antimicrobial growth promoters”. Anim. Biotechnol. 17 (2): 147–56.
doi:10.1080/10495390600956920. PMID 17127526.
58. Sapkota, AR; Lefferts, LY; McKenzie, S; Walker, P (May 2007). “What Do We Feed
to Food-Production Animals? A Review of Animal Feed Ingredients and Their Potential
Impacts on Human Health”. Environ. Health Perspect. 115 (5): 663–70. doi:10.1289/
ehp.9760. PMC 1867957. PMID 17520050.
59. Baker, R (2006). “Health management with reduced antibiotic use — the U.S.
experience”. Anim. Biotechnol. 17 (2): 195–205. doi:10.1080/10495390600962274.
PMID 17127530.
60. “Executive summary from the UCS report “Hogging It: Estimates of Antimicrobial
Abuse in Livestock””. Union of Concerned Scientists. January 2001.
61. Nelson, JM.; Chiller, TM.; Powers, JH.; Angulo, FJ. (Apr 2007). “Fluoroquinoloneresistant Campylobacter species and the withdrawal of fluoroquinolones from use
in poultry: a public health success story” (PDF). Clin Infect Dis 44 (7): 977–80.
doi:10.1086/512369. PMID 17342653.
62. “US Senate Bill S. 549: Preservation of Antibiotics for Medical Treatment Act of
2007”.
63. US House Bill H.R. 962: “Preservation of Antibiotics for Medical Treatment Act
of 2007”.
64. John Gever (March 23, 2012). “FDA Told to Move on Antibiotic Use in Livestock”.
MedPage Today. Retrieved March 24, 2012.
65. Gardiner Harris (April 11, 2012). “U.S. Tightens Rules on Antibiotics Use for
Livestock”. The New York Times. Retrieved April 12, 2012.
66. “FDA’s Strategy on Antimicrobial Resistance — Questions and Answers”. U.S.
Food and Drug Administration. April 11, 2012. Retrieved April 12, 2012. ““Judicious
use” is using an antimicrobial drug appropriately and only when necessary; Based
on a thorough review of the available scientific information, FDA recommends that
use of medically important antimicrobial drugs in food-producing animals be limited
to situations where the use of these drugs is necessary for ensuring animal health,
and their use includes veterinary oversight or consultation. FDA believes that using
medically important antimicrobial drugs to increase production in food-producing
animals is not a judicious use.”
67. Martinez, J. L., & Olivares, J. (2012). Envrironmental Pollution By Antibiotic
Resistance Genes. In P. L. Keen, & M. H. Montforts, Antimicrobial Resistance in the
Environment (pp. 151- 171). Hoboken, N.J.: John Wiley & Sons.
68. Martinez, J. L., & Olivares, J. (2012). Envrironmental Pollution By Antibiotic
Resistance Genes. In P. L. Keen, & M. H. Montforts, Antimicrobial Resistance in the
Environment (pp. 151- 171). Hoboken, N.J.: John Wiley & Sons.
69. Pruden, A., & Arabi, M. (2012). Quantifying Anthropogenic Impacts on
Environmental Reservoirs of Antibiotic Resistance. In P. L. Keen, & M. H. Montforts,
Antimicrobial Resistance in the Environment (pp. 173-202). Hoboken, N.J.: John
Wiley & Sons.
70. Ochiai, K.; Yamanaka, T; Kimura, K; Sawada, O (1959). “Inheritance of drug
resistance (and its transfer) between Shigella strains and Between Shigella and E.coli
strains”. Hihon Iji Shimpor, (in Japanese) 34: 1861.
71. Li, X; Nikadio, H (2009). “Efflux-Mediated Drug Resistance in Bacteria: an
Update”. Drug 69 (12): 1555–623. doi:10.2165/11317030-000000000-00000. PMC
2847397. PMID 19678712.
72. Morita, Y; Kodama, K; Shiota, S; Mine, T; Kataoka, A; Mizushima, T; Tsuchiya, T
(July 1998). “NorM, a Putative Multidrug Efflux Protein, of Vibrio parahaemolyticus
and Its Homolog in Escherichia coli”. Antimicrob. Agents Chemother. 42 (7): 1778–82.
PMC 105682. PMID 9661020.
Page 20
Elite
73. Robicsek, A; Jacoby, GA; Hooper, DC (October 2006). “The worldwide emergence
of plasmid-mediated quinolone resistance”. Lancet Infect Dis 6 (10): 629–40.
doi:10.1016/S1473-3099(06)70599-0. PMID 17008172.
74. Cirz, RT; Chin, JK; Andes, DR; de Crécy-Lagard, V; Craig, WA; Romesberg,
FE (2005). “Inhibition of Mutation and Combating the Evolution of Antibiotic
Resistance”. PLoS Biol. 3 (6): e176. doi:10.1371/journal.pbio.0030176. PMC 1088971.
PMID 15869329.
75. Chan, CX; Beiko, RG; Ragan, MA (August 2011). “Lateral Transfer of Genes and
Gene Fragments in Staphylococcus Extends beyond Mobile Elements”. J Bacteriol 193
(15): 3964–3977. doi:10.1128/JB.01524-10. PMC 3147504. PMID 21622749.
76. CDC: Get Smart: Know When Antibiotics Work
77. APUA: General Background: Antibiotic Resistance, A Societal Problem
78. Bozdogan, B. Ü.; Esel, D.; Whitener, C.; Browne, F. A.; Appelbaum, P. C. (2003).
“Antibacterial susceptibility of a vancomycin-resistant Staphylococcus aureus strain
isolated at the Hershey Medical Center”. Journal of Antimicrobial Chemotherapy 52
(5): 864–868. doi:10.1093/jac/dkg457. PMID 14563898.edit
79. Xie et al; Pierce, Joshua G.; James, Robert C.; Okano, Akinori; Boger, Dale L.
(2011). “A Redesigned Vancomycin Engineered for Dual d-Ala-d-Ala and d-Ala-dLac Binding Exhibits Potent Antimicrobial Activity Against Vancomycin-Resistant
Bacteria”. J. Am. Chem. Soc. 133, 133 (35): 13946–9. doi:10.1021/ja207142h. PMC
3164945. PMID 21823662.
80. Boyle-Vavra, S; Daum, RS (2007). “Community-acquired methicillin-resistant
Staphylococcus aureus: the role of Panton-Valentine leukocidin”. Lab. Invest. 87 (1):
3–9. doi:10.1038/labinvest.3700501. PMID 17146447.
81. Maree, CL; Daum, RS; Boyle-Vavra, S; Matayoshi, K; Miller, LG (2007).
“Community-associated Methicillin-resistant Staphylococcus aureus Isolates and
Healthcare-Associated Infections”. Emerging Infect. Dis. 13 (2): 236–42. doi:10.3201/
eid1302.060781. PMC 2725868. PMID 17479885.
82. CDCP (2005-10-11). “Group A Streptococcal (GAS) Disease (strep throat,
necrotizing fasciitis, impetigo) -- Frequently Asked Questions”. Centers for Disease
Control and Prevention. Archived from the original on 19 December 2007. Retrieved
2007-12-11.
83. a b Albrich, W; Monnet, DL; Harbarth, S (2004). “Antibiotic selection pressure
and resistance in Streptococcus pneumoniae and Streptococcus pyogenes”. Emerging
Infect. Dis. 10 (3): 514–7. doi:10.3201/eid1003.030252. PMC 3322805. PMID
15109426.
84. Hidron, AI; Edwards, JR; Patel, J; Horan, Teresa C.; Sievert, Dawn M.; Pollock,
Daniel A.; Fridkin, Scott K.; National Healthcare Safety Network Team et al.
(November 2008). “NHSN annual update: antimicrobial-resistant pathogens associated
with healthcare-associated infections: annual summary of data reported to the National
Healthcare Safety Network at the Centers for Disease Control and Prevention, 20062007”. Infect Control Hosp Epidemiol 29 (11): 996–1011. doi:10.1086/591861. PMID
18947320.
85. Poole,, K. (2004). “Efflux-mediated multiresistance in Gram-negative
bacteria”. Clinical Microbiology and Infection 10 (1): 12–26. doi:10.1111/j.14690691.2004.00763.x. PMID 14706082.
86. “Active Starvation Responses Mediate Antibiotic Tolerance in Biofilms and NutrientLimited Bacteria”. Sciencemag.org. Retrieved 2013-03-12.
87. Gerding, D.N.; Johnson, S.; Peterson, L.R.; Mulligan, M.E.; Silva, J. Jr. (1995).
“Clostridium difficile-associated diarrhea and colitis” (PDF). Infect. Control. Hosp.
Epidemiol. 16 (8): 459–477. doi:10.1086/648363. PMID 7594392.
88. McDonald, L (2005). “Clostridium difficile: responding to a new threat from an old
enemy” (PDF). Infect. Control. Hosp. Epidemiol. 26 (8): 672–5. doi:10.1086/502600.
PMID 16156321.
89. ^ Johnson, S.; Samore, M.H.; Farrow, K.A; Killgore, George E.; Tenover, Fred
C.; Lyras, Dena; Rood, Julian I.; Degirolami, Paola et al. (1999). “Epidemics of
diarrhea caused by a clindamycin-resistant strain of Clostridium difficile in four
hospitals”. New England Journal of Medicine 341 (23): 1645–1651. doi:10.1056/
NEJM199911253412203. PMID 10572152.
90. Loo, V; Poirier, L; Miller, M; Oughton, Matthew; Libman, Michael D.; Michaud,
Sophie; Bourgault, Anne-Marie; Nguyen, Tuyen et al. (2005). “A predominantly
clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea
with high morbidity and mortality”. N Engl J Med 353 (23): 2442–9. doi:10.1056/
NEJMoa051639. PMID 16322602.
91. Centers for Disease Control and Prevention (CDC) (2004). “Acinetobacter
baumannii infections among patients at military medical facilities treating injured U.S.
service members, 2002-2004”. MMWR Morb. Mortal. Wkly. Rep. (Centers for Disease
Control and Prevention (CDC)) 53 (45): 1063–6. PMID 15549020.
92. “Medscape abstract on Acinetobacter baumannii: Acinetobacter baumannii: An
Emerging Multidrug-resistant Threat”. “membership only website”
93. a b “Extensively drug-resistant tuberculosis : Current Opinion in Infectious
Diseases”. Journals.lww.com. doi:10.1097/QCO.0b013e3283229fab. Retrieved
2013-03-12.
94. “History of Tuberculosis — Karger Publishers”. Karger.com. 1998-02-20. Retrieved
2013-03-12.
95. “Drug Discovery Today: Disease Mechanisms — Transmission of MDR
tuberculosis”. ScienceDirect.com. 2010-10-06. Retrieved 2013-03-12.
96. McCusker, ME; Harris, AD; Perencevich, E; Roghmann, MC (2003).
“Fluoroquinolone Use and Clostridium difficile–Associated Diarrhea”. Emerging
Infect. Dis. 9 (6): 730–3. doi:10.3201/eid0906.020385. PMC 3000134. PMID
12781017.
97. Frost, F; Craun, GF; Calderon, RL (1998). “Increasing hospitalization and death
possibly due to Clostridium difficile diarrheal disease”. Emerging Infect. Dis. 4 (4):
619–25. doi:10.3201/eid0404.980412. PMC 2640242. PMID 9866738.
98. Keen, E. C. (2012). “Phage Therapy: Concept to Cure”. Frontiers in Microbiology 3.
doi:10.3389/fmicb.2012.00238.
99. Chanishvili, N; Chanishvili, T; Tediashvili, M.; Barrow, P.A. (2001). “Phages and
their application against drug-resistant bacteria”. J. Chem. Technol. Biotechnol. 76 (7):
689–699. doi:10.1002/jctb.438.
100.Jikia, D.; Chkhaidze, N.; Imedashvili, E.; Mgaloblishvili, I.; Tsitlanadze, G.;
Katsarava, R.; Glenn Morris, J.; Sulakvelidze, Alexander (2005). “The use of a novel
biodegradable preparation capable of the sustained release of bacteriophages and
ciprofloxacin, in the complex treatment of multidrug-resistant Staphylococcus aureusinfected local radiation injuries caused by exposure to Sr90”. Clinical & Experimental
Dermatology 30 (1): 23–6. doi:10.1111/j.1365-2230.2004.01600.x. PMID 15663496.
101.Weber-Dabrowska, B; Mulczyk, M; Górski, A (June 2003). “Bacteriophages as an
efficient therapy for antibiotic-resistant septicemia in man”. Transplant. Proc. 35 (4):
1385–6. doi:10.1016/S0041-1345(03)00525-6. PMID 12826166.
102.Mathur, MD; Vidhani, S; Mehndiratta, PL; Bhalla, P; Reddy, B S N (2003).
“Bacteriophage therapy: an alternative to conventional antibiotics”. J Assoc Physicians
India 51 (8): 593–6. doi:10.1258/095646202760159701. PMID 12194741.
103.^ Scientists discover possible antibiotics alternative - Australian Broadcasting
Corporation — Retrieved 29 July 2012.
104.https://www.wp.dh.gov.uk/publications/files/2013/03/CMO-Annual-ReportVolume-2-20111.pdf
105.^ a b Walsh, Fergus. “BBC News — Antibiotics resistance ‘as big a risk as terrorism’
- medical chief”. Bbc.co.uk. Retrieved 2013-03-12.
106.Mukhopadhyay, J.; Das, K.; Ismail, S.; Koppstein, D.; Jang, M.; Hudson, B.;
Sarafianos, S.; Tuske, S.; Patel, J., Jansen, R., Irschik, H., Arnold, E., Ebright, R.H.
(2008). “The RNA polymerase “switch region” is a target for inhibitors”. Cell 135 (2):
295–307. doi:10.1016/j.cell.2008.09.033. PMC 2580802. PMID 18957204.
107.“Modified Bee Peptide Slays Deadly Bacteria | Chemical & Engineering News”.
Cen.acs.org. 2012-05-29. Retrieved 2013-03-12.
108.Ponte-Sucre, A (editor) (2009). ABC Transporters in Microorganisms. Caister
Academic Press. ISBN 978-1-904455-49-3.
ANTIMICROBIAL drug Resistance
Final Examination Questions
Choose the best answer for questions
1 through 10, mark your answer on the final
examination answer sheet found on page 75
or complete your final examination online at
pharmacy.elitecme.com.
8. According to the CDC, which of the
following infections accounts for the most
health care-associated infections?
a. Pneumonia and lung infections.
b. Urinary tract infections.
c. Bloodstream infections.
d. Surgical site infections.
1. Pharmacists must develop guidelines
for best practices based on which of the
following?
a. Evidence and data.
b. Recommendations from drug reps.
c. Requests from patients.
d. All of the above.
9. Herpes simplex and varicella zoster are
treated successfully by all except:
a. Amantadine.
b. Famciclovir.
c. Valaciclovir.
d. None of the above.
2. MDRO is an abbreviation for:
a. Many drug relative organisms.
b. Multidrug-resistant organisms.
c. Marginal daily related ordinals.
d. None of the above.
10.Which of the following is a strain of
“superbugs” that can be traced back to
swine?
a. Streptococcus pyogenes CC456.
b. Staphylococcus aureus CC398.
c. Neisseria gonorrhea DD214.
d. Mycobacterium avium DDD42.
3. Which of the following increases the
chances that a bacterium will become
resistant to antibiotics?
a. Incorrect prescription.
b. Misuse of antibiotics.
c. Incorrect diagnosis.
d. All of the above.
4. Half of all Staphylococcus aureus
infections are resistant to which of the
following drugs?
a. Penicillin G.
b. Tetracycline.
c. Methicillin.
d. All of the above.
5. The drug of choice for vancomycinresistant Enterococcus is:
a. Levofloxacin.
b. Linezolid.
c. Ampicillin.
d. Vancomycin.
6. Which of the following should not be
used to help treat a Clostridium difficile
infection?
a. IV ciprofloxacin.
b. Proton pump inhibitors.
c. H2 receptor blockers.
d. All of the above.
7. What percentage of TB cases are resistant
to three or more antibacterials?
a. 65 percent.
b. 43 percent.
c. 85 percent.
d. 79 percent.
RPCO07DRE13
Elite
Page 21
CHAPTER 2
Chronic Fatigue and
Fibromyalgia Syndromes
(4 CONTACT HOURS)
By Katie Ingersoll, RPh, PharmD, and Staff Pharmacist
for national chain
Author Disclosure: Katie Ingersoll and Elite
Professional Education do not have any actual or
potential conflicts of interest in relation to this lesson.
Universal Activity Number (UAN):
0761-9999-13-169-H01-P
Activity Type: Knowledge-based
Initial Release Date: May 18, 2013
Expiration Date: May 18, 2015
Target Audience: Pharmacists in a community-based
setting
To Obtain Credit: A minimum test score of 70 percent
is needed to obtain a credit. Please submit your answers
either by mail, fax, or online at
pharmacy.elitecme.com.
Questions regarding statements of credit and other
customer service issues should be directed to 1-888666-9053. This lesson is $17.00.
Educational Review Systems is accredited
by the Accreditation Council of Pharmacy
Education (ACPE) as a provider of
continuing pharmaceutical education. This
program is approved for 4 hours (0.4
CEU’s) of continuing pharmacy education credit. Proof
of participation will be posted to your NABP CPE
profile within 4 to 6 weeks to participants who have
successfully completed the post-test. Participants must
participate in the entire presentation and complete the
course evaluation to receive continuing pharmacy
education credit.
Learning objectives
After a pharmacist has concluded this
knowledge-based activity, he or she will be
qualified and able to:
!! Identify and define chronic fatigue and
fibromyalgia syndromes.
!! Identify and discuss the symptomatology of
chronic fatigue and fibromyalgia syndromes.
!! Identify the prevalence of chronic fatigue and
fibromyalgia syndromes.
!! Describe the pathophysiology of chronic
fatigue and fibromyalgia syndromes.
!! Describe the pharmacist’s role in treating
chronic fatigue and fibromyalgia syndromes.
!! Describe the differential diagnosis of chronic
fatigue and fibromyalgia syndromes.
!! Identify and discuss the treatment modalities
for chronic fatigue and fibromyalgia
syndromes.
!! Describe the complexity of chronic fatigue
and fibromyalgia syndromes.
Summary
As pharmacists, it is critical that we are able to
identify the symptoms and characteristics of
both fibromyalgia and chronic fatigue syndrome.
Because of the relative similarity in the
presentation of these two maladies, it is important
that pharmacists have access to the most up-todate diagnostic tools, clinical information and
treatment modalities.
Conclusion
Clinical practice tells us that while there is
tremendous similarity between chronic fatigue
and fibromyalgia syndromes, there are even
greater differences between patients. While
prompt diagnosis and an effective treatment plan
can help some patients, full recovery is quite
rare, necessitating good pharmaceutical care to
enhance outcomes.
Patients living with chronic fatigue and
fibromyalgia endure great frustration from
bothersome symptoms that affect their daily
lives and a health care community that does not
understand the conditions as well as we should.
It is imperative that pharmacists understand the
complexity of the syndromes in their role in the
care of these patients.
according to the U.S. Department of Health
and Human Services and the National Institute
of Health (NIH) (2013), chronic fatigue and
fibromyalgia, when compared to other major
disorders, has had some of the least amount
of money spent on its research. Since 2009,
an average of $5 million per year has been
spent on chronic fatigue syndrome, whereas
from $9 million to $13 million has been spent
on fibromyalgia per year. To put that into
perspective, $237 million to $298 million has
been spent on asthma, $452 million to $529
million on alcoholism, $715 million to $833
million on breast cancer and billions more on
heart disease, diabetes and cancer per year.1
It has been estimated that the average patient with
fibromyalgia has been seen by approximately
15 physicians and has had the syndrome for five
Pre-assessment questions
years before properly being diagnosed. Typically,
Before beginning this activity, test your premost patients are misdiagnosed, enduring costly
course knowledge by answering the following
treatments with little benefit, or are informed
questions. Please be aware that these questions
that there is nothing medically wrong with
may be included as part of the final examination. them, and that it is “all in your head.” Therefore,
many patients and families become frustrated
1. According to 2013 financial figures from the
National Institutes of Health, the least amount with and skeptical of their provider. To this day,
some health care professionals do not believe
of research money has been spent on which
fibromyalgia truly exists.
of the following diseases?
a. Alcoholism.
Although most patients are relieved when a
b. Chronic fatigue syndrome.
correct diagnosis is finally made, the patient may
c. Breast cancer.
need to be convinced that the provider actually
d. fibromyalgia.
knows what is wrong and that a treatment plan
2. Which of the following disorders is not
has been formulated to alleviate his or her
typically associated with fibromyalgia?
symptoms.2
a. Morning stiffness.
Defining chronic fatigue syndrome and
b. Headaches, including migraines.
c. Celiac disease.
fibromyalgia
d. Irritable bowel syndrome.
Based upon the known criteria of each condition,
3. Which of the following medications have
pain is the major feature of fibromyalgia, whereas
received FDA approval for the treatment of
post-exertional malaise and fatigue are the major
fibromyalgia?
symptoms of chronic fatigue syndrome. Pain and
a. Pregablin (Lyrica).
fatigue are the most prevalent complaints seen in
b. Duloxetine (Cymbalta).
primary care that are common to both conditions.
c. Milnacipram (Savella).
However, both chronic fatigue and fibromyalgia
d. All of the above.
syndromes remain poorly understood because
both complaints may occur synonymously and
Introduction
can be a sign of many other medical conditions.
Any individual who has experienced debilitating
To add to the complexity, there is a significant
fatigue, malaise, chronic pain or other somatic
amount of overlap in the complex symptomology
complaints has probably endured years of
between chronic fatigue and fibromyalgia.
frustration from the health care system before
Currently, the majority of patients with chronic
being diagnosed with chronic fatigue syndrome
fatigue meet the criteria for fibromyalgia, and
(CFS), fibromyalgia (FMS) or myalgic
at least 70 percent of patients with fibromyalgia
encephalomyelitis (ME). CFS, FMS and ME
meet the criteria for chronic fatigue syndrome.4,5
are terms that are typically used interchangeably
Because of the significant complexity and
in most literature and textbooks. Nonetheless,
overlapping presentation of chronic fatigue
there are differences that must be considered to
syndrome and fibromyalgia, it is important to
provide for accurate diagnosis and treatment. In
define each of the syndromes.
this continuing pharmacy education course, the
terms fibromyalgia and chronic fatigue syndrome
Chronic fatigue syndrome
will be used.
Chronic fatigue syndrome is a debilitating
Fibromyalgia and chronic fatigue syndrome
syndrome that involves multiple body systems.
are among the most complex and misdiagnosed
It is characterized by profound fatigue that is not
syndromes seen in clinical practice. The majority improved by bed rest, and may be exacerbated
of the scientific literature implies that the
or re-kindled by physical or mental activity.
conditions remain poorly understood, despite
Patients with chronic fatigue syndrome function
an abundance of scientific research. However,
at substantially lower levels of activity than
they were capable of prior to the onset of their
Page 22
Elite
illness. Over the years, a great deal of debate
has surrounded the issue of how best to define
the syndrome, so the Department of Human
Health and Services and the NIH have outlined
the history in an effort to alleviate confusion
in the definition, uncertainties and overlapping
symptoms with fibromyalgia.6
In the early 1980s, patients with symptoms
including fatigue, muscle pain and depression
were often diagnosed with chronic EpsteinBarr virus syndrome or chronic mononucleosis
syndrome. These patients had symptoms that
suggested infection, such as low-grade fever,
recurrent sore throat and tender lymph nodes.
Epstein-Barr virus (EBV), which causes acute
mononucleosis, was considered a likely source.
However, at the time, researchers could not
isolate EBV as the cause of the syndrome and
as yet, have not definitively identified any
alternative infectious agents.
In 1988, in an effort to standardize research
definitions, a group of experts led by the U.S.
Centers for Disease Control (CDC), proposed a
new name for Epstein-Barr virus syndrome that
more accurately described it as chronic fatigue
syndrome. The new definition outlined two major
criteria:
Persistent or relapsing, debilitating fatigue
lasting at least six months in a person who
has no previous history of similar symptoms.
Exclusion of other clinical conditions that
may produce similar symptoms (such as
malignancy, autoimmune disease, chronic
psychiatric disease, and chronic inflammatory
disease, among others).
The definition also included the occurrence of
at least eight symptoms, including mild fever;
sore throat; painful lymph nodes; prolonged
fatigue after exercise; joint or muscle pain;
unexplained muscle weakness; headaches or
sleep disturbance.
Concurrently, while the CDC in the U.S. was
defining the syndrome, researchers in Australia
developed their own definition. The Australian
definition captured the CDC’s major criteria
and added the symptom of “neuropsychiatric
dysfunction,” which included impairment of
concentration and short-term memory.
In 1990, a consensus meeting of researchers in
Great Britain found neither of these definitions
satisfactory for use in clinical practice. Therefore,
the resulting guidelines included a glossary
describing in detail the principal symptoms of
fatigue, disability, mood disturbance, myalgia
(muscle pain), and sleep disturbance. The
“Oxford criteria,” as it came to be known, also
defined it as post-infectious fatigue syndrome
(PIFS), a subtype of chronic fatigue syndrome
that either followed an infection or was
associated with a current infection.
In 1990, because there was no consensus defining
the etiology of chronic fatigue syndrome, it
was impossible to classify the condition using
the International Classification of Diseases
(ICD-9). As a result, it needed a definitive
billing (ICD) code. ICD codes are required
to properly bill insurance companies for
payment reimbursements for services rendered
by physicians, nurse practitioners, clinics
or hospitals. Initially, the only entry in the
alphabetic index of the ICD-9 was “syndrome,
fatigue,” code 300. The ICD-9 then changed
it to include code 323.09: “benign myalgic
encephalomyelitis.” However, the 323.9 code did
not reference the condition to include it as a postviral syndrome. Later, in October 1, 1991, the
term “post-viral syndrome” was classified to code
780.7, malaise and fatigue.
In 1992, the World Health Organization
(WHO) published ICD-10 codes that included
many modifications. The WHO created a new
category, G93, that involved “other disorders
of the brain” and created a new code G93.3 to
include post-viral fatigue syndrome, a condition
that was previously mentioned in the ICD-9
code. The WHO also moved “benign myalgic
encephalomyelitis” to the new code G93.3.
In keeping with the placement in the ICD-10,
chronic fatigue syndromes (and its synonymous
terms) were to remain at G93.3 in ICD-10.
However, the WHO was not content with the
ICD-9 and ICD-10 coding because:7
It appeared that while chronic fatigue
syndrome was classified as a heterogeneous
group of disorders, not all were neurological
in nature.
Likewise, not all patients with chronic fatigue
experienced a viral infection before being
diagnosed with the syndrome.
Also of potential concern is the similarity
between the type of neurological findings in
chronic fatigue syndrome and in depression,
which is a psychiatric disorder.
In 2007, to avoid any confusion, the WHO
updated its codes and recommended that all
practitioners treating chronic fatigue syndrome
code it as G93.3 (post-viral fatigue syndrome)
and R 53 (malaise and fatigue). R is a newer
chapter that includes symptoms, signs, abnormal
results of clinical or other investigative
procedures, and ill-defined conditions that no
diagnosis is able to classify elsewhere.8
Because of confusion and criticism that chronic
fatigue syndrome diagnosis was too ambiguous
and over-exclusive and to facilitate a more
systematic collection of data internationally, the
International Chronic Fatigue Syndrome Study
Group was created in 1994. The group, headed
by the CDC and including representatives from
Australia and Great Britain, proposed a revised
definition of chronic fatigue syndrome. The
revised definition was known as the Fukuda or
research definition and was based on the presence
of the following:7
Clinically evaluated, unexplained, persistent
or relapsing chronic fatigue that is of new
or definite onset (has not been lifelong); is
not the result of ongoing exertion; is not
substantially alleviated by rest; and results
in substantial reduction in previous levels of
Elite
occupational, educational, social or personal
activities.
The concurrent occurrence of four or more of
the following symptoms, all of which must
have persisted or recurred during six or more
consecutive months of illness, and must not
have predated the fatigue:
ŠŠ Self-reported impairment in short-term
memory or concentration, severe enough
to cause substantial reduction in previous
levels of occupational, educational, social
or personal activities.
ŠŠ Tender cervical or axillary lymph nodes.
ŠŠ Muscle pain, multi-joint pain without
joint swelling or redness.
ŠŠ Headaches of a new type, pattern or
severity.
ŠŠ Unrefreshing sleep.
In 2001, an expert consensus panel convened
in Canada to develop a case definition of
myalgic encephalomyelitis, designed for clinical
diagnoses rather than for research purposes,
similar to the 1994 definition of chronic fatigue
syndrome. The panel outlined criteria for the
symptom categories, including:
Fatigue; post-exertional malaise or fatigue.
Sleep dysfunction.
Pain.
Body system manifestations, including
neurological/cognitive (i.e., difficulties with
memory or concentration), autonomic (i.e.,
vertigo), neuroendocrine (i.e., heat or cold
intolerance), and immunity (i.e., sore throat).
In 2003, the international group formed in 1994
revisited its research. The original definition
offered examples of conditions that would
preclude a diagnosis of chronic fatigue syndrome.
The study group elaborated on these exclusionary
criteria and recommended the use of several
specific standardized instruments in assessing
fatigue and accompanying symptoms.
Patients and patient advocates often prefer to
call chronic fatigue syndrome “chronic fatigue
and immune dysfunction syndrome” (CFIDS)
to convey the complexity of the illness and its
profound impact on people’s lives. The 2003
study group addressed the name “chronic
fatigue syndrome,” expressing sympathy with
those concerned that the name might trivialize
the illness. “However,” the report stated, “we
believe that changing the name without adequate
scientific justification will lead to confusion and
will substantially undermine the progress that
has been made in focusing public, clinical and
research attention on this illness.” 6
After all of the debates to define chronic fatigue
syndrome, physicians and practitioners may
safely diagnose the condition if the patient
satisfies the following criteria:­9
The individual has had severe chronic fatigue
for six or more consecutive months and the
fatigue is not due to ongoing exertion or other
medical conditions associated with fatigue
(these other conditions need to be ruled out
by a doctor after diagnostic tests have been
conducted).
Page 23
The fatigue significantly interferes with daily
activities and work.
Concurrently has four or more of the
following symptoms: substantial impairment
in short-term memory or concentration; sore
throat; tender lymph nodes; muscle pain;
multi-joint pain without swelling or redness;
headaches of a new type, pattern or severity;
unrefreshing sleep; and post-exertional
malaise lasting more than 24 hours.
The literature contains limited information
describing chronic fatigue and fibromyalgia
syndrome in children and adolescents. Children
are diagnosed with chronic fatigue syndrome
if they have experienced unexplained fatigue
present for at least three months as opposed to
a minimum of four symptoms persistent for at
least six months in adults.4,10 Symptom patterns
include the following:
Post-exertional fatigue or malaise.
Unrefreshing sleep.
Widespread pain.
Two or more neurocognitive disturbances:
common complaints include impaired
memory, difficulty focusing, disturbed
concentration and slowed thinking.
At least one symptom from two of the
following three categories:
ŠŠ Autonomic manifestations – hypotension,
tachycardia, palpitations, dizziness,
shortness of breath.
ŠŠ Neuroendocrine manifestations – hot
or cold spells, cold extremities, unusual
sweating, marked weight change.
ŠŠ Immune manifestations – recurrent sore
throat or flu-like symptoms, tender lymph
nodes in neck or armpits.
It is apparent that it has been a struggle over the
years to definitively define chronic fatigue in a
consensual, professional manner. Unfortunately,
that has not helped with the difficult task for
practitioners to recognize and diagnose the
syndrome promptly and accurately, often leading
to a delay in appropriate treatment.
Fibromyalgia
Fibromyalgia derived its name from “fibro-”
which means tissue-like ligaments and tendons,
“my-” meaning muscle, and “algia” indicating
pain. Previously, fibromyalgia was called
fibrositis, which was defined as diffuse noninflammatory muscular rheumatism. However,
the name was later changed because fibromyalgia
is no longer seen as an inflammatory disorder, but
instead as a chronic pain syndrome.11
Fibromyalgia is a disorder of unknown etiology
characterized by widespread pain, abnormal pain
processing, sleep disturbance, fatigue, and often,
psychological distress. Adults with fibromyalgia
may also have other symptoms, such as:12
Morning stiffness.
Tingling or numbness in hands and feet.
Headaches, including migraines.
Irritable bowel syndrome.
Problems with thinking and memory
(sometimes called “fibro fog”).
Painful menstrual periods and other pain
syndromes.
Children and adolescents with fibromyalgia,
which is known as juvenile fibromyalgia,
typically have the same symptoms as adults
except they also experience sleep disturbances,
morning fatigue, swelling of the extremities and
less ability to tolerate exercise.13
In 2010, the American College of Rheumatology
(ACR) developed specific criteria used
for clinical diagnosis and classification of
fibromyalgia. Diagnosis is based on the presence
of a Widespread Pain Index (WPI) of >7 and a
Symptom Severity (SS) scale of >5 or WPI >9.
Symptoms must have been present for at least
three months, and the patient must not have
another disorder that would explain the pain.
According to coding rules provided by the CDC
(2012), fibromyalgia is coded to 729.1, which
is labeled “myositis and myalgia, unspecified”
and can include other conditions. In addition,
the WHO (2010) recommends practitioners
code fibromyalgia under M 79.0 (rheumatism,
unspecified) and M 79.7 (fibromyalgia). M is a
coding system for diseases of the musculoskeletal
system and connective tissue.14 Ironically,
although chronic fatigue and fibromyalgia are
very similar in their presentation and often
overlap, both are coded differently, which
intensifies the complexity of the disorders and the
possibility of misdiagnosing the syndromes.
Epidemiology of chronic fatigue and
fibromyalgia syndrome
According to the CDC (2012), chronic fatigue
and fibromyalgia are debilitating and complex
syndromes. Social Security Ruling 99-2p states
that chronic fatigue syndrome is a disabling
condition. Patients with chronic fatigue syndrome
may be eligible for benefits.16
In 2005, the CDC reported that the prevalence
of fibromyalgia was approximately 2 percent,
affecting an estimated 5 million adults. The
prevalence in women is much higher than in men
(3.4 percent vs. 0.5 percent). One complication in
determining the prevalence of disease relates to
the case definition used. For example, according
to one study conducted in Iceland, prevalence
was estimated as 4.8 percent, 2.4 percent and 1.4
percent by using different criteria. Even when
the same case definition is applied across studies,
different outcomes are obtained.17 Additional
statistical information on chronic fatigue
syndrome is limited, because fatigue is such
a common complaint, and the data is not well
differentiated.
According to Jason, et al, comparable or higher
incidences of chronic fatigue syndrome are
observed in minorities than in Caucasians. For
example, they showed higher rates of prevalence
in African Americans, Native Americans and
Latinos relative to Caucasians. Further, they
determined that prevalence was higher in in
households with lower income levels.18
Fibromyalgia and chronic fatigue syndromes are
typically diagnosed in individuals between the
ages of 20 to 50 years; however, they may occur
in children and older adults, especially among
women. In 2008, it was estimated that most
children diagnosed with juvenile fibromyalgia are
pre-pubertal or adolescent girls aged 13-15 years,
with a mean onset at age 12. The earliest reported
case was in a 5-year-old. Juvenile fibromyalgia is
more common in white adolescent girls, although
35 percent boys of the same age or younger
have also been diagnosed.19 As women mature,
especially over the age of 70 years, there is a 7.4
percent risk of being affected by fibromyalgia.5
Fibromyalgia is the second-most common
musculoskeletal disorder, and causes more than
20 percent of all visits to a rheumatologist.
Numerous research studies have demonstrated
that more than 50 percent of fibromyalgia
patients have a history of eating disorders,
physical or sexual abuse. Up to 30 percent of
patients fall into a psychiatric diagnosis category
of depression, somatization and hypochondriasis,
with anxiety being the most common. Many
disagree as to whether psychiatric problems
develop in patients before chronic fatigue and
fibromyalgia or whether it occurs as a result of
the syndrome.5
As of January 2009, epidemiologists recognized
that the social, emotional, economic and
functional effects of fibromyalgia on an
individual’s life have been compared with those
of rheumatoid arthritis (RA). Research indicates
that the socioeconomic impact of fibromyalgia
includes the following estimates:12
Overall, fibromyalgia costs the American
economy more than $9 billion annually.
Average yearly service utilization cost per
person is $3,500.
Total annual cost (direct and indirect) per
person is $5,945.
According to the CDC (2008), in 1997, 7,440
hospitalizations listed ICD9-CM code 729.1 as
the principal diagnosis. People with fibromyalgia
have approximately one hospitalization every
three years, and the hospitalization rate among
women is higher than among men at all ages.
They also require extensive care, including 5.52
ambulatory care visits, and numerous physician
office and emergency room visits. It is estimated
that fibromyalgia leads to the mortality of about
23 Americans annually.12
Pathophysiology of chronic fatigue and
fibromyalgia syndrome
The pathophysiology of fibromyalgia and chronic
fatigue syndrome is complex because there are so
many aspects to consider as well as overlapping
conditions. The unique features of fibromyalgia
are manifested primarily with chronic pain,
dysregulation of neuroendocrine function and
alterations in the sleep pattern. At this time, the
pathophysiology of fibromyalgia and chronic
fatigue syndrome remain unclear, but it has been
hypothesized that fibromyalgia is a disorder
that may arise from muscle energy metabolism,
generalized disorder of pain perception,
Page 24
Elite
neuroendocrine disturbance, sleep disturbance,
stress and trauma from accidents or surgery,
infections, inflammatory or immunopathologic
disease of the muscle, dysregulated serotonin
secretion, genetics or as a result of sexual abuse
or domestic violence.5, 2, 21
However, there is limited data available relating
chronic fatigue syndrome to most of the proposed
etiologies and a stronger suggestion that it may
arise due to a viral illness or be psychological
in nature. It has also been speculated that
fibromyalgia may be a rare complication of
hypothyroidism, rheumatoid arthritis or, in men,
sleep apnea.22
Potential causes of fibromyalgia
syndrome
Muscle energy metabolism. For many years,
it was believed that fibromyalgia was a disorder
of muscle metabolism, possibly the result of
chronic hypoxia of muscular tissue. Research
studies have demonstrated an alteration in
muscle metabolism, such as lower adenosine
5’-triphosphate (ATP) adenosine diphosphate
(ADP), higher concentrations of adenine
monophosphate (AMP), and more alterations of
capillaries and fiber areas.23,24
Studies involving post-exertional pain, muscle
force and lactate levels have shown a similarity
among sedentary controls and fibromyalgia
patients.5 Over the years, there has been a
change documented in the muscle strength
of fibromyalgia patients, but it is speculated
that it may result from deconditioning. A few
researchers believe deconditioning results from
the repetitive microtrauma of daily living. The
daily fatigue along with physical inactivity may
lead to unfit muscles, making them even more
susceptible to microtrauma.
The inflammatory component of myalgias
in fibromyalgia has never been exposed,
which explains the reason non-steroidal antiinflammatory drugs (NSAIDs) and steroid
therapies usually lack efficacy as a treatment
modality.5
Generalized disorder of pain perception. Since
1979, the International Association for the Study
of Pain (IASP) has defined pain as an unpleasant
sensory and emotional experience associated with
actual or potential tissue damage, or described
in terms of such damage.25 Normally, pain is
the result of activation of nociceptors in the
peripheral tissues.20
The problem researchers face when trying to
definitively determine a distinct cause of the
chronic pain manifested in fibromyalgia is
that pain is a subjective symptom. Therefore,
the pathophysiological concept is speculated
based upon biological, behavioral and selfreport parameters associated with pain that
indicate it is due to an abnormal central
nervous system (CNS), exacerbated by central
sensitization, abnormalities of descending
inhibitory pain pathways and abnormal levels of
neurotransmitters.23
Central sensitization, an abnormal processing
of pain caused by sensory or nociceptive
stimuli. Sensory impulse amplification begins
at the level of the spinal cord, and is gated by
changes occurring in the sensitivity of the dorsal
horn neurons. In the dorsal horn of the spinal
cord at the postsynaptic membrane there is a
receptor N-methyl-D-aspartic acid (NMDA).
These receptors are normally inactive and do not
respond to initial acute stimuli. However, after
repeated neuronal depolarization, the receptors
undergo activation and are responsible for
windup and central sensitization.23
Another form of pain sometimes associated
with fibromyalgia is also a poorly understood
syndrome: myofascial pain, which is a disorder
of trigger points. Similar to tender points (seen
in fibromyalgia), trigger points are discreet areas
in muscle tissue or its associated fascia that are
exquisitely tender to compression; however, pain
occurs at the site of the applied pressure and also
at a distant site (zone of pain referral). Trigger
points are involuntary, transient contractions
found in taut bands (firm, elongated bands)
located in muscle fibers, elicited by snapping or
pinching the band.2
In patients with fibromyalgia, the NMDA
receptor antagonist ketamine attenuates windup
to “a painful stimulus” causing muscular
hyperalgesia, referred pain and muscle pain at
rest. Research has demonstrated that the NMDAreceptor antagonist dextromethorphan (a common
ingredient in cough medicine) has reduced the
windup in patients with fibromyalgia and control
participants.23
Chronic fatigue and fibromyalgia causes
This windup can occur directly or indirectly from
the brainstem via descending pathways. During a
central sensitization, the nociceptors or peripheral
pain nerves (such as those found in skeletal
muscles) are stimulated by pressure or repetitive
stretching. Once this process occurs, the nerves
become sensitized, because of an excess in the
following excitatory neurotransmitters and a
lower level of inhibitory neurotransmitters:20, 2
Excitatory neurotransmitters include
glutamate, aspartate, substance P and
calcitonin gene-related peptide. According to
the FDA (2009), the ACR also speculates that
patients with fibromyalgia have an abnormal
level of substance P in their spinal fluid.
Substance P helps transmit and amplify pain
signals to and from the brain. Researchers
are looking at the role of substance P and
other neurotransmitters and studying why
people with fibromyalgia have an increased
sensitivity to pain and whether there is a gene
or genes that make a person more likely to
have it.26
Inhibitory neurotransmitters include
serotonin, dopamine and norepinephrine.2
Decreased serotonin in the central nervous
system may lead to aberrant pain signaling.
Decreased dopamine transmission in the
brain may lead to chronic pain through
unclear mechanisms.23
The process allows the nerve impulses being
carried to the central nervous system to reduce
the pain threshold by central sensitization.
Fibromyalgia patients have a generalized
decrease in the pain perception threshold,
reflecting discrimination in the quality and
threshold of pain tolerance, such as allodynia
(pain due to a stimulus that does not normally
provoke pain) and hyperalgesia (an increased
response to a stimulus that is normally
painful).25,2
It is critical to note that deficient serotonin levels
affect other aspects correlated with fibromyalgia,
such as sleep, headaches and mood disorders.2
Elite
Neuroendocrine disturbance. Multiple
laboratory studies have suggested that the central
nervous system may have an important role
in the patient developing chronic fatigue and
fibromyalgia syndrome.22 There is some evidence
to suggest that fibromyalgia and chronic fatigue
patients may have a reduction in the secretion
of adrenocorticotropin hormone (ACTH)
and cortisol because of a dysfunction of the
hypothalamic-pituitary-adrenal (HPA) axis.5, 2
The HPA axis is a critical component of the
stress-adaptation response. In a normally
functioning system, corticotropin-releasing
hormone (CRH) stimulates the anterior pituitary
to release ACTH. ACTH then stimulates the
adrenal cortex to produce glucocorticoids, which
are powerful mediators of the stress-adaptation
response.
However, in chronic fatigue and fibromyalgia,
there are two proposed notions about what
precipitates a dysfunction in the HPA axis and
thus lowercortisol, CRH and ACTH:
Physical or emotional stress, which is
commonly reported as a pre-onset condition
in chronic fatigue and fibromyalgia syndrome
patients, activates the HPA axis, leading
to increased release of cortisol and other
hormones.­27
Decreased amounts of circulating serotonin
affect the circadian regulation and the stressinduced stimulation of the HPA axis.2, 23
Possible events precipitating chronic fatigue
and fibromyalgia. Since the exact causes of
chronic fatigue and fibromyalgia syndromes
continue to remain unknown, it is speculated that
certain events may precipitate a deficiency in the
immune system or the central nervous system in
some patients, thus triggering the syndrome.
Before developing the syndromes, many patients
lead healthy, full, active lifestyles. However,
after an acute prodromal infection, varying from
upper respiratory infections, bronchitis, sinusitis,
gastroenteritis or an acute flu-like illness, the
clinical symptoms supporting chronic fatigue or
fibromyalgia develop in some patients.28 The
CDC (2012) has identified the following possible
triggers.27
Genetics. There is increasing evidence that
suggests genetics has been associated with
fibromyalgia, especially a deficiency of serotonin.
Some researchers speculate that the genetic
Page 25
predisposition manifests into symptoms after
the individual is at a certain age, because of
environmental triggers, or when the person
sustains an external insult, such as trauma or
illness.2
Immunology. It has been proposed that
chronic fatigue syndrome may be caused by
an immunologic dysfunction, for example,
inappropriate production of cytokines, such
as interleukin-1, or altered capacity of certain
immune functions. One thing is certain at this
juncture: there are no immune disorders in
chronic fatigue syndrome patients on the scale
traditionally associated with disease. Some
investigators have observed anti-self antibodies
and immune complexes in many chronic
fatigue patients, both of which are hallmarks of
autoimmune disease. However, no associated
tissue damage typical of autoimmune disease has
been described in patients with chronic fatigue
syndrome.
T-cell activation markers have also been reported
to have differential expression in groups of
chronic fatigue syndrome patients compared with
controls, but again, not all investigators have
consistently observed these differences.
One intriguing hypothesis is that various
triggering events, such as stress or a viral
infection, may lead to the chronic expression
of cytokines and then to chronic fatigue
syndrome. Administration of some cytokines
in therapeutic doses is known to cause fatigue,
but no characteristic pattern of chronic cytokine
secretion has ever been identified in chronic
fatigue syndrome patients. In addition, some
investigators have noted clinical improvement in
patients with continued high levels of circulating
cytokines; if a causal relationship exists between
cytokines and chronic fatigue syndrome, it is
likely to be complex.
Finally, several studies have shown that chronic
fatigue patients are more likely to have a history
of allergies than are healthy controls. Allergy
could be one predisposing factor for chronic
fatigue syndrome, but it cannot be the only one,
because allergies are not present in all patients.27
Infections
Chronic fatigue. In the majority of literature
that discusses chronic fatigue syndrome, many
hypothesize that it is caused by an infection.
However, after the CDC completed a four-city
surveillance study, the results demonstrated
that there is no association between chronic
fatigue syndrome and infection by a wide variety
of human pathogens, including EBV, human
retroviruses, human herpesvirus 6, enteroviruses,
rubella, Candida albicans and more recently
bornaviruses and mycoplasma. Taken together,
these studies suggest that among identified
human pathogens, there appears to be no causal
relationship for chronic fatigue syndrome as a
whole.
However, the possibility remains that chronic
fatigue syndrome may have multiple causes
leading to a common endpoint, in which case
some viruses or other infectious agents might
have a contributory role for a subset of chronic
fatigue cases. Recently published research
suggests that infection with EBV, Ross River
virus and Coxiella burnetti will lead to a postinfective condition that meets the criteria for
chronic fatigue syndrome in approximately
12 percent of cases. The severity of the acute
illness was the only factor found to predict which
individuals would have persistent symptoms
characteristic of chronic fatigue syndrome at
the six-month and one-year periods following
infection.
Fibromyalgia. There are studies that indicate that
the development of fibromyalgia may be linked
to Borrelia burgdorferi, which causes Lyme
disease, brucella and the parvovirus.5 Research
has also demonstrated that patients with hepatitis
C and human immunodeficiency virus (HIV)
have higher rates of fibromyalgia than the general
population.
At this time, the exact mechanism is unknown,
but it is speculated that cytokines are activated in
the central nervous system via viral neurotropism
and subsequent glial activation.23 Although there
is a link to previous infections, antiviral agents
have not demonstrated an improvement in the
symptoms for patients with chronic fatigue and
fibromyalgia syndrome.22
Neurally mediated hypotension (NMH). In
1995, Dr. Rowe and his coworkers at Johns
Hopkins University conducted a study, The
Relationship Between Neurally Mediated
Hypotension and Chronic Fatigue Syndrome,
published in the September 1995 issue of Journal
of American Medical Association (JAMA). The
objective of this work was to determine whether
disturbances in the autonomic regulation of
blood pressure and pulse (neurally mediated
hypotension, or NMH) were common in chronic
fatigue syndrome patients. The investigators
were alerted to this possibility when they noticed
an overlap between their patients with chronic
fatigue syndrome and those who had neurally
mediated hypotension (NMH).
NMH can be induced by using tilt table testing,
which involves laying the patient horizontally
on a table and then tilting the table upright to
70 degrees for 45 minutes while monitoring
the blood pressure and heart rate. Persons with
NMH will develop lowered blood pressure under
these conditions as well as other characteristic
symptoms, such as lightheadedness, visual
dimming or a slow response to verbal stimuli.
Many chronic fatigue syndrome patients
experience lightheadedness or worsened fatigue
when they stand for prolonged periods or when
in warm places, such as in a hot shower. These
conditions are also known to trigger NMH. One
study observed that 96 percent of adults with a
clinical diagnosis of chronic fatigue syndrome
developed hypotension during tilt table testing,
compared with 29 percent of healthy controls. Dr.
Rowe later replicated the study in fibromyalgia
patients with the same results.29
Physical trauma. Fibromyalgia patients typically
endure excruciating pain in the cervical neck
region. Research has demonstrated that 22
percent of patients who have endured whiplash
from motor vehicle accidents go on to develop
fibromyalgia.23
Pre-existing conditions. Fibromyalgia has
increased prevalence among patients with
autoimmune disorders and rheumatic diseases
(20 to 65 percent), such as rheumatoid arthritis
(RA), systemic lupus erythematosus (SLE),
ankylosing spondylitis (AS), Sjogren’s syndrome,
osteoarthritis and Behcet’s disease. In addition,
the prevalence of the disease is increased in
chronic diseases, such as diabetes mellitus.12
Although fibromyalgia patients have an increased
risk of being affected if they have a pre-existing
autoimmune disorder, there is no increased risk
of developing an autoimmune disorder if the
patient has fibromyalgia and no prior history of
an autoimmune disorder.
Psychiatric aspects. Over the years, researchers
have debated whether psychiatric disorders are a
precursor to the development of chronic fatigue
and fibromyalgia syndrome or were simply
coincidental. In primary care practices, more
than half of all patients with depression present
with pain, one of the most common complaints
associated with fibromyalgia. In addition, patients
with chronic fatigue and fibromyalgia have
increased rates of depression, anxiety and mood
disorders.23, 5, 30
At this time, further research is required to
assess whether depression is independent of
chronic fatigue and fibromyalgia or secondary
to the consequences of the chronic illness.4
Unfortunately, patients with chronic fatigue and
fibromyalgia live in depressing situations with
severe social and activity restrictions beyond
their control because of the compounding
plethora of symptoms that are overwhelming and
debilitating.
Further research is required. At this time, it is
difficult to confirm whether the syndromes are
precipitated by life events or have organic causes.
In the meantime, health care professionals should
realize the complexity of the disease when
caring for a patient living with chronic fatigue or
fibromyalgia syndrome.
Differential diagnosis of chronic fatigue
syndrome and fibromyalgia
At this time, there is no diagnostic laboratory
value or radiological exam that confirms the
diagnosis of chronic fatigue or fibromyalgia
syndrome. However, there is a laboratory
test, anti-polymer antibody assay (APA assay)
that detects anti-polymer antibodies in the
blood of most patients with fibromyalgia and
fibromyalgia-like symptoms.31, 2 An article
published in the Journal of Rheumatology
entitled “Anti-Polymer Antibody Reactivity in a
Subset of Patients with Fibromyalgia Correlates
with Severity” demonstrated that 47 percent of
patients with fibromyalgia and 61 percent of
patients with severe symptoms of fibromyalgia
Page 26
Elite
reacted positively to the APA assay.32 But
because the APA assay is not exclusive to
fibromyalgia and is not reactive to all patients, a
diagnosis is made by exclusion of other diagnosis
with similar manifestations.
Depending upon the history of present illnesses,
symptoms exhibited by the patient and physical
examination, the physician or practitioner will
contemplate a diagnosis by ruling out other
conditions that present with overlapping, similar
clinical manifestations.
Some of the more common differential medical
conditions that may mimic or present in the same
manner include acquired immunodeficiency
disease (AIDS) anemia, autoimmune disease,
cancer, depression, hypothyroidism, Lyme
disease, multiple chemical sensitivities,
myofascial pain, polymyalgia rheumatica
(PMR) and sleep apnea.4, 2,11 The conditions and
symptoms manifested similar to chronic fatigue
and fibromyalgia syndrome include:
Acquired immunodeficiency syndrome
(AIDS) is the most common secondary
immunodeficiency disease in the world.
AIDS is caused by human immunodeficiency
virus (HIV). The symptomatology of AIDS/
HIV may include enlarged lymph nodes
(chronic fatigue), flu-like symptoms (chronic
fatigue) and fatigue (chronic fatigue and
fibromyalgia). AIDS/HIV is ruled out by
making the following assessments.5,33,11
ŠŠ Lymphocyte count and white blood cell
(WBC) count both will be decreased.
ŠŠ Cluster of differentiation or cluster of
designation, also known as the CD 4
count, will be decreased.
ŠŠ HIV antibody test will assess the patient’s
response to the virus (antigen) measured
by enzyme-linked immunosorbent assay
(ELISA) and Western blot analysis.
Either exam will test positive in response
to the patient developing HIV antibodies.
Anemia is defined as a reduction of red blood
cells, hemoglobin or hematocrit, manifested
by a variety of abnormal conditions. The
patient with anemia may present with
increased fatigue (chronic fatigue and
fibromyalgia), and may also exhibit pallor,
intolerance to cool temperatures (also seen in
Raynaud’s, a common phenomenon prevalent
in chronic fatigue and fibromyalgia),
tachycardia, murmurs or dyspnea on exertion
(DOE). A complete blood count (CBC) will
be completed to assess for anemia because it
measures the hemoglobin (Hgb), hematocrit
(HCT), mean cell hemoglobin (MCH), mean
cell hemoglobin concentrate (MCHC), mean
cell volume (MCV) and relative or red cell
distributive width (RDW). The levels will
vary depending upon the type of anemia.
If the laboratory values suggest anemia,
the clinician will order additional tests to
assess the specific type of anemia, such as
megaloblastic (Folate or Vitamin B 12),
macrocytic or microcytic (iron deficiency).
34,33
Autoimmune diseases are the third-most
common category of disease in the United
States, after cancer and heart disease,
affecting approximately 5 to 8 percent of
the population or 14 million to 22 million
persons. There are more than 80 autoimmune
diseases affecting virtually every part of
the body, including the endocrine system,
connective tissue, gastrointestinal tract, heart,
skin and kidneys.
Autoimmune diseases occur as a result of the
body’s attack on itself. Autoimmune diseases
typically affect women, and have very similar
symptoms that often show overlap between
chronic fatigue and fibromyalgia. The most
common autoimmune diseases that present
similarly to chronic fatigue and fibromyalgia
include: 35,36
ŠŠ Ankylosing spondylitis (AS): A chronic
progressive inflammation of the spine,
sacroiliac and larger joints of the
extremities, leading to ankylosis of the
bone and deformity. AS is characterized
by pain, forward flexion in the
cervical and lumbar region and flexion
deformities of the hips and knees.
ŠŠ Multiple sclerosis (MS): A chronic,
demyelination of the central nervous
system. MS presents as weakness and
trouble with coordination, balance,
speaking and walking (fibromyalgia)
and numbness and tingling feeling in
arms, legs, hands and feet (may occur
with chronic fatigue and fibromyalgia).
Diagnosis of AS and MS are usually by
symptoms, history and radiographs.
ŠŠ Rheumatoid arthritis (RA): A chronic
systemic inflammatory disease in the
joints and surrounding connective tissue.
RA is a symmetrical, bilateral condition
that is characterized by heat, erythema,
edema and painful motion of the affected
joints. RA is associated with fatigue,
weakness, anorexia, weight loss, lowgrade fever and lymphadenopathy.37
In 2010, the American College of
Rheumatology developed specific criteria
used in the clinical diagnosis of RA, and
to define RA in epidemiologic studies.
Persons must obtain a score of at least
6 of 10 based on certain classification
criteria.
Classification criteria are based on
clinical observation (i.e., number of
joints affected), laboratory tests (i.e.,
positive rheumatoid factor), and duration
of symptoms.38 Therefore, to confirm a
diagnosis, the patient will have a positive
rheumatoid factor, which is not present
in fibromyalgia. In addition, radiography
tests will demonstrate joint erosion and
narrowing of joint spaces.5
Systemic lupus erythematosus (SLE) is
seen in young women with complaints of
fatigue. Other signs may include malar
Elite
rash, especially over the cheeks producing a
“butterfly appearance”; photosensitivity; oral
ulcers; renal disorders with proteinuria; and
arthritis involving two or more peripheral
joints (fibromyalgia).
ŠŠ Diagnoses of RA and SLE are confirmed
by assessing for antinuclear antibodies
(ANA) to screen for collagen-vascular
disease.33 The ANA level is elevated
(positive) in patients with autoimmune
disease, such as SLE and RA. Research
has demonstrated that patients with
autoimmune diseases often have comorbid fibromyalgia.31 It should also be
noted that a low-titer ANA is common in
the general population, and may be of no
clinical significance if diagnostic features
of SLE or related autoimmune disorders
are absent.33
ŠŠ An erythrocyte sedimentation rate
(ESR) and c-reactive protein (CRP):
nonspecific laboratory tests that measure
inflammation in the body.
Cancer: Regardless of the type of cancer,
most patients will present with fatigue
(chronic fatigue and fibromyalgia). Other
symptoms of cancer that may present in
chronic fatigue and fibromyalgia include
weakness and fever (chronic fatigue). There
is no specific diagnostic test for cancer, but
additional screenings and laboratory values
may be analyzed, based upon the symptoms
and history of the patient presented to the
clinician.
Depression is the most common mental
health/behavioral disorder that may occur
from multiple life stresses, situations,
primary disorders or a problem associated
with dementia. Researchers have speculated
that depression is the result of a lack of
neurotransmitters, such as serotonin and
epinephrine (both decreased in chronic
fatigue and fibromyalgia).11 Depressed
patients without fibromyalgia will not have
the characteristic “tender points. ” Symptoms
that may occur include depressed mood and
lack of energy, both occurring in chronic
fatigue and fibromyalgia.11
Hypothyroidism is the result of decreased
metabolism from low levels of thyroid
hormones.11 The patient may present with
muscle aches and pain (fibromyalgia);
delayed contraction and relaxation of
muscles (fibromyalgia); slowed intellectual
functions, such as slow, slurred speech,
impaired memory (chronic fatigue and
fibromyalgia); depression (chronic fatigue
and fibromyalgia); and weakness and
fatigue (chronic fatigue and fibromyalgia).
Hypothyroidism shares many clinical
features with fibromyalgia and may produce
a secondary fibromyalgia syndrome.22
Other symptoms found in hypothyroidism
that are not seen in chronic fatigue and
fibromyalgia include lid lag and dry skin.21
Page 27
Hypothyroidism is confirmed by decreased
levels of triiodothyronine (T3) and thyroxine
(T4) and increased levels of thyroid
stimulating hormone (TSH) (greater than
5.3).
Lyme disease is a reportable systemic
infection caused by the spirochete Borrelia
burgdorferi that results from a tick bite.11
Initially, the patient will present with a large
“bull’s eye” circular rash, although some
patients may not notice it. Other symptoms
include malaise, fatigue (chronic fatigue and
fibromyalgia), headache (chronic fatigue
and fibromyalgia) or muscle/joint aches
(fibromyalgia). The CDC (2009) recommends
a two-step process when assessing for Lyme
disease:40
ŠŠ The first step uses an ELISA assay. These
tests are designed to be very “sensitive,”
meaning that almost everyone with
Lyme disease – and some who do not
have it – will test positive. If the ELISA
is negative, it is highly unlikely that the
person has Lyme disease, and no further
testing is recommended. If the ELISA
is positive or indeterminate (sometimes
called “equivocal”), a second step should
be performed to confirm the results.
ŠŠ The second step uses a Western blot test.
Used appropriately, this test is designed
to be “specific,” meaning that it will
usually be positive only if a person has
been truly infected. If the Western blot
is negative, it suggests that the first test
was a false positive, which can occur
for several reasons. The CDC does not
recommend testing blood by Western blot
without first testing it by ELISA.
Multiple chemical sensitivity (MCS) is a
controversial syndrome in which multiple
symptoms reportedly occur after low-level
chemical exposure. It is so controversial
that the American Academy of Allergy
and Immunology, the American Medical
Association (AMA), the California Medical
Association, the American College of
Physicians and the International Society of
Regulatory Toxicology and Pharmacology
have all rejected it as an organic disease.
The most common symptoms associated
with MCS includes fatigue (chronic fatigue
and fibromyalgia), difficulty concentrating
(chronic fatigue and fibromyalgia),
depressed mood (chronic fatigue and
fibromyalgia), memory loss (chronic
fatigue and fibromyalgia), weakness
(fibromyalgia), dizziness (fibromyalgia),
headaches (fibromyalgia), heat intolerance
(fibromyalgia) and arthralgias (aching
around the joints, also seen in fibromyalgia)
that typically interfere with daily life and
work (chronic fatigue and fibromyalgia).
Typically, all symptoms have been attributed
to exposure to low-level chemical exposures.
Although there is no specific diagnostic test
for MCS, patients should be encouraged
to see a physician who specializes in
environmental health.
Myofascial pain is a common, painful
disorder that affects the skeletal muscles.
Myofascial pain is more prevalent in men
than in women seen with chronic fatigue
and fibromyalgia.21 The patient will present
with a localized, unilateral muscular pain,
stiffness (fibromyalgia), limited movements
and muscle weakness (fibromyalgia). Upon
examination, “trigger points” will be noted
from referred pain.42 Trigger points are
typically more “nodular” type areas with
radiating pain and muscle twitching.21
Patients with fibromyalgia pain typically have
more localized pain rather than radiating.
Polymyalgia rheumatica (PMR) is a
disorder characterized by stiffness worse
in the morning (fibromyalgia), weakness
(chronic fatigue and fibromyalgia), fatigue
(chronic fatigue and fibromyalgia) and pain
(fibromyalgia) symptoms that are proximal,
not distally within the neck, shoulders,
back and upper thigh. Other symptoms
include low-grade fever (chronic fatigue)
and arthralgias (fibromyalgia). There
is no available diagnostic test, and it is
diagnosed based upon symptoms, history
(typically women over 50 who respond
to steroid therapy) an increased ESR and
a normochromic, normocytic anemia.5, 11
Erythrocyte sedimentation rate (ESR) is a
nonspecific inflammatory test that is useful
to monitor the course of a disease (such as
PMR) or malignancy. A normochromic,
normocytic anemia is noted, demonstrated
with a low Hgb and HCT but normal MCV.
Sleep apnea is a disruption of breathing
while sleeping that lasts less than 10 seconds
and occurs a minimum of five times in an
hour.11 Many times, patients will not be
aware of their sleep apnea; it will be reported
by a significant other or parent, and the
patient may complain of “waking up tired”
and irritability. Other signs include loud
snoring and thrashing in bed.21 Sleep apnea
is confirmed by a polysomnography (PSG)
device and observation during an overnight
exam while the patient is sleeping.11
Other potential laboratory and diagnostic tests
that may be analyzed include:
Basic metabolic panel (BMP), sometimes
known as chem-7 or SMA-7: assesses
calcium, carbon dioxide (CO2), chloride,
creatinine (cr), glucose, potassium, sodium
and blood urea nitrogen (BUN) levels. A
BMP is an important laboratory test to rule
out dehydration (CO2), diabetes (glucose),
and kidney failure (BUN/cr).
Complete blood count (CBC) with a
differential count. Typically, a CBC includes
white blood count (WBC), red blood cell
(RBC), hemoglobin (Hgb), hematocrit
(HCT), mean cellular hemoglobin (MCH),
mean cellular hemoglobin concentration
(MCHC), mean cell volume (MCV), red
cell distribution width (RDW) and platelets.
A white blood cell can be expected to be
increased with a bacterial infection, and
the red blood cell count, Hgb, HCT, MCH,
MCHC, MCV and RDW can be used to
assess anemia. The differential count can be
used to provide the clinician additional clues
on the type of infection (viral, bacterial or
allergic in nature). It includes lymphocytes
(increased or decreased with viral infection,
AIDS, influenza), neutrophils (increased
bacterial infections and decreased with
infectious mononucleosis), and eosinophils
(decreased with stress and ACTH imbalance),
basophils (increased with infection and
hypothyroidism) and monocytes increased
bacterial infection.
Creatinine phosphokinase (CPK) to
exclude myocardial infarctions (MI) and
inflammatory myopathies (heart, skeletal
muscle and bone) demonstrated by an
elevated CPK level.33 A CPK test may be
completed if the patient complains of noncardiac chest pain.
Serum cortisol. Cortisol and corticotrophinreleasing hormone (CRH), which are also
produced during the activation of the HPA
axis, influence the immune system and many
other body systems. Recent studies revealed
that chronic fatigue and fibromyalgia patients
often produce lower levels of cortisol than
do healthy individuals. However, at this
time it is not a conclusive diagnostic marker
because some patients do not produce an
abnormality.27 Overall, neuroendocrine
disturbances are associated with dysfunction
of the HPA axis in the following manner:2
ŠŠ Low free-cortisol levels in 24-hour urine
samples.
ŠŠ Loss of the normal circadian rhythm
with elevated evening cortisol level
(when it should be at its lowest level).
Many patients with chronic fatigue
and fibromyalgia experience sleep
deprivation. Research has demonstrated
that fibromyalgia patients have an
intrusion of alpha waves (during the
first few hours of sleep) into slow delta
wave stage III/IV (deep) sleep, the first
objective abnormality noted.2
ŠŠ Insulin-induced hypoglycemia associated
with an overproduction of pituitary
ACTH.
ŠŠ Low levels of growth hormone.
ŠŠ Stimulated ACTH secretion leading
to insufficient adrenal release of
glucocorticoids.
The use of the tilt test is indicated if there is a
fall in blood pressure, or excessive rapidity of the
heart beat upon standing, which improves when
sitting or lying down. Patients often report that
they experience dizziness or are light-headed
upon standing. The tilt test involves the patient
lying horizontally on a table and then tilting
the table upright to a 60-70 degree angle for
Page 28
Elite
approximately 45 minutes, during which time
blood pressure and heart rate are continuously
monitored.27 A positive tilt test may occur from
cardiac origin or coincide with chronic fatigue
syndrome and fibromyalgia.
Treatment of fibromyalgia and chronic
fatigue syndrome
Managing chronic fatigue and fibromyalgia
can be as complex as the illness itself.
Unfortunately, at this time there is no cure or any
prescription drugs developed specifically for the
syndromes. Therefore, the treatment of chronic
fatigue and fibromyalgia syndromes involve a
multidisciplinary approach and collaboration with
the patient and family. Although there is not a
precise, ideal treatment plan, each plan should be
individually compiled based upon the symptoms
of the patient.
Pharmacists should be professional, supportive
and empathetic to the patient and his or her
family because there has most likely been
a delay in proper diagnosis, work-up and
previously failed treatment modalities. Effective
communication and educating the patient and
family will alleviate many of their fears and
concerns. Pharmacists should take the time to
explain the diagnosis and plan of care to the
patient and family.
It may take some time to find a combination of
traditional and alternative therapies that works for
the patient, but it is important to begin symptom
management without delay. For instance,
untreated sleep problems can actually make other
symptoms, such as pain and memory problems,
worse.43 One key to successful management of
the syndromes is to develop a collaborative,
multidisciplinary approach with the patient and
family to ensure individualized treatment is
developed and revised as needed.
The following treatment modalities are used in
children, adults and the elderly:
Cognitive behavioral therapies (CBT)
is a non-pharmacological measure, often
prescribed to help chronically ill patients
cope with illness and develop behaviors
and strategies to help alleviate problematic
symptoms, such as pain and fatigue. It has
been successful in helping patients with
cardiovascular disease, diabetes and cancer,
and recent studies indicate that CBT can be
useful in treating some chronic fatigue and
fibromyalgia patients.43,5 The goal of CBT
is to reduce pain, enhance self-efficacy and
improve the overall function of patients by
helping them learn to manage their activity
levels, stress and symptoms. Optimally, CBT
can help patients change their perceptions
and behaviors that may be perpetuating
symptoms and disability.4, 5, 22
Counseling is recommended for many
patients living with chronic fatigue and
fibromyalgia because living with the
syndromes can be difficult. Similar to other
debilitating chronic illnesses, chronic fatigue
and fibromyalgia can have a profound impact
on daily life, requiring patients to make
significant lifestyle changes and adapt to a
series of new limitations.5
Consulting a trained professional will help
most patients build effective coping skills and
problem-solving techniques. A supportive
counselor may help the patient cope with
the prospects of long-term illness as well
as the anxiety, depression, grief, anger and
guilt that often accompany chronic illness. A
competent therapist using problem-solving
techniques, standard psychotherapy and
counseling methods can help the patient
work through these issues. In some cases, a
therapist may recommend a combination of
medication and psychotherapy.
The CDC (2006) has outlined some common
difficulties faced by patients coping with
chronic fatigue and fibromyalgia syndrome.5
ŠŠ The severe, changing and unpredictable
symptoms of varying severity.
ŠŠ A decrease in stamina that interferes with
activities of daily living (ADL).
ŠŠ Memory and concentration problems
that seriously impact work or school
performance.
ŠŠ An uncertain prognosis that makes it hard
to plan for the future.
ŠŠ Loss of independence, livelihood and
economic security.
ŠŠ Alterations in relationships with family
and friends.
ŠŠ Worries about raising children.
ŠŠ Concerns about the potential impact of
decreased sexual activity on intimate
relationships.
ŠŠ Skepticism and misconceptions about the
illness.
ŠŠ Many patients may feel anger, guilt,
anxiety, isolation and abandonment
that can intensify other symptoms, such
as depression, sleep deprivations or
anxiety. It is important for patients to
acknowledge the life-altering changes
imposed by their illness, and to develop
effective coping strategies to deal with
these changes.
Exercise is a great component to enhance
strength, reconditioning of the muscles
and release endorphins to alleviate stress.
However, some patients may never be able
to achieve the ideal level of exercising or
continue it. As many as 40 percent of all
fibromyalgia patients discontinue exercise
because of the associated pain and fatigue.5
The percentage may be higher in patients
with chronic fatigue and extensive malaise
after exercising. Therefore, the pharmacist
should encourage patients to exercise at the
highest level possible without exacerbating
or worsening their symptoms. Always assess
patients’ progress or decline in function to
ensure that the treatment plan is adjusted to
meet their needs.
Elite
ŠŠ Researchers recommend daily aerobic
and flexibility exercises, such as aquatic
therapy (swimming and water exercises),
walking, rowing and biking as essential
components of the rehabilitation
program.2, 11 The goal is to encourage
the patient to perform 60 to 75 percent
of age-adjusted maximum heart rate
(210 minus the person’s age) two to
three times a week.5 Encourage the
patient to begin with gentle warm-up,
flexibility exercises, slowly progressing
to stretching all of the major muscle
groups.2 The goal of warming up
should stretch to only the point of slight
resistance, not to the point of pain.4
ŠŠ Pharmacists should reiterate to patients
that they need to exercise safely without
increased pain. If increased pain is
noted, patients should alter their exercise
regimen, speak with their primary care
provider and possibly be referred to
rehabilitation therapy. Physical therapists
(PT) ensure proper exercise techniques
and promote strengthening of the
muscles, ligaments and joints. The patient
should also be informed that continuous,
ongoing exercise is imperative to
maintain exercise-induced gains. Ideally
the patient should avoid exercising late
in the evening because endorphins are
released, which can cause difficulty
sleeping. A number of randomized,
controlled trials of multidisciplinary
treatment and exercise combined with
education or cognitive behavioral
therapy demonstrated that patients with
fibromyalgia had improvements on a sixminute walk with significant decreases
in pain and efficacy in their overall
symptoms.2
ŠŠ If the patient is unable to complete an
exercise regimen privately or with a
therapist, the patient may then suffer
a condition often associated with
fibromyalgia, the inability of the muscles
to relax. Patients can have a surface
electromyogram (sEMG), a biofeedback
therapy that teaches them to learn to relax
their muscles.44
ŠŠ The pharmacist needs to reiterate to the
patient with chronic fatigue syndrome to
avoid post-exertional malaise, a common
symptom defined as an exacerbation of
symptoms following physical or mental
exertion, with symptoms typically
worsening 12 to 48 hours after activity
and lasting for days or even weeks. It is
important, however, not to avoid activity
and exercise altogether. Such avoidance
can lead to serious deconditioning, and
can actually worsen other symptoms.
It is also important not to engage in an
endless “push-crash” cycle in which
patients do too much, crash, rest, start
to feel a little better, do too much again,
and so on. Instead, encourage patients
Page 29
to learn to pace activities and work with
their health care professionals to create
individualized exercise programs that
focus on interval activity or graded
exercise. The goal is to balance rest and
activity to avoid both deconditioning
from lack of activity and flare-ups of
illness caused by overexertion. Effective
activity management may help improve
mood, sleep, pain and other symptoms so
patients can function better and engage in
activities of daily living.5
Lifestyle changes, including prevention
of overexertion, stress reduction, dietary
restrictions and nutritional supplementation,
are frequently recommended in addition to
drug therapies to treat sleep, pain and other
specific symptoms.11
Diet. There is no specifically recommended
diet, but many patients report intolerances for
certain substances that may be found in foods
or over-the-counter medications, such as
alcohol or the artificial sweetener aspartame.
While evidence is currently lacking for
nutritional defects in chronic fatigue and
fibromyalgia syndrome patients, it should
also be added that a balanced diet may be
conducive to better health in general, and
would be expected to have beneficial effects
in any chronic illness. In addition, encourage
the patient to limit caffeine, alcohol and
chocolate because they may interfere with
adequate sleep.11
ŠŠ In 2001, a research study conducted
by Donaldson et al, demonstrated that
19 of 30 participants responded very
favorably to a raw vegetable diet, seeing
marked improvement in all fibromyalgia
symptoms. The authors implied that a
diet composed of fresh fruit and salads
results in high intakes of fiber, vitamin
C, folate, potassium and magnesium.
Animal product consumption was very
low, especially intakes of meat, poultry
and fish. Intakes were mainly from once
weekly to none, resulting in low intakes
of fat, cholesterol, vitamins B12 and D,
and zinc. This dietary intervention shows
that many fibromyalgia subjects can
be helped even without understanding
the full cause of their symptoms.
Further controlled studies are needed
to reproduce and extend the results
obtained here to see whether this dietary
intervention is a viable adjunctive therapy
for managing fibromyalgia in a clinical
setting.45
Manage stress. Encourage patients to
identify and recognize stressors in their
lives. The pharmacist should ask the patient,
“How do you respond to stress and potential
stressors?” Once the stressors are identified
and the patient recognizes his own responses,
they may be able to make changes or learn to
adapt adequately.
Sleep apnea. Continuous positive airway
pressure (CPAP) is a nonsurgical approach
to provide air during sleep for a patient with
sleep apnea. CPAP delivers air nasally via a
continuous set positive pressure device.11
Sleep education. The CDC (2008)
recommends educating patients with
sleep deprivation to practice the following
techniques:43
ŠŠ Establish a regular bedtime routine.
ŠŠ Avoid napping during the day.
ŠŠ Incorporate an extended wind-down
period.
ŠŠ Use the bed only for sleep and sex.
ŠŠ Schedule regular sleep and wake times.
ŠŠ Control noise, light and temperature.
ŠŠ Light exercise and stretching earlier
in the day, at least four hours before
bedtime, may also improve sleep.
Support systems are imperative and beneficial for
the patient. Because of the enormous amount of
stress and symptoms, patients need a supportive
system surrounding them. In addition to support
from families and friends, there are local support
groups available, which may be located by using
the Arthritis Foundation (AF), chronic fatigue
and fibromyalgia websites.21
Medications are used to alleviate many of the
“problematic” symptoms, such as anxiety,
depression, pain and sleep deprivation.
Pharmacists should assess the baseline
medications, prescribed medications and use of
any herbals and over-the-counter (OTC) drugs to
avoid contraindications.
In addition, at this time, many prescribed
medications are initiated based on the patient’s
complaints and the primary care provider’s
knowledge and experience of other patients in
their practice who use the drugs. Therefore,
what may work now or for somebody else, may
need to be tailored to meet the needs of another
patient. No two patients should be treated
identically, but the care should be individualized.
At this time, there are only three medications
approved by the United States Food and Drug
Administration (FDA) for the medical treatment
of fibromyalgia:26
In June 2007, Lyrica (pregabalin) became
the first FDA-approved drug for specifically
treating fibromyalgia. Lyrica (pregabalin),
marketed by Pfizer Inc., was previously
approved to treat seizures, as well as pain
from damaged nerves that can happen in
people with diabetes (diabetic peripheral
neuropathy) and in those who develop pain
following the rash of shingles. Lyrica is
not considered an antidepressant but it is
related to gabapentin (neurontin) classified
as an analgesic/anticonvulsant. The major
side effects of Lyrica include sleepiness,
dizziness, blurry vision, weight gain, trouble
concentrating, swelling of the hands and feet,
and dry mouth. Allergic reactions, although
rare, can occur.
In June 2008, Cymbalta (duloxetine
hydrochloride) became the second FDAapproved drug for specifically treating
fibromyalgia. Cymbalta (duloxetine
hydrochloride) marketed by Eli Lilly and
Co., a serotonin-norepinephrine (SNRI),
was previously approved to treat depression,
anxiety and diabetic peripheral neuropathy.
The major side effects of Cymbalta include
nausea, dry mouth, sleepiness, constipation,
decreased appetite and increased sweating.
Similar to other antidepressants, Cymbalta
may increase the risk of suicidal thinking
and behavior in people who take the drug
for depression. Therefore, the pharmacist
should assess the patient’s mood and suicidal
ideations with each encounter and educate the
patient and family about the risk.
ŠŠ Both Lyrica and Cymbalta reduce pain
and improve the overall function in
people with fibromyalgia. While those
with fibromyalgia have been shown to
experience pain differently from other
people, the mechanism by which these
drugs produce their effects is unknown.
Eli Lilly announced that, although it is
not understood how Cymbalta works
in people, medical experts believe it
increases the activity of two naturally
occurring substances called serotonin
and norepinephrine.46 There is some
data suggesting that these drugs affect
the release of neurotransmitters in the
brain. The FDA (2009) has stated that
studies of both drugs demonstrated
that a substantial number of people
with fibromyalgia received good pain
relief, but there were others who did not
benefit. This reiterates the importance
of assessing each patient’s response to
therapy.
ŠŠ Lyrica and Cymbalta are approved for
use in adults 18 years and older. As of
May 2013, there is no data available
describing the efficacious and safe use of
these drugs in children and breastfeeding
women.
In January 2009, Forest Laboratories Inc.
and Cypress Bioscience Inc. announced that
Savella (Milnacipran HCl), an SNRI, was
approved by the FDA for the management
of fibromyalgia. The safety and efficacy of
Savella was established in two U.S. pivotal
phase III clinical trials involving more than
2,000 patients with fibromyalgia. The two
studies demonstrated that Savella doses of
100 mg/day and 200 mg/day demonstrated
statistically significant and clinically
meaningful concurrent improvements in
pain, patient global assessment and physical
function. The most common side effects
noted during the clinical trials were nausea,
constipation, hot flush, hyperhidrosis
(abnormal perspiration), vomiting,
palpitations, heart rate increased, dry mouth
and hypertension.47
Page 30
Elite
Although there are no FDA-approved
medications for chronic fatigue, the other most
common medications prescribed for chronic
fatigue and fibromyalgia are:5
Antidepressants are recommended as the
initial treatment of fibromyalgia to alleviate
depression and promote sleep. Sleepmaintenance disorders are more difficult to
manage than are sleep onset problems. In
general, antidepressants are most commonly
used because of their effect on serotonin.
Pharmacists should educate patients taking an
antidepressant to take the dose as prescribed
and avoid double-dosing; understand relief
and change in problematic symptoms
may take two to four weeks; avoid abrupt
discontinuation; and notify the primary care
provider if they feel suicidal.48
antidepressants to children and
adolescents. According to the National
Institute of Mental Health (2009), in
the FDA review, no completed suicides
occurred among nearly 2,200 children
treated with SSRI medications. However,
about 4 percent of those taking SSRI
medications experienced suicidal thinking
or behavior, including actual suicide
attempts – twice the rate of those taking
placebo. In response, the FDA adopted
a “black box” label warning indicating
that antidepressants may increase the
risk of suicidal thinking and behavior in
some children and adolescents with major
depressive disorder (MDD). A blackbox warning is the most serious type of
warning in prescription drug labeling.
The warning also notes that children and
adolescents taking SSRI medications
should be closely monitored for any
worsening in depression, emergence
of suicidal thinking or behavior, or
unusual changes in behavior, such as
sleeplessness, agitation or withdrawal
from normal social situations.
Close monitoring is especially important
during the first four weeks of treatment.
SSRI medications usually have few side
effects in children and adolescents, but
for unknown reasons, they may trigger
agitation and abnormal behavior in
certain individuals.
Tricyclic antidepressant agents (TCAs) have
the strongest evidence for efficacy, such as
amitriptyline (Elavil, apo-amitriptyline) 10
milligrams (mg) orally at bedtime, gradually
increasing to 40 to 50 mg depending upon
the efficacy.22 Research studies have
indicated that amitriptyline (Elavil) has
been effective in improving sleep and
increased the non-REM stage four sleep, by
increasing serotonin levels in the patient [10].
Nortriptyline (Pamelor) also has a unique
component to help alleviate neurogenic
pain.48
Avoid TCA medications in older adult
patients, because it can cause confusion
and orthostatic hypotension. Therefore,
Trazodone (Desyrel) may be a preferred
option for an elderly patient because of its
minimal side effects.11
ŠŠ The most common side effects with
TCAs include anticholinergic reactions,
such as urinary retention, dry mouth, dry
eyes, blurred vision and constipation and
sedative properties.48
If the patient is not staying asleep, adding a
serotonin-selective reuptake inhibitor (SSRI)
may be helpful. Selective serotonin reuptake
inhibitors (SSRIs) such as citalopram
hydrobromide (Celexa), escitalopram oxalate
(Lexapro sertraline, fluoxetine (Prozac)
and sertaline hydrochloride (Zoloft), can
be prescribed alone or in combination with
TCAs for pain relief and depression.5,11
However, the pharmacist should inform the
patient that the SSRIs do not help alleviate
fatigue.
Fluoxetine (Prozac) should be the
first antidepressant agent used to treat
depression in children and adolescents;
however, all of these medications should
be used only with extreme caution and
extensive parental education. Psychiatric
consultation is recommended. The doses of
all antidepressants should be individualized,
based upon the symptoms and history:
ŠŠ Over the years, there has been
numerous literature cautioning health
care professionals about prescribing
Herbal supplements and vitamins are
frequently used by people with chronic
fatigue syndrome for symptom relief.
Although there have been few clinical trials,
many chronic fatigue syndrome patients
report symptom relief with supplements.
The potential danger is these products are
unregulated, and information on potency
and side effects is frequently unknown.
Pharmacists and health care professionals
need to question patients about supplement
use and OTC products to determine safety,
efficacy and possible negative interactions
with prescribed medications and therapies.
The CDC (2008) discourages patient use of
herbal remedies like comfrey, ephedra, kava,
germander, chaparral, bitter orange, licorice
root, yohimbe and any other supplements that
are potentially dangerous.43
Pain is the primary symptom, especially for
the patient with fibromyalgia, and it needs to
be addressed appropriately by the primary care
provider. Ideally, patients should avoid the use of
any pain medication if possible, but many endure
excruciating, debilitating pain and it needs to be
addressed. The goal is to ensure that the patient
is prescribed pain medications that alleviate the
pain but are non-addicting.
Gabapentin (Neurontin) and zonisamide
(Zonegran), (analgesics/anticonvulsants)
are typically prescribed for neuropathic
pain; however they may be useful for
fibromyalgia patients.5 The typical dose is
100 mg/day and increased to 200 to 800
ŠŠ The most common side effect of SSRIs is
mg/day.39 Pharmacists should work with
insomnia.48
patients prescribed gabapentin (Neurontin)
Serotonin-norepinephrine (SNRI), Cymbalta
to discontinue gradually, over one week,
(duloxetine hydrochloride) and Savella
because a rapid discontinuation may cause
(milnacipran HCl).
seizures. In addition, the patient should avoid
Anti-anxiety medications include
taking it within two hours of an antacid.
antidepressants, such as SSRIs;
Women of childbearing age should speak
paroxetine (Pexeva), trazodone (Desyrel),
with their doctor if they are contemplating a
benzodiazepines, nonbenzodiazepine
pregnancy or breastfeeding.48
sedatives, or L-dopa and carbidopa may be
Guaifenesin (cold expectorant/cough
used in fibromyalgia syndrome, especially
medicine) appears in some reviews of the
if the patient suffers sleep disturbances from
literature as demonstrating “significant
restless leg syndrome.2
benefits in decreasing pain, improving
other symptoms as it works on the NMDA
Clonazepam (Klonopin) an anticonvulsant/
receptor.”23, 2 At this time, there are no
benzodiazepine that should never be
convincing clinical data to support this, and
confused with clonidine (Catapres) an
the validity is questionable. Further research
antihypertensive/cardiac medication.
is needed to determine the true effectiveness
Clonazepam is ideal for the chronic fatigue/
of guaifenesin in the treatment of the
fibromyalgia patient with concomitant
symptoms of fibromyalgia. Pharmacists
restless legs syndrome or mitral valve
should be especially mindful of this, because
prolapsed (MVP). The starting dose is 0.125
it is available over the counter.
or 0.25 mg, with titration to the lowest
effective dose. The pharmacist should instruct Muscle relaxants, such as cyclobenzaprine
(Flexeril) 5 to 40 milligrams daily,
the patient to take it as prescribed, never
are typically prescribed to alleviate
take double doses or abruptly discontinue it
musculoskeletal pain, especially spasms;
because of the risk of seizures. Side effects
however they are also effective in improving
include: increased fatigue, bleeding, sore
sleep when taken at bedtime as well as
throat, fever, clay-colored stools, jaundice or
providing relief the subsequent day.5
48
behavioral changes.
Pharmacists should assess patients taking
Corticosteroids are not useful in the treatment
muscle relaxants for drowsiness, dizziness
of fibromyalgia without concomitant
and blurred vision. In addition, muscle
rheumatic illness, such as joint, bursa or
relaxants may cause anticholinergic side
tendon inflammation.2
Elite
Page 31
effects (urinary retention and dry mouth),
especially in the elderly, or if a patient is
already prescribed a medication that induces
anticholinergic side effects.48
Non-steroidal anti-inflammatory drugs
(NSAIDs), including COX-2 selective
agents, and acetaminophen are not effective
analgesics when used alone, but when
combined with a TCA, may provide
some efficacy. Pharmacists should assess
patients receiving NSAIDs for a history
of hypersensitivity, bleeding disorders,
gastrointestinal bleed and severe hepatic or
cardiovascular diseases before administering.
The patient should be instructed to take
NSAIDs with a full glass of water and to
remain upright for a minimum of 15 to 30
minutes after administration to reduce the
risk of ulcer formation.48
Opioid/narcotics, such as codeine, fentanyl,
hydrocodone, methadone, oxycodone and
tramadol (Ultram), should be avoided
altogether, or used sparingly to avoid
addiction and overuse.
Tramadol (Ultram) (50 to 100 mg two or
three times daily) is prescribed for pain
relief in patients with fibromyalgia. The dose
should be slowly tapered gradually when
discontinued. Tramadol can be used alone
or in combination with acetaminophen.
Significant side effects of tramadol include
respiratory distress, hypotension and seizures.
The risk of seizures is exacerbated if the
patient is taking an anti-depressant (SSRIs,
TCAs or monoamine oxidase inhibitors).48
Lidocaine/trigger point injections may be
useful if the pain is confined to a specific
region. Interestingly, there is limited data
available in the review of literature about
Lidocaine/trigger point injections for the
treatment of chronic fatigue and fibromyalgia
syndrome. Nonetheless, it is mentioned on
multiple supportive websites for patients with
fibromyalgia and treatment of myofascial
pain. Trigger-point injections involve
inserting a needle directly into the “trigger
point” of the muscle. The beneficial goal of
the injection is the mechanical disruption of
scar tissue. The patient may require multiple
injections to infiltrate several centimeters of
the tendon and muscle. After the injection
procedure, the site of injection should be iced
to reduce swelling and edema.51
Memory and concentration may be enhanced
by encouraging the patient to participate in
relaxation and meditation training and memory
aids, such as organizers, schedulers and written
resource manuals, and can be helpful in
addressing cognitive problems. Stimulating the
mind with puzzles, word games, card games and
other activities may also be beneficial for some
patients.43
Other treatment modalities commonly
known as alternative therapy
Alternative therapy has evolved in Western
medicine over the past 20 years. Alternative
therapy may include acupuncture, balneotherapy,
chiropractic manipulation, electro-therapeutic
point stimulation, heat/ice, hypnosis and
biofeedback, journaling, massage, meditation
and yoga to reduce pain.2 More specific examples
include the following:
Acupuncture, a type of traditional Chinese
medicine, is one of the most ancient and
widely used treatments for a vast array of
conditions. It involves poking thin, solid
needles in various areas in the skin to
alleviate pain and/or nausea.52
Balneotherapy is a relaxing measure that
involves the patient bathing in warm water
containing sulfur or other minerals.52
Chiropractic manipulation is completed
to manipulate a joint barehanded or by a
chiropractor, using a machine or instrument
to apply pressure.
Electro-therapeutic point stimulation
(ETPS) is a form of transcutaneous electrode
nerve stimulation (TENS) that combines
acupuncture, massage therapy, electrotherapy
and physical therapy to increase or decrease
circulation, stimulate the central nervous
system, relax contracted muscles and release
endorphins, the body’s natural painkillers.49
Heat/ice alterations may provide some pain
relief.
Hypnosis and biofeedback is a natural state
of mind that provides relaxation during an
altered state of consciousness.53
Journaling is a tool for recording one’s
own personal life. Some patients may find
writing as a way to express feelings, to gain
new perspectives and to pay attention to the
patient’s true feelings. The pharmacist can
encourage the patient to practice “free-flow
journaling,” writing anything that comes to
his or her mind and to keep it without the
worry that others will read it.11
Massage is a relaxing, healing mechanism
that involves manipulating soft tissues in
the body by using touch.11, 52 In patients with
fibromyalgia, massage may help stretch tense
muscles, improve flexibility and diminish the
pain and stress.52 Many massage therapists
are trained on releasing the tight bands that
contain “trigger points.” In addition, they
specialize in a variety of myofascial release
techniques.53
Meditation may help the patient reduce
anxiety and pain and promote health.11
Yoga is an ancient practice that involves
controlling breathing, meditation and
exercise to enhance the mind and body. Yoga
postures help the patient to develop body
awareness, strength, flexibility, balance and
coordination.53
According to personal stories of patients living
with fibromyalgia reported online on various
support sites, there is no one therapy ideal for
patients, but a combination of medications,
lifestyle changes, exercise and alternative
therapies help many of them. In addition, patients
require a support system to help them in day-to-
day life and dealing with the disease that remains
so complex and misunderstood by health care
professionals.
Summary and conclusions
The prognosis of chronic fatigue and
fibromyalgia syndrome varies among each
individual, but neither condition is progressive
in nature, so long as the person receives
prompt, adequate diagnosis and appropriate,
individualized treatment. With prompt diagnosis
and an effective treatment plan, the CDC
(2012) estimates that chronic fatigue syndrome
improvement rates varied from 8 percent to 63
percent, based on a review of published studies,
with a median of 40 percent of patients improving
during follow-up. However, full recovery from
chronic fatigue syndrome is rare, with an average
of only 5 to 10 percent of patients sustaining total
remission.
Each patient is affected differently; some
people with chronic fatigue syndrome remain
homebound and others improve to the point that
they can resume work and other activities, even
though they continue to experience symptoms.15
There is limited data available in the literature
on the prognosis of fibromyalgia. However,
fewer than 50 percent of patients experience a
substantial improvement in their symptoms.22
According to various support networks accessed
online, many patients with fibromyalgia
enjoy some improvement with a combination
therapeutic regimen.
Patients living with chronic fatigue and
fibromyalgia endure great frustration from
bothersome symptoms that affect their daily
lives and a health care community that does not
understand the conditions as well as we should. It
is imperative that as pharmacists, we understand
the complexity of the syndromes while caring
for all patients. Pharmacists should also provide
reassurance to their patients that their symptoms
are real and can be managed. Although complete
resolution of pain and the associated symptoms
is unlikely, appropriate therapies can reduce the
pain and improve the patient’s overall quality of
life.
References
1.United States Department of Health and Human Services/National Institute of Health.
(2013). Estimates of Funding for Various Research, Condition, and Disease Categories
(RCDC). Retrieved online May 11, 2013 at http://report.nih.gov/categorical_spending.
aspx
2.Medscape. (2013). Fibromyalgia. Retrieved online May 11, 2013 at http://emedicine.
medscape.com/article/329838-overview
3.Berger, A., Dukes, E., Martin, S., Edelsberg, J., and Oster, G. “Characteristics and
health care costs of pa-tients with fibromyalgia syndrome,” International Journal of
Clinical Practice 61 (2007): 1498-1508
4.Carruthers, B., et al (2003). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome:
Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of
Chronic Fatigue Syndrome, Vol. 11(1). Retrieved online May 11, 2013 at http://www.
cfids-cab.org/MESA/ccpccd.pdf
5.Dunphy, L., Winland-Brown, J., Porter, B., and Thomas, D. Primary Care: Art and
Science of Advanced Practice. (Philadelphia: F.A. Davis, 2007)
6.Virology Blog. (2011) Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale.
Retrieved online May 12, 2013 at http://www.virology.ws/2011/11/23/chronic-fatiguesyndrome-and-the-cdc-a-long-tangled-tale/
7.Centers for Disease Control and Prevention, National Center for Health Statistics,
Office of the Centers Director, Data Policy and Standards. (2001). A Summary of
Chronic Fatigue Syndrome and Its Classification in the International Classification of
Diseases. Retrieved online May 11, 2013 at http://www.co-cure.org/ICD_code.pdf
8.World Health Organization. (2013). ICD Version 2010: Chronic Fatigue Syndrome.
Retrieved online May 11, 2013 at http://apps.who.int/classifications/apps/icd/
icd10online/
9.Centers for Disease Control and Prevention (2012). Chronic Fatigue Syndrome:
General Information, Case Definition. Retrieved online May 11, 2013 at http://www.
cdc.gov/cfs/general/
10. David S. Bell, E. Van Hoof. Guidelines for the Diagnosis of Pediatric Chronic
Fatigue Syndrome: Things Parents Need to Know. Retrieved online May 11, 2013 at
http://www.cfids-cab.org/rc/Bell.pdf
11. Ignatavicus, D. & Workman, M. Medical-surgical nursing: Critical thinking for
collaborative care (St. Louis: Elsevier Saunders, 2006)
12. Centers for Disease Control and Prevention. (2012). Fibromyalgia. Retrieved online
Page 32
Elite
May 11, 2013 at http://www.cdc.gov/arthritis/basics/fibromyalgia.htm
13. WebMD. (2013). Fibromyalgia in children and teens. Retrievedonline May 11, 2013
at http://www.webmd.com/fibromyalgia/guide/fibromyalgia-in-children-and-teens
14. ICD-10 Version:2010. Retrieved online May 12, 2013 at http://apps.who.int/
classifications/icd10/browse/2010/en#/M79.0
15. Centers for Disease Control and Prevention. (2012). Chronic Fatigue Syndrome:
Background. Retrieved online May 12, 2013 at http://www.cdc.gov/cfs/
16. Centers for Disease Control and Prevention (2011). Disability and Chronic Fatigue
Syndrome. Retrieved online May 12, 2013 at http://www.cdc.gov/cfs/news/features/
disability.html
17. Johnston S, Brenu EW, Staines D, Marshall-Gradisnik S. “The prevalence of
chronic fatigue syndrome/ my-algic encephalomyelitis: a meta-analysis,” Clinical
Epidemiology, 5 (2013): 105-110
18. Leonard Jason, Susan Torres-Harding and Mary Gloria Njoku. The Face of CFS in
the U.S. Retrieved online May 12, 2013 at http://www.cfids.org/special/epi.pdf
19. Medscape (2013). Juvenile Primary Fibromyalgia Syndrome. Retrieved online May
12, 2013 at http://emedicine.medscape.com/article/1006715-overview
20. Pillemere, S. (1998). The Neuroscience and Endocrinology of Fibromyalgia:
National Institute of Health Conference. Haworth: New York
21. Uphold, C. & Graham, M. (2003). Clinical Guidelines in Family Practice. (4th ed).
Barmarrae:Gainsville
22. McPhee, S., Papadakis, M. & Tierney, L. (2008). Current Medical Diagnosis and
Treatment (47th ed). McGraw:Lange
23. Abeles, A., Pilinger, M., Solitar, B., Abeles, M. (2007). Narrative Review: The
Pathophysiology of Fibromyalgia. Ann Intern Med. 2007; 146:726-734
24. Huether, S. & McCance, K. (2008). Understanding Pathophysiology. (4th ed).
Mosby: St Louis
25. International Association for the Study of Pain. (2009). IASP Pain Terminology.
Retrieved May 12. 2013 at http://www.iasp-pain.org/AM/Template.cfm?Section=Pain_
Definitions&Template=/CM/HTMLDisplay.cfm&ContentID=1728
26. United States Food and Drug Administration. (2009). Living with Fibromyalgia,
Drugs Approved to Manage Pain. Retrieved online July 14, 2009 at http://www.fda.
gov/ForConsumers/ConsumerUpdates/ucm107802.htm
27. Centers for Disease Control and Prevention. Chronic Fatigue Syndrome (CFS)
Causes (2012). Retrieved online May 12, 2013 at http://www.cdc.gov/cfs/causes/
index.html
28. Lily. (2008). FDA Approves Cymbalta for the Management of Fibromyalgia.
Retrieved online July 8, 2009 athttp://newsroom.lilly.com/releaseDetail.
cfm?ReleaseID=316740
29. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. “The relationship between neurally
mediated hypotension and the chronic fatigue syndrome,” JAMA, 274 (1995): 961-967
30. Richards, S.C.M., 2001. “The pathophysiology of fibromyalgia,” CPD
Rheumatology, 2 (2001): 31-35
31. Autoimmune Technologies. (2007). Science Summary: The Anti-polymer Antibody
Assay and Fibromyalgia Syndrome. Retrieved online May 12, 2013 at http://www.
autoimmune.com/APASciSum.pdf
32. Wilson RB, Gluck OS, Tesser JR, Rice JC, Meyer A, Bridges AJ. “Antipolymer
antibody reactivity in a sub-set of patients with fibromyalgia correlates with severity,” J
Rheumatol, 26 (1999):402-407
33. Gomella, L. & Haist, S. (2004). Clinician’s Pocket Reference. (10th ed). McGrawHill: New York
34. Desi, S. & Isa-Pratt, S. (2000). Clinician’s Guide to Laboratory Medicine: A Practical
Approach. Lexi-Comp: Hudson
35. Centers for Disease Control and Prevention (2004). Women and Autoimmune
Diseases. Retrieved online May 12, 2013 at http://wwwnc.cdc.gov/eid/
article/10/11/04-0367_article.htm
36. U.S. Department of Health and Human Services Office of Women’s Health
(2010) retrieved online May 12, 2013 at http://womenshealth.gov/publications/ourpublications/fact-sheet/autoimmune-diseases.cfm
37. Jarvis, C. (2008). Physical Examination & Health Assessment. (5th ed). Saunders:
St Louis
38. American College of Rheumatology (2010) Rheumatoid Arthritis Classification.
Retrieved online May 12, 2013 at https://www.rheumatology.org/ACR/practice/
clinical/classification/ra/ra_2010.asp
39. Uphold, C. & Graham, M. (2003). Clinical Guidelines in Family Practice. (4th ed).
Barmarrae:Gainsville
40. Centers for Disease Control and Prevention. (2013). Lyme disease: Two-step
laboratory Testing Process. Retrieved online May 12, 2013 at http://www.cdc.gov/
lyme/diagnosistesting/LabTest/TwoStep/index.html
41. Magill, M., & Suruda, A., (1998). Multiple Chemical Sensitivity Syndrome.
American Family Physician. Retrieved online May 12, 2013 at http://www.aafp.org/
afp/980901ap/magill.html
42. Finley, J. (2008). Myofascial Pain. Retrieved online May 12, 2013 at http://
emedicine.medscape.com/article/313007-overview
43. Centers for Disease Control and Prevention. (2012). Management of CFS. Retrieved
online May 12, 2013 at http://www.cdc.gov/cfs/management/index.html
44. Ostalecki, S. (2008). Fibromyalgia: The Complete Guide from Medical Experts and
Patients. Jones & Bartlett: Massachusetts
45. Donaldson MS, Speight N, Loomis S. “Fibromyalgia syndrome improved using a
mostly raw vegetarian diet: an observational study,” BMC Complement Altern Med,
1 (2001):1-7
46. Lily. (2008). FDA Approves Cymbalta for the Management of Fibromyalgia.
Retrieved online July 8, 2009 athttp://newsroom.lilly.com/releaseDetail.
cfm?ReleaseID=316740
47. Forest Laboratories. (2009). Forest and Cypress Announce FDA Approval of
Savella(TM) for the Management of Fibromyalgia. Retrieved online May 12, 2013
at http://news.frx.com/press-release/product-news/forest-and-cypress-announce-fdaapproval-savellatm-management-fibromyalgi
48. Hopfer-Deglin, J., & Hazard-Vallerand, A. (2009). Davis’s Drug Guide for Nurses
(11th ed). F.A Davis: Philadelphia.
49. Goldberg, B. & Trivieri, L. (2004). Chronic Fatigue, Fibromyalgia, & Lyme Disease.
(2nd ed). Celestial Arts: Berkeley.
50. National Institute of Mental Health. (2009). Antidepressant Medications for Children
and Adolescents: Information for Parents and Caregivers. Retrieved online May 12,
2013 at http://www.nimh.nih.gov/health/topics/child-and-adolescent-mental-health/
antidepressant-medications-for-children-and-adolescents-information-for-parents-andcaregivers.shtml
51. Salinas, J. & Rosenberg, J. (2008). Corticosteroid Injections of Joints and
Soft Tissues. Retrieved online July 13, 2009 at http://emedicine.medscape.com/
article/325370-overview
52. Simmons, K. (2003). Natural Treatments for Fibromyalgia. Arthritis Foundation
53. Ostalecki, S. (2008). Fibromyalgia: The Complete Guide from Medical Experts and
Patients. Jones & Bartlett: Massachusetts.
Chronic Fatigue and
Fibromyalgia Syndromes
Final Examination Questions
Choose the best answer for questions
11 through 20, mark your answer on the final
examination answer sheet found on page 75
or complete your final examination online at
pharmacy.elitecme.com.
17.According to conclusions based on the
Donaldson research on the impact of diet
on the symptoms of fibromyalgia, all
BUT the following dietary choices were
beneficial?
a. Vegetables.
b. Fruit.
c. Foods high in fiber.
d. Meat.
11. According to 2013 financial figures from
the National Institutes of Health, the least
amount of research money has been spent
on which of the following diseases?
a. Alcoholism.
b. Chronic fatigue syndrome.
c. Breast cancer.
d. Fibromyalgia.
18.Which of the following medications has
received FDA approval for the treatment of
fibromyalgia?
a. Pregablin (Lyrica).
b. Duloxetine (Cymbalta).
c. Milnacipram (Savella).
d. All of the above.
12. What percentage of patients with
fibromyalgia also meet the clinical criteria
for chronic fatigue syndrome?
a. 70 percent.
b. 25 percent.
c. 50 percent.
d. 100 percent.
19.The most common side effect observed
after administration of serotonin-selective
uptake inhibitors is:
a. Insomnia.
b. Urinary retention.
c. Blurred vision.
d. Constipation
13. Which of the following disorders is not
typically associated with fibromyalgia?
a. Morning stiffness.
b. Headaches, including migraines.
c. Celiac disease.
d. Irritable bowel syndrome.
20.Which category of medications should be
avoided when treating pain in fibromyalgia
patients?
a. Muscle relaxants.
b. Opioids.
c. Anticonvulsants.
d. Non-steroidal anti-inflammatory drugs.
14. Which of the following is an inhibitory
neurotransmitter?
a. γ-aminobutyric acid (GABA).
b. Histamine.
c. Acetylcholine.
d. Dopamine.
15. Patients suffering from fibromyalgia or
chronic fatigue syndrome have increased
rates of which of the following psychiatric
disorders?
a. Depression.
b. Anxiety.
c. Mood disorders.
d. All of the above.
16. Describe the best-known cure for
fibromyalgia and chronic fatigue
syndrome?
a. Anti-retroviral therapy.
b. Chemotherapy.
c. There is no known cure for
fibromyalgia and chronic fatigue
syndrome.
d. Immunotherapy.
RPCO04CFE13
Elite
Page 33
CHAPTER 3
PAIN MANAGEMENT AWARENESS FOR
PHARMACISTS
(2 CONTACT HOURS)
By Brad Gillespie, PharmD who has over 20 years’
experience spanning the regulatory, pharmaceutical
biotech and human nutritional supplement industries.
Keywords: Pain, nociceptors, neuralgia,
neuropathy, sciatica, arthritis, fibromyalgia,
acupuncture.
Learning objectives
After the pharmacist has concluded this
knowledge-based activity, he or she will be able
to:
Author Disclosure: Bradley Gillespie and Elite
!! Define pain in general terms.
Professional Education do not have any actual or
!! Recognize the individuality of pain and its
potential conflicts of interest in relation to this lesson.
perception.
!! Distinguish between different sources and
Universal Activity Number (UAN):
0761-9999-13-220-H01-P
types of pain.
Activity Type: Knowledge-based
!! Recognize the extent of the pain problem and
Initial Release Date: July 2, 2013
its cost to society.
Expiration Date: July 2, 2015
!! Adopt a general understanding of the process
Target Audience: Pharmacists in a community-based
of pain signaling.
setting.
!! Be familiar with the main sources of pain
experienced by patients.
To Obtain Credit: A minimum test score of 70 percent
is needed to obtain a credit. Please submit your answers !! Be familiar with the various treatment
either by mail, fax, or online at
options available to combat pain, including
pharmacy.elitecme.com.
potential indications and side effects for each.
!
!
Become aware of the use of acupuncture
Questions regarding statements of credit and other
and how it may be integrated into an
customer service issues should be directed to 1-888666-9053. This lesson is $10.00.
individualized pain management strategy.
Educational Review Systems is accredited
by the Accreditation Council of Pharmacy
Education (ACPE) as a provider of
continuing pharmaceutical education. This
program is approved for 2 hours (0.2
CEU’s) of continuing pharmacy education credit. Proof
of participation will be posted to your NABP CPE
profile within 4 to 6 weeks to participants who have
successfully completed the post-test. Participants must
participate in the entire presentation and complete the
course evaluation to receive continuing pharmacy
education credit.
Abstract
Objective: To increase pharmacist awareness
about the needs and concerns of patients stricken
with acute or chronic pain.
Summary: As pharmacists, it is critical that we
are able to identify the various types of pain and
correlative symptoms experienced by the patients
that we serve. Because of the relative complexity
in the pathophysiology and perception of pain
experienced, it is important that pharmacists have
a solid understanding of the most commonly
experienced types of pain, the sources of such
pain, and how it is signaled to the body. Lastly, to
best treat these patients, pharmacists must have
access to the most up-to-date clinical information
and treatment modalities and know how to best
implement them.
Conclusion: Clinical practice tells us that pain
in the patient setting is common. A review of
available pain literature confirms this and makes
us aware of the diversity of pain as it relates
to its pathophysiology and patient perception.
Best practices dictate that effective pharmacists
be fully versed on different types of pain, their
pathophysiology, how it is communicated to the
body, and how the patient perceives it. There
are a number of different treatment approaches
available to combat pain, and it is critical that
pharmacists understand the complexity of pain
syndromes and are aware of treatment options to
have the most significant impact on patient care.
Pre-assessment questions
Before beginning this activity, test your precourse knowledge by answering the following
questions. Please be aware that these questions
may also be included as part of the CPE final
examination.
1. Nociceptive pain can be described as:
a. A process where stimuli are detected by
peripheral nerve fibers.
b. A type of pain resulting from the
activation of pain receptors on the surface
of the body or within tissues, called
somatic pain.
c. A kind of pain felt as a result of injury to
internal organs, called visceral pain.
d. All of the above.
2. The most common cause of nerve damage is
related to:
a. Diabetes.
b. Cancer.
c. Hypertension.
d. Multiple sclerosis.
3. Which of the following statements about
acupuncture is true?
a. Its basis is the depression of specific
points in the body.
b. The most common ailment leading to the
use of acupuncture is Parkinson’s disease.
c. Based on results obtained in recently
conducted placebo-controlled trials,
acupuncture is a robust treatment
modality, resulting in pain relief in the
majority of patients.
d. According to traditional Chinese
medicine, it regulates the flow of vital
energy (qi) along the meridians.
Introduction
According to the International Association for
the Study of Pain (IASP), pain can be defined
in general terms as an unpleasant emotional
and sensory experience that is associated with
potential or actual damage to tissue. It is critical
to note that in some cases, people may be unable
to verbalize the pain they are experiencing, but
still require appropriate therapy for its treatment.
Further, pain is not objective; each individual will
have divergent pain thresholds, and will describe
what he or she is feeling differently.1
At times, people will report that they are
experiencing pain even in the absence of tissue
damage or pathophysiology. In these cases, the
cause is typically psychological. There is no
way to distinguish this experience from injurybased pain based on their subjective report.
Nonetheless, if reported as pain, it should be
accepted and treated as such.1
While pain is quite common, there are a
number of approaches that may be useful in its
treatment. The appropriate treatment plan can
vary, depending on the cause of the pain. In
addition to pain relievers, some patients may
find relief through alternative approaches, such
as acupuncture. In other cases, surgery may be
indicated.2
Defining pain
Everyone’s pain and their perception of it is
different. This variation is likely due to the
assortment of pathologies contributing to the
presence of pain. Some of the main sources of
pain are described below.
Nociceptive pain: According to a concept paper
issued by the European Medicines Agency,
nociceptive pain has been internationally defined
as a process where intense thermal, chemical
or mechanical stimuli can be detected by a
group of peripheral nerve fibers that are called
nociceptors.3
Nociceptive pain can be subdivided further into
somatic pain and visceral pain.
Somatic pain – Somatic pain is typically
a result of the activation of pain receptors
on either the surface of the body or within
musculoskeletal tissues. One common cause
of somatic pain is post-surgical pain from
an incision. This type of pain is typically
described as dull or aching in nature. In
general, somatic pain is usually aggravated
by increased activity and relieved by rest.4
Visceral pain – Visceral pain is felt as a
result of injury or damage to internal organs.
This is likely the most common form of pain
experienced. Visceral pain is a reaction to
activation of pain receptors located in the
pelvic, abdominal or chest areas of the body.
This type of pain is not easily localized
and is vague in nature. Visceral pain is
sometimes described using terms such as
dull, diffuse, pressure-like or deep squeezing.
Actual organ injuries can include distension,
impaction, perforation or inflammation.
Symptoms associated with visceral pain may
include nausea, fever and malaise. On other
occasions, visceral pain can be caused by
issues with muscles, such as spasms.4
Page 34
Elite
Neuropathic pain – In 2009, an expert
committee of the Neuropathic Pain Special
Interest Group of the International Association
for the Study of Pain (NeuPSIG) revised the
definition of neuropathic pain as “pain arising
as a direct consequence of a lesion or disease
affecting the somatosensory system.”5 There are a
variety of sources of neuropathic pain, including
post-herpetic neuralgia, trigeminal neuralgia or
diabetes. This pain is often described in bizarre
terms, including burning or electrical in nature.
Neuropathic pain is often associated with a
sensitivity of the skin.
Psychogenic pain – According to an article
published by the Cleveland Clinic, psychogenic
pain is a disorder stemming from psychological
factors, including mental or emotional problems.
The symptoms of psychogenic pain include
headaches, stomach pain, back pain or muscle
soreness. If all organic causes of pain can be
ruled out, a diagnosis of psychogenic pain is
usually established. In most cases, a patient
complaining of psychogenic pain does not
have correlating symptoms. Often, medical
practitioners will work together with mental
health specialists to reach an appropriate
diagnosis.6
It is important to know that a patient with
psychogenic pain is truly suffering and should be
treated as such.
Epidemiology of pain
To form a representation of the frequency of pain
in the United States, Johannes, et al, conducted
a national survey of 35,718 Americans aged
18 years, and older. A secondary analysis was
designed to try to correlate the characteristics of
chronic pain with socio-demographic variables.
Of all of the subjects surveyed, a total of 27,035
individuals responded.
Chronic pain, defined as recurrent or long-lasting
pain lasting at least six months, was reported
in nearly 31 percent of respondents. These
prevalence estimates were then broken down by
demographics. The prevalence of chronic pain
was higher in females (34 percent) than males
(27 percent), and tended to increase in frequency
with age.
Lower back pain was the most commonly
reported source of pain, occurring in 8 percent
of respondents, with osteoarthritis-derived pain
occurring the second most frequently (4 percent).
Approximately one-half of chronic pain patients
experienced pain every day, with an average pain
rating of severe (>7 on a scale of 0-10) in 32
percent of respondents.
Logistical regression of all respondents suggested
that low household income and unemployment
significantly correlated with chronic pain
incidence.8
Pathophysiology of pain
Without question, pain is a mystery. As a result,
the topic of pain generates intense interest
and enthusiasm as treatment approaches are
considered. Although it is evident that pain exists,
it may be difficult to find its cause. Even in cases
where a cause is found, there may be little or no
correlation between the extent of disease and the
degree of suffering experienced by the patient.
A pathology that may bring excruciating pain to
one person could be easily tolerated by another.
In some cases, even if the cause is identified
and removed, the suffering may continue. Pain
is certainly subjective, although if it exists, it is
usually evident in a distressed patient.8
The system that is pain might be better referred
to as the “nociceptive system” because that pain
is simply the result of nociception. Nociception
is the act of encoding and processing whatever
noxious stimuli is encountered by the nervous
system.9
The movement of pain signals is a highly
complicated process involving the activation of
peripheral nerves, interactions with the spinal
dorsal horn and activating the circuits connecting
the spinal cord to supraspinal structures.
Ultimately, the nerve impulses excite nociceptive
inputs at the level of the spinal cord.
Although this process appears to be part of a
normal process of transmitting and interpreting
pain, the system has the ability to undergo
transformations when pain is encountered over
a period of time as an adaptive feedback loop.
Therapies aimed at disrupting any of the parts of
the loop may be effective at diminishing or even
abolishing the pain.
To avoid interfering with normal sensory
processing, it is critical to fully understand
pain circuits so that rational therapies can be
designed.10
Potential causes of pain
Because of its diversity in source and the
perception of it, pain can stem from any number
of insults to the body. While pain may be formed
from an acute injury or illness, pain can remain
after the removal of the original insult in the form
of psychogenic pain. Some key sources of pain
are discussed below.
Nerve pain. There are more than 100
different types of nerve damage that may lead
to nerve pain. A comprehensive discussion of
all of these is beyond the scope of this course.
Nerve damage is quite common, with more
than 20 million Americans afflicted with
nerve damage to some extent. The incidence
of nerve damage appears to increase with
advancing age. The most common cause of
nerve damage (one in three cases) is related
to diabetes. In another third of patients,
the cause of the nerve damage is never
determined. Known causes of nerve damage
and nerve pain include:11
ŠŠ Various autoimmune diseases can lead
to symptoms of nerve pain and nerve
damage. Some implicated autoimmune
diseases include multiple sclerosis,
Guillain-Barré syndrome, myasthenia
gravis, lupus and inflammatory bowel
disease.12
Elite
ŠŠ In addition to its many deleterious
effects, cancer is capable of causing
nerve pain and damage in a variety
of ways. In some cases, tumors may
actually press up against or crush nerves.
In other instances, certain cancers
may lead to nutritional deficiencies
effecting nerve function. Certain radioand chemotherapy regimens have the
potential to lead to nerve pain in some
patients.13
ŠŠ Anything leading to trauma or the
compression of nerves can lead to nerve
damage and subsequent nerve pain.
Examples include pinched nerves in the
neck, or carpal tunnel syndrome.11
ŠŠ According to a fact sheet published by
the National Institutes of Health, National
Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK), nearly 70
percent of people stricken with diabetes
develop some form of nerve pain. Over
time, nerves throughout the body can
experience such damage and pain. While
some patients have no pain or symptoms,
others experience pain, tingling or
numbness. Although these kinds of nerve
problems can develop at any time, the
incidence increases as a function of age
and duration of disease. The greatest
incidence is in patients who have had
diabetes for at least 25 years. A higher
frequency of symptoms also occurs in
patients with high levels of cholesterol,
increased blood pressure, and those who
are overweight.14
ŠŠ A variety toxins and medications have
the potential to damage nerves and
cause nerve pain. Examples of toxins
leading to nerve pain include lead,
mercury, thallium, pesticides, arsenic,
acrylamide, and ethanol. Further, a
number of medications may cause
nerve pain. Some key examples include
various chemotherapeutics (vincristine,
cisplatin, paclitaxel), anti-HIV
medications (zalcitabine and didanosine),
isoniazide, ethambutol, certain
antimicrobials (dapsone, metronidazole,
chloramphenicol, chloroquine), lithium,
amiodarone, phenytoin, thalidomide,
colchicine, cimetidine, disulfiram and
hydralazine.15
ŠŠ Diseases that affect motor neurons,
including amyotrophic lateral sclerosis,
have the potential to cause nerve pain.
Investigators at the Frenchay Hospital
in Bristol, United Kingdom, evaluated
the incidence of nerve pain in 42
patients with motor neuron disease.
They determined that of those patients,
27 experienced significant pain. The
etiology of this pain and its treatment are
unclear.16
ŠŠ Sustained low vitamin B12 levels
can lead to nerve damage and pain.
Symptoms of nerve damage caused by
Page 35
low vitamin B12 may include confusion
or dementia (in severe cases), depression,
balance issues, numbness and tingling of
extremities. Such nutritional deficiencies
are often linked to excessive alcohol
consumption or occur after gastric
surgery.17
ŠŠ Multiple infectious diseases have the
potential to affect nerves and cause nerve
pain. Infectious diseases implicated
in nerve pain include Lyme disease,
varicella zoster, herpes, HIV and
hepatitis.18
Chest pain. This is often described in terms
ranging from a sharp, stabbing sensation
to a dull ache, to a crushing or burning
feeling. In some cases, the pain may move
throughout the body, radiating down the
arms. Several different conditions may
lead to chest pain, with many having little
significance. Nonetheless, chest pain can also
be associated with life-threatening conditions
involving the heart or lungs.
Differentiating between the various pains
can be difficult, so chest pains need to be
carefully evaluated by a qualified health
professional. Chest pain is certainly a
condition where it is critical to determine and
treat the underlying cause of the pain instead
of just focusing on treating the pain itself.
Burns. Pain attributed to burns is often
present from a wide variety of burn types as
well as differing levels of severity. In general,
burns are categorized into three types:
ŠŠ First-degree burns are typically
considered mild relative to other burns.
First-degree burns affect only the
epidermis and are characterized by pain
and reddening.
ŠŠ Second-degree burns affect not only the
epidermis but also the dermis. Seconddegree burns are associated with pain,
redness, swelling and blistering.
ŠŠ Third-degree burns go beyond the
dermis, affecting deeper tissues. Patients
with third degree burns have white or
blackened, charred skin that may be
numb.
Burns can be a result of contact with dry heat
(fire), wet heat (steam), radiation, heated
objects, the sun, electricity or chemicals.
The degree of pain experienced may not be
related to the severity of the burn; some of
the most serious burns may be painless, while
first-degree burns could be excruciating to
some patients.20
Pinched nerves. Whenever surrounding
tissues (bones, cartilage, tendons, muscles)
exert excessive pressure on a nerve, a
pinched (compressed) nerve may result. In
addition to causing pain, tingling, numbness
or weakness, the pressure can also actually
disrupt the function of the nerve. A pinched
nerve can occur at various sites in the body.
Some frequent examples of pinched nerves
include pressure on a root nerve, leading
to pain that radiates down the back of the
leg (sciatica). A pinched nerve in the wrist,
causing pain and numbness in the hand may
be carpal tunnel syndrome. In extreme cases,
surgery may be required to relieve the pain
presented by a pinched nerve.21
meniscus or ligament tear, strain, or sprain.
Less commonly, knee pain can be caused by
bone tumors.24
Lower leg pain. The lower leg is a common
site of pain. Because lower leg muscles
control the foot, changes in footwear or
changes in activity level can lead to lower
Foot pain. Just about any part of the foot can
leg pain. While increases in activity levels
be afflicted with pain, including the instep,
are the leading cause of lower leg pain, there
arch, toes, heel, or sole. The causes of foot
are a variety of medical conditions that can
pain are many. Some situations pre-disposing
also contribute to the discomfort. Some of the
patients to foot pain include aging, being
more common causes of leg pain include:
overweight, spending extended periods of
ŠŠ Muscle strain or fatigue typically results
time on the feet, congenital foot deformities,
from increased activity, and usually is
injuries, poorly fitted shoes, inadequate shoe
not overly painful. Nonetheless, sudden,
cushioning, and excessive walking or other
severe injuries can lead to muscular tears
sporting activities. In addition, the following
or ruptured tendons, which represent a
medical issues can lead to foot pain: gout,
more serious and painful situation.
broken bones, arthritis, bunions, sprains,
ŠŠ Medial tibial syndrome, also known as
plantar fasciitis, hammer toes, fallen arches,
shin splints, is a common injury, often
and stress fractures.22
affecting runners and jumpers. The pain
is felt where the calf muscles attach to
Hand pain. The human hand is composed of
the bone. Stress fractures of the tibia are
a number of muscles, ligaments and sheaths.
another condition often seen in these
The complexity of the hand allows for a
same patients.
number of things that can go wrong, leading
ŠŠ While tendonitis of the lower leg can
to pain. Some of the more common ailments
strike anyone, it is most commonly
of the hand leading to pain include:
diagnosed in sports overuse-type
ŠŠ Arthritis. A degenerative joint disease
injuries. Tendonitis is an inflammation
called osteoarthritis is the most common
surrounding tendons found in the lower
form of arthritis in older patients. It is a
leg. Tendonitis usually presents as pain
slowly progressing disease that affects
that increases with activity or stretching
the hands. Osteoarthritis can be genetic
of the affected tendon.
or be caused by injuries, muscle strain,
ŠŠ When leg veins become unable to
fatigue or overuse. Joint inflammation,
properly return blood to the heart,
called rheumatoid arthritis, can occur
edema of the leg occurs, sometimes
throughout the hand and wrist. Associated
accompanied with pain or tenderness.
pain can result from inflammation.
One common problem is varicose veins.
ŠŠ Ganglion cysts. These are soft, fluidA potentially life-threatening cause of leg
filled cysts that can mimic other medical
pain is known as deep vein thrombosis,
conditions or problems. Symptoms
which is a clot in a leg vein that can
associated with ganglion cysts include
break off and then become lodged in the
wrist pain, localized swelling with mild
lung, brain or other organs.
aching, and weakness. If ganglion cysts
ŠŠ Peripheral artery disease (PAD) is a
are suspected, a proper diagnosis by a
condition where blood flow to the leg
qualified health professional should be
is restricted because of a narrowing of
conducted. If the cyst grows and becomes
one or more of the arteries that supplies
painful or interferes with the functionality
blood to the leg. PAD is associated with
of the hand, treatment is typically
leg pain while walking that disappears
warranted.
upon rest. PAD is often also associated
ŠŠ Tendonitis. Remarkable problems
with a cold, pale limb with an increased
associated with the tendons include
sensitivity to pain.
tendonitis (inflammation of the tendon,
ŠŠ Pregnant women are especially prone to
common in the wrist and fingers) and
foot and leg problems, especially during
tenosynovitis (inflammation of the lining
the last trimester of pregnancy. Often,
of the tendon sheaths). It is not known
the pain is due to increases in weight and
23
what causes tenosynovitis.
hormonal changes that may cause the
Knee pain. This is a very common complaint
foot’s arch to collapse to some extent.
occurring in patients of all ages. While it
This increases the workload on the leg,
may have a sudden onset, often as a result
resulting in sore legs. Leg cramps may
of an injury or excessive exercise, it may
be caused by blood volume changes or
also begin as a mild discomfort and slowly
from sciatica resulting from the expanded
worsen over time. Being overweight is a
uterus.
risk factor for knee problems and associated
ŠŠ Miscellaneous medical conditions such
pain. Knee pain can be caused by a variety
as fibromyalgia, multiple sclerosis,
of insults, including arthritis, gout, bursitis,
rheumatoid arthritis and thyroid disease
lupus, dislocation, joint infection, tendinitis,
are also sometimes associated with lower
Page 36
Elite
leg pain. Further, other medications
including diuretics and statins have been
known to cause lower leg pain.
ŠŠ Compression of the large sciatic nerve in
the back can lead to pain in the foot. This
sort of pain typically starts in the buttocks
and is felt on the side and back of the leg.
This is often caused by a herniated disc,
spinal stenosis or irritation from a tight
muscle.25
Pelvic pain. Pain felt in the lowest part of
the abdomen, or pelvis, is usually referred
to as pelvic pain. Pelvic pain may be the
result of issues in the reproductive, urinary or
musculoskeletal systems. Because the causes
are diverse, the pain can be felt in different
ways; it can be sharp or dull in nature.
Further, its intensity can range from mild to
severe. On some occasions, pelvic pain can
move to the lower back, thighs, or buttocks.
Pelvic pain can occur acutely or chronically.
Chronic pelvic pain is usually thought of as
pain that has been present for more than a
few months. Some people may experience
pelvic pain only at certain times, such as after
sexual activity or during urination.26
Elbow pain. The elbow, a hinged joint found
between the humerus and the radius and ulnar
bones is stabilized by ligaments on its front,
back and sides. A number of issues with the
elbow can lead to pain. Examples include
osteoarthritis, rheumatoid arthritis, bursitis
(caused by trauma, prolonged pressure,
infection, arthritis or gout), fractures,
dislocations or repetitive strains leading to
inflammation.27
Lower back pain. According to a fact
sheet issued by the National Institute of
Neurological Disorders and Stroke, bone
strength, muscle elasticity and tone usually
all decrease as people age. Further, the discs
in their spine lose their fluid and flexibility,
decreasing their ability to cushion the
vertebrae. Pain can then occur from heavy
lifting or overstretching. More serious
outcomes are possible if a disc ruptures or
bulges.
methodology that can locate, characterize and measure pain with any degree of precision. As a result,
health professionals need to rely on the patients’ description of their discomfort. Defining the pain
as dull/sharp, constant/on-off, burning or aching may be useful questions to ask when obtaining a
pain history. While some technologies may be of some diagnostic value, it is usually best to make a
patient-specific diagnosis and treatment plan.
Pharmacologic treatment of pain
Just like the causes of pain, available treatments are also diverse. Treatment modalities run the gamut,
from over-the-counter pain relievers to controlled substances to acupuncture, with many alternatives
in between. Because of the many different pathologies, it is critical that if one approach fails, another
is tried. When it comes to pain management, no single treatment is guaranteed to work as intended.
Further, relief may be found using a combination treatment approach.
Milder episodes of pain can often be treated using over-the-counter medications. Common over-thecounter medications include31:
Name
Dose
Relative pain
relief score1
Indications
Potential issues
Aspirin (ASA)
81 mg., 325 mg
1
Minor aches,
pains,
cold,
headache,
muscle ache
Allergy,
asthma,
Reyes syndrome
Acetaminophen
(APAP)
500 mg.
2
Headache
Liver damage
Aspirin +
acetaminophen
325 mg. (ASA)
500 mg. (APAP)
2.25
Headache,
muscle ache
Allergy,
asthma,
Reyes syndrome,
liver damage
Ibuprofen
200 mg.
2.5
Fever,
muscle ache
Aspirin allergy,
asthma,
upset stomach,
contraindicated in
final trimester of
pregnancy
Naproxen sodium
220 mg
3
Joint and
muscle pain
Heart risk,
upset stomach,
contraindicated in
nursing mothers
Ketoprofen
12.5 mg
3.6
Antiinflammatory,
analgesic
Allergies, GI
bleed, nausea,
stomach pain,
muscle weakness
Lower back pain may also be a result of
nerve or muscle irritation following injury
to the back or degenerative diseases, viral
infections or congenital abnormalities of the
spine. In some cases, lower back pain can
indicate a more serious medical problem.
If the pain is accompanied by fever, loss
of bowel/bladder control, or progressive
weakness in the legs, a pinched nerve or other
serious medical condition may be in play.
Diabetic neuropathy often presents itself as
lower back pain. Patients with this condition
should immediately seek treatment from a
qualified medical professional in order to
prevent permanent damage.28
The diagnosis of pain can be complex because
of its extremely personal and subjective
nature. There is no available technology or test
Elite
Page 37
If over-the-counter drugs are inadequate for pain
control, stronger prescription medications may
be indicated. Examples of stronger medications
include:
Muscle relaxants. Although muscle
relaxants, such as metaxolone, have gained
wide usage as adjuvants in the treatment of
pain, according to a recent review article,
muscle relaxants showed no advantage over
a placebo, either alone or in combination
with non-steroidal anti-inflammatory drugs.
Nonetheless, even short-term use of muscle
relaxants was associated with significant
adverse events, including drowsiness and
dizziness.32
Anti-anxiety drugs. Anti-anxiety drugs
(benzodiazepines, including diazepam,
alprazolam, triazolam and lorazepam) that
also reduce muscle spasms are widely used
in combination with other drugs to combat
pain. A recent review article that examined
several clinical studies employing these drugs
showed no advantage over a placebo, either
alone or in combination with non-steroidal
anti-inflammatory drugs. Nonetheless, even
short-term use of muscle relaxants was
associated with significant adverse events,
including drowsiness and dizziness.32
Antidepressants. Although not FDA
approved for the treatment of many types
of pain, antidepressants are an important
modality in the treatment for many painful
conditions. Antidepressants seem to work
best for treating pain caused by arthritis,
neuropathy, nerve damage (post-herpetic
neuralgia), migraine, fibromyalgia, lower
back pain and pelvic pain. The mechanism
by which these drugs kill pain is not
clearly understood, but they may modulate
neurotransmitters that transmit pain signals.
Usually, these drugs take several weeks to
take full effect, so some patience is required.
Antidepressants are classified based on
their chemical structure and how they work.
Examples include:33
ŠŠ Tricyclic anti-depressants are likely
the most effective antidepressant used
for pain. Important tricyclics include
amitriptyline, imipramine, clomipramine,
nortriptyline and desiprmaine. Side
effects of tricyclics may include
blurred vision, drowsiness, dry mouth,
constipation, weight gain and changes
in blood pressure. Most patients find
that they can take relatively low doses
of tricyclics (typically lower than the
doses used to treat depression) with only
minimal side effects.
ŠŠ In addition to tricyclics, other classes of
antidepressants have become commonly
used in the treatment of pain. Examples
include:
Serotonin and norepinephrine
reuptake inhibitors (SNRI), such as
venlafaxine and duloxetine, don’t
usually work as well as tricyclics, but
may be associated with fewer side
effects.
Selective serotonin reuptake
inhibitors (SSRI), such as paroxetine
and fluoxetine, do not appear to work
well when used as monotherapy, but
may help to boost the efficacy of
tricyclics.
NSAIDs. Prescription non-steroidal
anti-inflammatory drugs are effective at
reducing pain by decreasing inflammation.
These medications are most commonly
used in the treatment of pain caused by
rheumatologic disorders, osteoarthritis and
painful musculoskeletal conditions, such as
back pain. Some common prescription nonsteroidal anti-inflammatory drugs include
celecoxib, diclofenac, etodolac, flurbiprofen,
indomethacin, ketorolac, naproxen sodium,
piroxicam and sulindac. When large or
extended doses are taken, some side effects
may occur, most commonly gastrointestinal
symptoms, including bleeding. In many
cases, these adverse events can be avoided by
taking the drug with food, milk or antacids.34
Narcotics. According to a 2002 publication,
chronic pain affects at least 50 million
Americans at an annual cost of $70 billion.
This represents a significant health burden
to our society. While cancer pain therapy
has improved substantially, the treatment of
non-malignant pain, primarily in the primary
care setting, is often a challenge. This use
of narcotic drugs is less comprehensively
studied than their use in malignant settings
and is much more controversial, with the fear
of addiction frequently cited as a barrier to
their use.35
Nonetheless, when used appropriately,
narcotics are useful for the treatment of pain
that is not helped by weaker drugs. Narcotics
should typically be used for periods of less
than 3-4 months. Commonly used narcotics
include codeine, fentanyl, meperdidine,
morphine, oxycodone, tramadol,
hydrocodone and hydromorphone. These
medications are known to cause drowsiness,
impaired judgment, itching, constipation,
nausea and vomiting. Nausea and vomiting
may be limited by taking narcotics with
food.36
Cortisone injections. These may be useful
to treat pain and inflammation in a specific
area or region of the body. In most cases,
cortisone injections are given directly into
effected joints, such as the ankle, wrist,
shoulder, elbow, hip or knee. Typically, the
cortisone shot is accompanied by a local
anesthetic. The total number of injections that
can be received in a one-year period is often
limited because of potential side effects.
Patient-controlled analgesia (PCA). This
is a delivery system that allows patients to
self-administer analgesic medications to
relieve their pain. Over the course of the past
30 years, the use of this technology has been
increasing because of its proven advantages
over conventional injections of painkillers.
These include improved pain relief, greater
patient satisfaction, fewer complications
and reduced sedation. In addition to an
initial loading dose, each program is set up
to include a demand dose level, a lockout
interval, and a background infusion rate.
Although other drugs are used, morphine
is the most commonly studied intravenous
compound used in PCA.
Nerve blocks. Several types of nerve
blocks can be used for the management of
pain. Typically, a group of nerves referred
to as a plexus or ganglion causes pain to a
specific region or organ in the body. Pain can
sometimes be blocked to that part of the body
by injecting medication into that ganglion.
This procedure is called a nerve block. Nerve
blocks are used in various ways to serve
different purposes, including therapeutic
nerve blocks to treat painful conditions,
diagnostic nerve blocks to determine sources
of pain, prognostic nerve blocks to predict the
outcome of treatment and pre-emptive nerve
blocks, which can sometimes prevent pain
from a procedure.
Like all medications and procedures, nerve
blocks are not without risk. Common adverse
events include elevated blood sugar, rash,
itching, soreness at injection site, bleeding,
and rarely, death. Nerve blocks are most
effective in cases where pain is emanating
from a single or small group of nerves.
Acupuncture
Acupuncture, a part of traditional Chinese
medicine, is one of the oldest healing practices
in the world. The basis of acupuncture is the
stimulation of specific points in the body, usually
by inserting thin needles through the skin.
According to the traditional Chinese medicine
theory, this regulates the flow of vital energy
(called qi) along pathways called meridians.
Based on the results obtained in a 2007 survey,
approximately 1.4 percent of Americans said
they had used acupuncture in the previous year.
Analysis of data obtained in a previous survey
found that pain or musculoskeletal complaints
accounted for 70 percent of the conditions
leading people to acupuncture. The most common
pain complained of was in the back, followed by
headache/migraine, joint pain and neck pain.
Because of divergent study design, it is not
straightforward to compare results obtained in
different studies of acupuncture. Main differences
included techniques used, comparison groups and
outcome measurements.
More recent studies tend to include placebo
control groups. In a 2009 review of the literature
evaluating placebo-controlled clinical studies,
the pain-relieving effects of acupuncture were
found to be inconclusive. The investigators
determined that there was a small difference
observed between acupuncture and a placebo,
Page 38
Elite
and a moderate difference between placebo and
no acupuncture.40
In spite of the objective proof of efficacy, some
success has been observed in cases where
acupuncture is used alone or in combination
with conventional treatment approaches. It may
be appropriate to consider acupuncture in some
cases of pain management.
Summary and conclusions
The source and pathophysiology of pain is as
diverse as each patient’s characterization of
the misery that he or she is experiencing. To
further complicate matters, with myriad of
treatment options available, it is crucial that the
effective pharmacist be familiar with them all.
As such, it is important for the pharmacist to
truly understand the underlying mechanisms of
pain and then apply this knowledge by carefully
and comprehensively determining individual
patient needs before contributing to their care.
Lastly, it is critical for pharmacists to be aware
that because pain is so individualized, it may be
necessary in some cases to combine treatment
approaches, including such unconventional
treatment methods as acupuncture.
30. WebMD (2013). Pain management: treatment overview. Retrieved online 15 June
2013 at: http://www.webmd.com/pain-management/guide/cause-treatments
31. Vaughn’s Summaries (2013). Pain killers comparison chart. Retrieved online 15 June
2013 at: http://www.vaughns-1-pagers.com/medicine/painkiller-comparison.htm
32. Richards BL, Whittle SL, Buchbinder R. Muscle relaxants for pain management
in rheumatoid arthritis. Cochrane Database Syst Rev. 2012 Jan 18;1:CD008922. doi:
10.1002/14651858.CD008922.pub2
33. Mayo Clinic (2010). Antidepressants: Another weapon against chronic pain.
Retrieved online 15 June 2013 at: http://www.mayoclinic.com/health/pain-medications/
PN00044
34. Cleveland Clinic (2008). Non-steroidal anti-inflammatory medicines. Retrieved
online 15 June 2013 at: http://my.clevelandclinic.org/drugs/non-steroidal_antiinflammatory_drugs/hic_non-steroidal_anti-inflammatory_medicines_nsaids.aspx
35. Olsen Y, Daumit GL. Chronic Pain and Narcotics A Dilemma for Primary Care. J
Gen Intern Med. 2002; 17: 238–240
36. US National Library of Medicine, MedlinePlus (2013). Pain medications – narcotics.
Retrieved online 15 June 2013 at: http://www.nlm.nih.gov/medlineplus/ency/
article/007489.htm
37. Mayo Clinic (2010). Cortisone shots. Retrieved online 15 June 2013 at: http://www.
mayoclinic.com/health/cortisone-shots/MY00268
38. Momeni M, Crucitti M, De Kock M. Patient-controlled analgesia in the management
of postoperative pain. Drugs. 2006; 66:2321-37
39. WebMD (2013). Pain management and nerve blocks. Retrieved online 15 June 2013
at: http://www.webmd.com/pain-management/guide/nerve-blocks
40. National Institutes of Health- National Center for Complementary and Alternative
Medicine (NCCAM) (2010). Acupuncture for pain. Retrieved online 15 June 2013 at:
http://nccam.nih.gov/health/acupuncture/acupuncture-for-pain.htm#use
References
1.International Association for the Study of Pain (2013). Pain Terms. Retrieved online 15
June 2013 at: http://www.iasp-pain.org/AM/Template.cfm?Section=General_Resource_
Links&Template=/CM/HTMLDisplay.cfm&ContentID=3058
2.US National Library of Medicine, MedlinePlus (2013). Pain. Retrieved online 15 June
2013 at: http://www.nlm.nih.gov/medlineplus/pain.html
3.European Medicines Agency (2011). Concept paper on the need for revision of Note
for Guidance on Clinical Medicinal Products for Treatment of Nociceptive Pain
and Guideline on clinical investigation of products intended for the treatment of
neuropathic pain. Retrieved online on 15 June 2013 at: http://www.ema.europa.eu/docs/
en_GB/document_library/Scientific_guideline/2011/09/WC500115353.pdf
4.Louis Calder Memorial Library, the University of Miami. (2013). Rehab Team Site:
Somatic Pain. Retrieved online 15 June 2013 at: http://calder.med.miami.edu/pointis/
typepain.html
5.Geber C, Baumgärtner U, Schwab R, et al. Revised definition of neuropathic pain and
its grading system: an open case series illustrating its use in clinical practice. Am J
Med. 2009 Oct;122(10 Suppl):S3-12. doi: 10.1016/j.amjmed.2009.04.005
6.Cleveland Clinic (2008). Health Hub: What is psychogenic pain? Retrieved
online 15 June 2013 at: http://my.clevelandclinic.org/services/pain_management/
hic_psychogenic_pain.aspx
7.Johannes CB, Le TK, Zhou X, Johnston JA, et al. The prevalence of chronic pain in
United States adults: results of an Internet-based survey. J Pain. 2010 Nov;11(11):12309. doi: 10.1016/j.jpain.2010.07.002
8.Goodman CE. Pathophysiology of Pain. Arch Int Med. 1983; 143:527-530
9.Schaible HG, Richter F. Pathophysiology of Pain. Langenbecks Arch Surg. 2004;
389:237-243
10. Vanderah TW. Pathophysiology of Pain. Medical Clinics of North America. 2007;
91:1-12
11. WebMD (2013). Nerve pain and nerve damage. Retrieved online 15 June 2013 at:
http://www.webmd.com/brain/nerve-pain-and-nerve-damage-symptoms-and-causes
12. Medical News Today (2012). What is neuropathy? Neuropathy causes and
treatments. Retrieved online 15 June 2013 at: http://www.medicalnewstoday.com/
articles/147963.php
13. Mayo Clinic (2011). Cancer pain, relief is possible. Retrieved online 15 June 2013
at: http://www.mayoclinic.com/health/cancer-pain/CA00021
14. US Department of Health and Human Services, National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) (2012). Diabetic Neuropathies: The nerve
damage of diabetes. Retrieved online 15 June 2013 at: http://diabetes.niddk.nih.gov/
dm/pubs/neuropathies/
15. NYU Langone Medical Center (2013). Peripheral neuropathy. Retrieved online 15
June 2013 at: http://www.med.nyu.edu/content?ChunkIID=11627
16. Newrick PG, Langton-Hewer R. Pain in motor neuron disease. J Neurol Neurosurg
Psych. 1985; 48:838-840.
17. US National Library of Medicine, MedlinePlus (2013). Anemia – B12 deficiency.
Retrieved online 15 June 2013 at: http://www.nlm.nih.gov/medlineplus/ency/
article/000574.htm
18. Portsmouth Regional Hospital (2013). Nerve pain. Retrieved online 15 June 2013 at:
http://portsmouthhospital.com/service/nerve-pain
19. Mayo Clinic (2012). Chest Pain. Retrieved online 15 June 2013 at: http://www.
mayoclinic.com/health/chest-pain/DS00016
20. Cleveland Clinic (2013). Burn Pain. Retrieved online 15 June 2013 at: http://
my.clevelandclinic.org/disorders/burns/hic_burn_pain.aspx
21. Mayo Clinic (2011). Pinched nerve: definition. Retrieved online 15 June 2013 at:
http://www.mayoclinic.com/health/pinched-nerve/DS00879
22. US National Library of Medicine, MedlinePlus (2012). Foot pain. Retrieved online
15 June 2013 at: http://www.nlm.nih.gov/medlineplus/ency/article/003183.htm
23. The Ohio State University: Wexner Medical Center (2013). Hand pain & problems.
Retrieved online 15 June 2013 at: http://medicalcenter.osu.edu/patientcare/healthcare_
services/orthopaedics/hand/Pages/index.aspx
24. US National Library of Medicine, MedlinePlus (2012). Knee pain. Retrieved online
15 June 2013 at: http://www.nlm.nih.gov/medlineplus/ency/article/003187.htm
25. About.com: Podiatry (2013). 8 causes of lower leg pain. Retrieved online 15 June
2013 at: http://foothealth.about.com/od/exercisefeet/tp/Lower-Leg-Pain.htm
26. Mayo Clinic (2013). Pelvic Pain. Retrieved online 15 June 2013 at: http://www.
mayoclinic.com/health/pelvic-pain/MY00124
27. The Ohio State University: Wexler Medical Center (2013). Elbow pain. Retrieved
online 15 June 2013 at: http://medicalcenter.osu.edu/patientcare/healthcare_services/
orthopaedics/joint/elbow_pain/Pages/index.aspx
28. National Institutes of Health- National Institute of Neurological Disorders and Stroke
(2013). Low back pain fact sheet. Retrieved online 15 June 2013 at: http://www.ninds.
nih.gov/disorders/backpain/detail_backpain.htm#230763102
29. US National Library of Medicine, MedlinePlus (2011). Chronic Pain: symptoms,
diagnosis & treatment. Retrieved online 15 June 2013 at: http://www.nlm.nih.gov/
medlineplus/magazine/issues/spring11/articles/spring11pg5-6.html
Elite
PAIN MANAGEMENT AWARENESS
FOR PHARMACISTS
Final Examination Questions
Choose the best answer for questions
21 through 25, mark your answer on the final
examination answer sheet found on page 75
or complete your final examination online at
pharmacy.elitecme.com.
21.Pain can be defined in general terms as:
a. A broken bone.
b. An unpleasant emotional and sensory
experience.
c. A discomfort that can always be
verbalized.
d. A response always caused by actual
tissue damage or pathophysiology.
22.Patients with cancer often experience nerve
damage and pain. The cause of pain in
these patients includes all but which of the
following?
a. Tumors exerting pressure on nerves.
b. Cancer-caused nutritional deficiencies
effecting nerve function.
c. A direct consequence of certain radioand chemotherapy regimens.
d. Hormonal imbalances.
23.Which of the following statements about
pinched nerves is false?
a. They are a result of excessive pressure.
b. They can occur only in the legs.
c. One common example is a pain
radiating down the leg, called sciatica.
d. One type of pinched nerve in the wrist
is called carpal tunnel syndrome.
24.Which of the following over-the-counter
pain medications are ranked in order of
their relative pain-relief scores, from
lowest to highest?
a. Naproxen sodium, ketoprofen, aspirin,
ibuprofen.
b. Aspirin, acetaminophen, ibuprofen,
ketoprofen.
c. Ketoprofen, ibuprofen, acetaminophen,
aspirin.
d. Acetaminophen, ibuprofen, ketoprofen,
aspirin.
25.Although not FDA approved for many
types of pain treatment, antidepressants
have been found to be effective in the
treatment of all of the below pain types
except:
a. Arthritis.
b. Headache.
c. Neuropathy.
d. Fibromyalgia.
RPCO02PME13
Page 39
CHAPTER 4
PATIENT SAFETY AND MEDICATION
ERRORS
(3 CONTACT HOURS)
By Brad Gillespie, PharmD who has over 20 years’
experience spanning the regulatory, pharmaceutical
biotech and human nutritional supplement industries.
Pre-assessment questions
Prior to beginning work on this activity, test your
baseline knowledge by answering the following
questions. These questions may be repeated in the
final examination.
1. Which of the following is not a component of
a safe medication system?
a. Administration of the drug.
Author Disclosure: Bradley Gillespie and Elite
Professional Education do not have any actual or
b. Preparation and dispensation of the drug.
potential conflicts of interest in relation to this lesson.
c. Selecting the generic equivalent that
provides the best profit margin.
Universal Activity Number (UAN):
d. Selection and procurement of the drug by
0761-9999-13-168-H05-P
Activity Type: Knowledge-based
a pharmacy.
Initial Release Date: May 18 2013
2. Many Internet pharmacies try to alleviate
Expiration Date: May 30, 2015
patient anxiety by noting that they are
ordering their prescriptions under the concept
Target Audience: Pharmacists in a community-based
setting.
of “responsible self-treatment.” Which of
the following are components of responsible
To Obtain Credit: A minimum test score of 70 percent
self-treatment?
is needed to obtain a credit. Please submit your answers
a. There are no medications with guaranteed
either by mail, fax, or online at
pharmacy.elitecme.com.
efficacy.
b.
Most medications are safe.
Questions regarding statements of credit and other
c. The Internet pharmacy takes full
customer service issues should be directed to 1-888responsibility for the patient’s safety.
666-9053. This lesson is $15.00.
d. All medications act independent of each
Educational Review Systems is accredited
other.
by the Accreditation Council of Pharmacy
3.
FDA
has determined that it is always safe
Education (ACPE) as a provider of
to purchase medications from Internet
continuing pharmaceutical education. This
pharmacies.
program is approved for 3 hours (0.3
CEU’s) of continuing pharmacy education credit. Proof
a. True
of participation will be posted to your NABP CPE
b. False.
profile within 4 to 6 weeks to participants who have
successfully completed the post-test. Participants must
participate in the entire presentation and complete the
course evaluation to receive continuing pharmacy
education credit.
Learning objectives
At the conclusion of this knowledge-based
learning activity, the pharmacist will be able to:
!! Describe the significance of the Institute
of Medicine’s 1999 and 2006 report on
medication errors.
!! Define and distinguish between the following
terms: safe medication, drug safety, quality
issues, medication errors and adverse drug
events.
!! List each of the governing bodies involved in
medication safety (FDA, AHRQ, IOM, USP,
NCC, ISMP, JCAHO).
!! Identify the types of medication errors made
by pharmacists.
!! Discuss additional reasons that pharmacists
may cause a medication error, as defined by
the Food and Drug Administration.
!! Identify the ways a patient may be
responsible for initiating a medication error.
!! Discuss the format for reporting a medication
error.
!! Identify ways to promote medication safety
for patients.
!! Identify the six medication “rights” to
improve patient safety.
!! Discuss recommendations to improve patient
safety during the distribution phase of drug
administration.
!! Identify the consumer’s role in improving
medication safety.
Introduction
Over the past decade, medication safety has been
a big concern for pharmacists who dispense or
administer medications to patients. The Institute
of Medicine (IOM) states that even though
medication errors can occur anywhere within a
safe medication system, it occurs more frequently
in the prescription and administration processes.1
Pharmacists need to be especially concerned with
the prevention of errors during the process of
preparing and dispensing medications.
In 1999, the public learned about medication
errors when the Institute of Medicine (IOM)
released a report, “To Err is Human: Building a
Safer Health System.” The IOM report disclosed
that an estimated 44,000 to 98,000 deaths result
from medical errors in hospitals alone, with 7,000
of the deaths related to medications.2 The report
was a revelation to patients, families and the
entire health care team.
As pharmacists, it is imperative to understand
the legalities, responsibilities and accountability
that we have to patients while participating in
any component of the medication administration
process.
In 2004, the Food and Drug Administration
(FDA) reported alarming data provided by the
Slone Epidemiology Center at Boston University,
showing that in a given week, half of U.S. adults
will use prescription drugs, and 10 percent will
take at least five different medications.3
In 2006, the IOM reiterated the data, as it
estimated that in any given week, four out of
every five adults will use a prescription medicine,
over-the-counter (OTC) drug, or dietary
supplement, and nearly one-third of adults will
ingest five or more different medications.4
In 2001, Ernst and Grizzle estimated that the
total cost of drug-related morbidity and mortality
in the ambulatory care setting was more than
$177 billion, which is greater than the cost of the
medications themselves.5
To avoid even unintentional harm to patients,
health care professionals must understand and
abide by the expectations bestowed upon them.
Patients and their families put their trust in health
care professionals each time they enter a health
care facility. It is our duty as pharmacists to
serve and protect each patient by appreciating
the power of each drug before dispensing any
medication to a patient.
Definitions related to the safety of
medications
The FDA defines “safe” medication as one whose
benefits outweigh the risks for patients.27 The
IOM uses the terms “drug safety” and “quality
issues” in discussion of the safe, effective,
appropriate and efficient use of medications.6
There are five components in a safe medication
system:
1. Selection and procurement of the drug by a
pharmacy.
2. Prescription and selection of the drug for the
patient.
3. Preparation and dispensation of the drug.
4. Administration of the drug.
5. Monitoring of the patient for its effect.30
Although all of these items are not always
under the watchful purview of the pharmacist,
he or she should be at least mindful, if not fully
responsible, for all of these critical points.
A medication error is defined by the National
Coordinating Council (NCC) as “any preventable
event that may cause or lead to inappropriate
medication use or patient harm while the
medication is in the control of the health care
professional, patient or consumer.”7
In 1996, the NCC classified a medication error
based upon the severity of the outcome to ensure
that all health care professionals use the same
terminology and to track errors in a consistent,
systematic manner.8 In July 2006, the National
Academies of the IOM released a report that
claimed 1.5 million people are harmed annually
by medication errors, which cost more than
$3.5 billion a year.9 This figure alone should be
adequate to get the attention of all practicing
pharmacists. Further, in 2006, a study showed
that the most common medical errors are related
to medications.10
Adverse drug events are defined as “any response
to a drug which is noxious or unintended, and
which occurs at doses normally used in humans
for the prophylaxis, diagnosis, or therapy
of disease.”11 According to the Agency for
Healthcare Research and Quality (AHRQ), more
than 770,000 people are injured or die each year
in hospitals from adverse drug events, which may
Page 40
Elite
cost up to $5.6 million each year per hospital,
depending on hospital size.12
Although the data is alarming, this estimate did
not include the effect of adverse drug events
on the length of the admission, malpractice and
litigation costs, or the costs of injuries to patients.
The AHRQ estimates that the cost to U.S.
hospitals to treat patients who suffer adverse drug
events during hospitalization is between $1.56
and $5.6 billion annually.35
According to the IOM, although adverse drug
events are rising and considered preventable, it
is difficult to obtain an accurate measurement of
how often preventable adverse drug events occur
in the various phases of the drug use process.
The IOM alludes to studies over the past few
years estimating that anywhere from 380,000 to
800,000 preventable adverse drug events occur
annually – however, the committees believe that
these are underestimates. According to the IOM
committee, although the data varies depending
on the study, it is estimated that 1.5 million
preventable adverse drug events occur in the U.S.
annually.13
Governing bodies
To have a better understanding of medication
safety, it is important to understand that there
are many agencies and organizations eager to
promote the safety of medications for patients
and health care professionals alike. Each is
geared toward monitoring the efficacy of
every medication on the market, and providing
education to the public and health care
professionals. Below are a few of the agencies
and organizations that monitor adverse drug
events and medication errors every year.
HHS: The U.S. Department of Health and
Human Services (HHS) is the government’s
principal agency for protecting the health of
all Americans and providing essential human
services, especially for those who are least able
to help themselves. HHS encompasses more than
300 programs related to the health of Americans,
including safe monitoring and administration of
medications.
For fiscal year 2014, the HHS budget is
approximately $967.3 billion.14 There are two
U.S. public health agencies under the HHS
responsible for the efficacy encompassing
medications, the Food and Drug Administration
and the Agency for Healthcare Research and
Quality.15
FDA: The Food and Drug Administration
(FDA) is well known to the public and health
care professionals. The FDA began as a
single agency with a single chemist in 1862.
In 1906, the Federal Food and Drug act was
passed, but the FDA did not get its name until
July 1930.16 The FDA’s mission is to protect
public health by assuring the safety, efficacy
and security of human and veterinary drugs,
biological products, medical devices, the
nation’s food supply, cosmetics and products
that emit radiation.17
While FDA regulates and approves all
medications, it does not usually conduct
the research supporting these approvals.
Within the FDA, there are numerous groups
responsible for ensuring patient safety, public
knowledge and the prevention of medication
errors. FDA has collaborated with other
agencies to establish a standard framework
to electronically share important data about
medications to promote efficiency and
safety.18 FDA has a subsidiary component,
called MedWatch, that is responsible for
safety information and adverse event
reporting.19
AHRQ: The Agency for Healthcare Research
and Quality (AHRQ) was established in 1989
as the Agency for Health Care Policy and
Research. Reauthorizing legislation passed
in November 1999 established AHRQ as the
lead federal agency on health care quality
research. AHRQ, part of the U.S. Department
of Health and Human Services, is the lead
agency charged with supporting research
designed to improve the quality of health
care, reduce its cost, and broaden access to
essential services. AHRQ has completed a
vast amount of research on medication errors,
medication safety and the effect on patients.20
The National Academy of Sciences is an
adviser on scientific and technological matters.
It was chartered by the U.S. government under
the auspices of President Abraham Lincoln in
1863. In 1970, the Institutes of Medicine (IOM)
was founded as an independent, nonprofit
organization that provides unbiased and highly
authoritative information needed to guide
government decision makers and the public.
Although the IOM is independent and works
outside of the government, it serves as the health
arm of the National Academy of Sciences.21 The
unique component of the IOM is that researchers
and scientists are unpaid volunteer experts,
dedicated to promoting safe medication practices.
IOM: The Institute of Medicine (IOM)
encompasses experts and scientists tasked with
improving the lives of millions of people around
the world using evidenced-based practice.22
The IOM is mandated by Congress, through the
Medicare Modernization Act of 2003 (Section
107 (c)), to “carry out a comprehensive study of
drug safety and quality issues in order to provide
a blueprint for system-wide change.”23
One of the committees involved in promoting
medication safety within the IOM is formed
from within the Center for Drug Evaluation and
Research (CDER) at FDA. CDER’s goal is to
review the drug information, safety surveillances
and key aspects of the contributions of the
pharmaceutical industry, academic research,
Congress and patients using medications.24
For-profit organizations
USP: The United States Pharmacopeia (USP) is
the official public standards-setting authority for
all prescription and over-the-counter medicines,
dietary supplements and other health care
Elite
products manufactured and sold in the United
States. USP sets standards for the quality of these
products, and works with health care providers
to achieve those standards. The USP standards
are also recognized and used in more than 130
countries. It has helped ensure the manufacture of
high quality pharmaceuticals, as well as reliable
pharmaceutical care, for people throughout the
world, for more than 185 years.25
NCC: In 1995, the National Coordinating
Council (NCC) was established to promote the
safe use of medications. The mission of the
National Coordinating Council for Medication
Error Reporting and Prevention (NCC-MERP) is
to maximize the safe use of medications and to
increase awareness of medication errors through
open communication, increased reporting,
and promotion of medication error prevention
strategies.26 The NCC-MERP helps to heighten
awareness of medication reports within the
health care system and provides education on
medication errors for consumers and health
care professionals. Further to that, NCC-MERP
develops comprehensive literature reviews,
describing the safe use of medications. Its goal is
to protect patients by not allowing any patient to
be harmed by a medication error.27
Nonprofit organizations promoting
patient safety
ISMP: The Institute for Safe Medication
Practices (ISMP) began in 1975 as a nonprofit
organization that receives no advertising revenue
and is devoted entirely to medication error
prevention and safe medication use.28 The ISMP
took over management of the United States
Pharmacopeia-developed Medication Errors
Reporting Program (USP-MERP) in late 2008,
re-branding it as ISMP MERP.
ISMP MERP is designed for reporting the
cause of medication errors and provides
recommendations for preventing future errors,
always identifying the erroneously used
medication. In addition, the ISMP reports to
the appropriate regulatory agency and the
manufacturer of the company. To assess whether
any medication has been incorrectly listed
anywhere, the Institute for Safe Medication
Practices continuously updates its website, noting
any incorrect data published in textbooks and
publications.29
JCAHO: Joint Commission on Accreditation of
Healthcare (JCAHO) is a nonprofit organization
that has been affiliated with monitoring patients
in some capacity since 1910. In 1965, Congress
passed the Social Security amendment that
incorporated a provision in which each hospital
needs to be JCAHO-accredited to receive
reimbursement for patient care from Medicare or
Medicaid.30 The goal of JCAHO is to improve the
safety and quality of care provided to the public
through the provision of health care accreditation
and related services that support performance
improvement in health care organizations.
Page 41
Background
As pharmacists, we enter the profession so that
we may care for others, and to ensure that no
harm comes as a result of this care. Although
one’s intentions may be good while caring for
a patient, medication errors do occur on a daily
basis, often at the expense of the patient.
Regardless of the circumstances, while caring for
another, it is important to remember: “I am here
to care for this patient and family; they have put
their trust in me.” We must remember to treat
each patient as we would want our loved ones to
be cared for while in the hands and at the mercy
of the health care system.
Throughout our health care system, with today’s
economic realities, professionals encounter
shortages in their departments. Although it
may induce more stress in the workplace, that
should not affect safe medication practices and
pharmaceutical care.
To bring change to the system, it is imperative
to recognize the components that contribute to
medication errors. According to McLeod (2007),
the Joint Commission Journal on Quality and
Patient Safety has said that nearly 5 percent
of errors reported to the national database for
medication errors from 2004 to 2006 involved
medication abbreviations, and the majority (81
percent) occurred during the prescribing phase.31
Based upon the study of nearly 30,000
abbreviation-related medication errors, JCAHO
in 2005 initiated the “Official Do Not Use
List” that was implemented in the hospitals
nationwide (See Table 1).32 Of the common
abbreviations used by many experienced health
care professionals, “QD” for “once daily” was
associated with more errors than any other
abbreviation, followed by “U” for units (13.1
percent), “cc” for milliliter (12.6 percent) and
“MSO4” or “MS” for morphine sulfate (9.7
percent).28 The “Official Do Not Use List”
is being used by health care professionals
nationwide, and it was also incorporated into
JCAHO’s patient safety goals.32
The ISMP recommends that health care
professionals do not stop at the minimum
guidelines of JCAHO standards on abbreviations
to avoid preventing medication errors.
Since 2006, the ISMP has offered a more
comprehensive list that can be accessed on the
Internet.33
Types of medication errors involving
health care professionals
According to FDA, medication errors contribute
to at least one death every day, and injure
approximately 1.3 million people annually in the
United States. Between 1993 and 1998, the FDA
completed a study in which it found that the most
common medication errors were the following:
Administration of an improper dose of
medicine, accounting for 41 percent of fatal
medication errors.
Administration of the wrong drug, accounting
for 16 percent of fatal medication errors.
Administration of medicine using the wrong
route of administration, accounting for 16
percent of fatal medication errors.
Almost half of the fatal medication errors
occurred in people over the age of 60. Older
people may be at greatest risk for medication
errors because they often take multiple
prescription medications.34 With the pharmacist’s
combination of training and experience, we are
often in an ideal position to identify and correct
these types of errors and have a favorable impact
on overall patient well-being.
The FDA has stated that a medication error can
occur during any of the following components of
the drug-use process:35
Prescribing.
Repackaging.
Dispensing.
Administering.
Monitoring the patient for side effects and
adverse drug events.
Additionally, FDA has provided other common
causes of medication errors:35
Poor communication between doctors, nurse
practitioners, nurses or pharmacists.
Ambiguities in the product name, directions
for use, medical abbreviations or the
legibility of the writing.
Poor procedures and techniques.
Patient misuse because of poor understanding
of the directions for use of the product.
Again, pharmacists will often find themselves in
a position to rectify many of these trouble points
in the medication process.
In 2006, new data confirmed the FDA’s study of
1990, stating that the most common medication
errors included nurses administering the wrong
medications or wrong dose in an intravenous
drip, physicians prescribing drugs that could
cause a dangerous interaction with patient’s
other medications, and pharmacists dispensing
100-milligram tablets when 50-milligram tablets
were prescribed.36 Through training and intense
attention to detail, pharmacists can work to
eliminate errors directly under their purview.
And they are also well positioned to collaborate
with nurses and prescribers to help reduce the
incidence of most errors in the prescription or
administration of medications.
Types of medication errors initiated by a
patient
Although health care professionals have made
many medication errors over the years, an
error can also be committed intentionally or
unintentionally by the patient. The first potential
problem as noted by the IOM in 2006 is that 50
percent of patients do not take their medications
as prescribed.10 As pharmacists, we have to
change the way that we communicate with our
patients, sharing our education and knowledge in
the hope that they will take their medications as
prescribed, safely.
Patients may perceive that a medication is simply
a “quick fix” to a problem; as pharmacists, we
need to teach them about each medication’s
purpose, potential side effects, drug-drug
interactions, drug-food interactions and safety
concerns. Patients should also be reminded that
before using any OTC medication or herbal
product, they should check with their doctor or
health care practitioner because those products
may interact with current medications and
health conditions in the same manner as other
medications.
Another potential problem is drug abuse. In 1999,
the National Institute on Drug Abuse (NIDA)
reported that 4 million Americans 12 years or
older had used a prescription medication for nonmedical reasons.37 Therefore, it is incumbent on
the pharmacist to be aware of this fact and assess
each patient who may abuse a prescriptive or
non-prescriptive medication provided to them.
A third potential medication error initiated by
a patient is purchasing a medication, with or
without a prescription, on the Internet. A patient
may have a preconceived notion that he or she
wants or needs to be on a certain medication
after reading or hearing an advertisement from a
pharmaceutical company. If the patient’s primary
care physician refuses to write a prescription, a
patient often can purchase the medication online
without a prescription. In other cases, Internet
pharmacies are abused by patients who have
tendencies towards self-medication, not believing
that they need the guidance of a qualified
prescriber.
Some websites and companies attempt to
alleviate patients’ concerns about the practice by
noting that they are ordering under the concept of
“responsible self-treatment”:
The term “self-treatment” means that the
patient takes responsibility for the results
obtained by controlling their own access
to medication. Responsible self-treatment
assumes that the patient owns the information
on an accepted preparation, and realizes the
following:
ŠŠ There is no such thing as an absolutely
safe medicine.
ŠŠ There are no medicines with guaranteed
efficacy.
ŠŠ Any medicines accepted simultaneously
can interact positively or negatively with
each other.
According to the World Health Organization
(WHO), responsible self-medication is a practice
where patients can treat their conditions and
ailments using medicines that are approved and
available in their region without a prescription.
Further, these medications must be proven to be
safe and effective. This WHO definition does
not seem to align with the message inferred by
Internet pharmacies promoting this practice.38
It is unfortunate that there are unprofessional,
misleading and illegal sites available to
encourage and promote the purchase of more
than 1,800 medications, including high-risk
medications such as Viagra, Vicodin and
Xanax. These sites sometimes even provide a
“consultation” with a physician for the patient
Page 42
Elite
to obtain a prescription for a narcotic or other
dangerous medications.
Another reason why patients may consider
purchasing a medication online is concern about
their rising medication costs. It is estimated that
4 percent of Americans have purchased their
medications online.39 Because other countries do
not regulate their medications to the standards
of the FDA, the agency conducted a research
investigation into the importation of medications
from various countries, focusing on the safety
of the medication and the potential efficacy of
these imported medications for patients. The FDA
investigation discovered the following:
Of the 2,069 drug orders examined,
88 percent appeared to be prescription
medications available in the United
States. The remaining 12 percent were
dietary supplements, had illegible or
incomprehensible labeling, or were not
available in the U.S. “The most surprising
finding was the motivation of patients to
use Internet pharmacies. FDA investigators
believed that many people were not buying
the drugs to save money, but to bypass the
need for a prescription.”40
FDA recommends that patients can purchase
medications safely online if they are purchased
through a pharmacy physically located in
the United States. It also said the following
medications should never be purchased online
or from a foreign source because safety controls
are often bypassed, placing patients at risk for
adverse drug events:
Accutane (isotretinoin) – indicated for the
treatment of severe, recalcitrant nodular acne.
Actiq (fentanyl citrate) – indicated for the
management of severe cancer pain in patients
who are tolerant to opioid therapy.
Clozaril (clozapine) – indicated for the
management of severe schizophrenia in
patients who fail to respond to standard drug
treatments for schizophrenia.
Humatrope (somatropin for injection) –
indicated for the treatment of non-growth
hormone-deficient short stature.
Lotronex (alosetron hydrochloride) –
indicated for the treatment of severe irritable
bowel syndrome in women.
Mifeprex (mifepristone or RU-486) –
indicated for the medical termination of early
intrauterine pregnancy.
Plenaxis (abarelix for injectable
suspension) – indicated for the treatment
of advanced symptomatic prostate cancer in
men who are not able to receive other types
of treatment.
Thalomid (thalidomide) – indicated
for the acute treatment of the cutaneous
manifestations of moderate to severe
erythema nodosum leprosum.
Tikosyn (dofetilide) – indicated for the
maintenance of normal sinus rhythm in
patients with certain cardiac arrhythmia.
Tracleer (bosentan) – indicated for the
treatment of severe pulmonary arterial
hypertension.
Trovan (trovafloxacin mesylate or
alatrofloxacin mesylate injection) – an
antibiotic administered at in-patient health
care settings for the treatment of severe, lifethreatening infections.
Xyrem (sodium oxybate) – indicated for
the treatment of cataplexy in patients with
narcolepsy.41
Reporting a medication error
If a medication error should occur in any
format, as a registered pharmacist, you have
a professional, ethical and legal obligation
to report it to the appropriate authorities.
Within the United States, the Medication Error
Reporting program (MER) and the FDA work
in conjunction to monitor the efficacy of each
medication to prevent future medication errors.
Since March 13, 2003, the FDA has required that
all actual and potential medication errors must
be submitted to the agency within 15 calendar
days.42 Additionally, FDA reviews medication
error reports that come from drug manufacturers
using the MedWatch reporting system and ISMP
MERP.
The following organizations are obligated to
track medication errors:
FDA – Accepts reports from consumers,
health professionals and drug companies
about products regulated by FDA, including
drugs and medical devices, through
MedWatch, the FDA’s safety information and
adverse event reporting program.
Institute for Safe Medication Practices MERP
– Accepts reports from consumers and health
professionals on medications and publishes
Safe Medicine, a consumer newsletter on
medication errors.43
Quantros – MedMARX is an anonymous
medication error reporting program used by
hospitals that was developed by USP but
managed by Quantros since late 2008.44
According to the ISMP MERP program,43 all
health care professionals should report actual or
potential medication errors that occur due to any
of the following reasons:
Errors in the prescribing, transcribing,
dispensing, administering and monitoring of
medications and vaccines.
Wrong drug, wrong strength, or wrong dose.
Wrong patient.
Confusion over look-alike/sound-alike drugs
or similar packaging.
Wrong route of administration.
Calculation or preparation errors.
Misuse of medical equipment.
It should be noted that a potential medication
error is considered a “near-miss.” Consider this
example:
An order for a fourth dose of medication to
be administered to a patient is listed on a
medication administration record (MAR).
Prior to administration, the pharmacist
reviews the chart and notes that the
medication was supposed to be discontinued
after the third dose. Based on the
pharmacist’s vigilance, the mistake is averted.
Elite
This potential dosing error would be considered
a near-miss, because the potential was present for
an error but it did not occur and the patient did
not receive the incorrect medication.
It is recommended that pharmacists adhere to
the following reporting methods for an actual or
potential medication error in a confidential and
anonymous format:45
ISMP Medication Errors Reporting Program
(MERP): 800-233-7767 or https://www.ismp.
org/orderforms/ERP_Portal.asp
U.S. Food and Drug Administration’s
MedWatch Reporting Program: 800-FDA1088 or https://www.accessdata.fda.gov/
scripts/medwatch/medwatch-online.htm
Once a medication error has been reported,
the FDA’s Office of Post Marketing Drug Risk
Assessment (OPDRA) will review and classify
the taxonomy of the medication error using a
system developed by National Coordinating
Council for Medication Errors Reporting and
Prevention (NCC-MERP).46 It is important to
understand that the FDA receives an abundance
of reports on cases and therefore will only review
reports that are properly completed. Between
2000 and 2008, the FDA received in excess of
95,000 reports of actual or potential medication
errors.47
FDA defines serious as any adverse event
that is fatal, life-threatening, or associated
with a disability, hospitalization or congenital
anomaly.48 The ISMP reports medication errors
through a variety of newsletters to ensure that all
health care professionals are properly targeted,
regardless of their practice setting.66
In addition, it is imperative to thoroughly
complete all reporting forms to ensure the
provision of appropriate data to FDA. Failure
to do so may lead to a delay in the investigation
of the medication involved and the reasons why
the problem occurred, impeding the agency’s
ability to warn and prevent future episodes.
See Table 2 for recent examples of drug safety
communication advisories from FDA.49
Promoting medication safety
The IOM is the innovative leader in eliciting
change in America’s medication safety
guidelines. Since the IOM released data in
1999 to health care professionals and the
public, government agencies such as FDA have
collaborated with the IOM to promote change.
After the 1999 report, FDA encouraged the IOM
to review the current data and provide factual,
concrete suggestions to promote medication
safety for all Americans. Because errors are
preventable, all pharmacists should take
responsibility and accountability for all of their
actions to ensure medication safety.
In 2006, an IOM report requested that
U.S. government agencies take the lead in
implementing steps to reduce medication errors,
with precise deadlines and recommendations.
The IOM estimated that the government should
expect to spend $100 million annually to research
Page 43
the most useful and cost-effective ways to reduce
medication errors.36
The 2006 IOM recommendations (and response
to them, where applicable) were:
FDA and the Agency for Healthcare Research
and Quality should be charged with working
with the pharmaceutical industry to address
problems with drug labels and packaging
by the end of 2007 and possibly implement
standardized drug names and labels.
ŠŠ FDA acted on this in 2008, shifting
increased responsibility to the Office of
Surveillance and Epidemiology.50
By 2008, all health care providers were to
develop a plan to transition to electronic
prescribing systems.
ŠŠ A report from Office of the National
Coordinator for Health IT (June 2012)
estimated that 45 percent of new
and renewal prescriptions were sent
electronically in 2012.51
By 2010, all health care providers were to
begin using electronic prescribing systems.
ŠŠ The same report noted that 48 percent
of U.S. physicians now use electronic
prescribing systems, compared to only 7
percent in December 2008.51
The National Library of Medicine should
create a central online database for consumers
to find information on medications and work
with FDA and CMS to consider creation of a
nationwide telephone hotline for patients who
cannot read printed information.
ŠŠ The National Library of Medicine
manages a suite of drug information
portals to provide consumers with
information on drugs, herbs and
supplements.52 Patients can call the FDA
Division of Drug Information (DDI) for
drug information by telephone at 855543-3784 or 301-796-3400.53
All health care providers should report
medication errors to patients and family
members, regardless of whether harm
occurred.
Pharmaceutical companies should disclose
all clinical trial results and limit the practice
of providing physicians with free samples of
medications because the samples are poorly
regulated.
ŠŠ Many scientific journals require the
posting of all clinical trials prospectively
(as well as results, when available) as a
condition for publication. The value of
this transparency should strengthen the
science and preserve the integrity of the
medical literature.54 Although some new
limitations are in place, pharmaceutical
companies still distribute samples.
Pharmaceutical companies should package
pills in blister packs to simplify identification
and make it easier for consumers to
remember whether they took a dose.
ŠŠ Although some medications are contained
in blister packages, this is the exception,
not the norm.
Patients should maintain a list of all
prescription and nonprescription treatments
that they take and review the document with
their health care providers to ensure that there
are no potential drug interactions.
Patients need to become responsible for
reading, understanding and abiding by the
medication instructions.60
Although the IOM has provided many
recommendations for U.S. government agencies
to implement, the first step in promoting
medication safety is to allow and encourage each
patient to take a more active role in his or her
own medical care. In the past, many patients and
their families thought they would be perceived
as disrespectful or rude if they questioned their
health care practitioner. However, a new way of
thinking, according to the IOM 2006 brief report,
is to promote a partnership between the health
care provider and the patient.
To initiate and implement this paradigm
shift, doctors, nurses, and pharmacists need
to communicate with patients by listening,
consulting and educating them appropriately
about each of their medications at various stages
of their care.37
It is a wonderful idea, but many practitioners
argue that restrictive reimbursement by insurance
companies, Medicaid and Medicare make it
difficult to spend a large amount of time with
each patient. Many times, these professionals
assume that another professional will spend
the quality time that each patient deserves. It
is a vicious cycle, but pharmacists can be the
leaders in turning it around by promoting quality
communication.
The governing agencies encourage health
care professionals to keep up-to-date on the
latest information on available technological
advances. For instance, the IOM states in its 2006
brief report that it is impossible to remember
every detail about a medication; therefore, it
recommends health care professionals use a
point-of-care reference to assess components of
the desired medication.37
As a result of the IOM recommendations, there
have been numerous positive outcomes designed
to enhance patient safety. Some examples
include:
The Center for Quality Improvement and
Patient Safety (CQuIPS) has been established
at AHRQ to integrate patient safety into the
broader quality framework, conduct research
on how to reduce medical errors, and educate
patients about their safety.
National summits have been conducted,
including AHRQ’s Patient Safety Research
and Practices Summit (September 2000), the
Food and Drug Administration’s Drug and
Device Safety Summit (throughout 2001),
and the Department of Veterans Affairs’ (VA)
Patient Safety Practices (September 2001).
The Health Care Financing Administration
(HCFA, now the Centers for Medicare and
Medicaid Services [CMS]) is considering
regulations requiring hospitals participating
in Medicare to have ongoing medical error
programs in place.
The Office of Personnel Management (OPM)
will require all plans in the federal employee
health benefits program to seek accreditation
that includes the evaluation of patient safety
and programs to reduce errors.
The VA and Department of Defense (DOD)
are leaders in computer order entry systems.55
Recommendations for improving
medication safety during the dispensing
phase
It is imperative that pharmacists adhere to
the recommendations and guidelines of our
governing agencies to improve our medication
practices. This can ensure that pharmacists are
more conscious about their actions before they
dispense a medication to a patient.
All pharmacist programs emphasize the six
medication “rights” before administering any
medication:
The right patient.
The right medication.
The right dose.
The right route.
The right time.
The right documentation. Before dispensing
any medication, one of the first precautionary
steps to take is to always check the physician’s
orders against what is known about the patient:
What is the disease; are there any concomitant
medications that could lead to a drug-drug
interaction; does the patient have any comorbidities that could complicate the use of the
medication?
Second, the pharmacist is responsible for
verifying that the prescriber has ordered the
correct medication at the correct dose, to be
administered at an appropriate frequency. Even
though there are technologies in place to assess
and scrutinize the prescriber’s orders, never
assume that the available systems will detect a
problem or that another colleague verified the
order. It is better and safer to check and re-check
the order.
Once the medication on the record matches the
correct, safe dose that the prescriber ordered, the
pharmacist is responsible for ensuring that the
correct quantity of the correct medication at the
correct dose is accurately provided to the patient
at the correct time.
If the pharmacist is not familiar with a
medication, he or she should look it up in a
drug reference before beginning the process of
dispensing the medication. The pharmacist must
never assume that the prescriber is fully aware
of the medication classification, use, safe dose,
side effects, drug-drug interactions, drug-food
interactions and other implications. There are
so many medications on the market that it is
impossible for anyone to fully understand the
implications of all drugs that might be prescribed
to a patient.
Page 44
Elite
In November 2005, the FDA mandated that all
prescription drug information had to be submitted
in a searchable electronic format database to
provide information for health care professionals
and the public.48
In January 2006, the FDA revised the format in
which prescription drug inserts were to be written
and laid out. During that time, the FDA mandated
that inserts be written in a clear, concise manner
to provide each health care professional the most
up-to-date and easy-to-read information to best
promote patient safety.42
Every year, JCAHO releases the updated
National Patient Safety Goals, customized
to various inpatient and outpatient settings,
to which hospitals and clinics must abide by
for accreditation. In June 2007, the board of
commissioners at JCAHO approved the 2008
National Patient Safety goals. The third goal
involves the safety of medications:
Identify and, at a minimum, annually review
a list of look-alike/sound-alike drugs used by
the organization, and take action to prevent
errors involving the interchange of these
drugs.
Label all medications, medication containers
(for example, syringes, medicine cups,
basins) or other solutions on and off the
sterile field.
Reduce the likelihood of patient harm
associated with the use of anticoagulation
therapy.56
Bar code label rule
In February 2004, the FDA issued a final rule
requiring bar codes on certain drugs, biologicals
and blood product labels.57 According to
21 CFR 201.25, “manufacturers, repackers,
relabelers, and private label distributors of human
prescription drug products, biological products,
and over-the-counter (OTC) drug products
that are dispensed pursuant to an order and are
commonly used in hospitals are subject to the bar
code requirement, regardless of the method they
use to distribute their drug products.”58
After the initiation of bar codes, the FDA
estimated that their implementation would help
prevent nearly 500,000 adverse events and
transfusion errors, while saving $93 billion in
health costs over 20 years.59
With the advances in technology, the governing
bodies also recommended that facilities
incorporate electronic prescriptions by 2010 to
avoid mistakes with handwritten prescriptions.
Over the years, many pharmacists have
complained that physicians’ handwriting can be
illegible. Pharmacists are trained to verify the
medication with the ordering physician instead
of making educated guesses about what the
doctor meant. The IOM promotes e-prescription
software programs because they can also help
by assessing for drug allergies, drug-drug
interactions and overly high doses during the
writing phase to prevent potential medication
errors.37
According to the Health Care Quality
Modernization, Cost Reduction, and Quality
Improvement Act, prescribing errors were
reduced by 95 percent and hospital costs lowered
by 13 percent with automated prescribing. The
government has also included e-prescribing
adoption in the Medicare Prescription Drug
Improvement and Modernization Act of 2003,
and many payors are sponsoring e-prescribing
initiatives for their providers. E-prescribing can
increase patient safety by preventing errors,
improving continuity of care, and by tracking and
providing feedback about adverse events.60
label on foods and medications to ensure that
consumers have the appropriate information on
the product’s ingredients, uses, warnings, dosage,
directions and proper storage.66
Drug name confusion
In 2000, the FDA proposed a new package insert
that was more user-friendly and highlighted
the critical information needed for physicians
prescribing products.66 In January 2006, the
FDA initiated new changes in the format for the
labeling of prescription drugs to provide health
care professionals clear and concise prescribing
information.85 The IOM committee recommends
that the drug industry and the appropriate federal
agencies work together to improve nomenclature,
which encompasses drug names, abbreviations
and acronyms.37 It is also is critical to teach
patients to recognize that if the medication does
not look right based upon its color or shape, they
should never assume it is the correct, prescribed
medication.10
FDA collaborates with the ISMP to assess and
review potential medications that look alike,
sound alike and have labels that could cause
a medication error.61 FDA is adamant about
eliminating potential confusion because of the
name, appearance or sound of the medication.
The goal is to prevent errors during the
procurement of a medication.
The last time a medication name was
changed was in 1994: Levoxine, used to treat
hypothyroidism, was often confused with the
heart medication Lanoxin. Therefore, FDA
recommended a name change. Subsequent to this
request, Levoxine was changed to Levoxyl.66
It should be noted that after drugs are approved,
FDA monitors each medication for errors caused
by name confusion. If errors or confusion are
noted, FDA informs health care professionals
about it in an effort to avoid additional problems.
For example, FDA has reported errors involving
the administration of methadone instead of the
prescribed Metadate ER, (methylphenidate) for
the treatment of attention deficit/hyperactivity
disorder (ADHD). Unfortunately, there
was a case reported where an 8-year-old
boy died because the pharmacist filled the
opiate, methadone, rather than the intended
methylphenidate.66
As a pharmacist, it is imperative to recognize
the vast array of potential errors from drug name
confusion: the data is staggering. In addition,
according to Meadows, other examples of drug
name confusion reported to FDA include:
Serzone (nefazodone) for depression and
Seroquel (quetiapine) for schizophrenia.
Lamictal (lamotrigine) for epilepsy, Lamisil
(terbinafine) for nail infections, Ludiomil
(maprotiline) for depression and Lomotil
(diphenoxylate) for diarrhea.
Taxotere (docetaxel) and Taxol (paclitaxel),
both for chemotherapy.
Zantac (ranitidine) for heartburn, Zyrtec
(cetirizine) for allergies and Zyprexa
(olanzapine) for mental conditions.
Celebrex (celecoxib) for arthritis and Celexa
(citalopram) for depression.66
Drug labeling
In January 2002, a study found that consumers
tend to overlook important label information on
OTC drugs. Four months later, in May 2002,
FDA mandated a standardized “drug facts”
Elite
For example, during the fall of 2007, news
media reports claiming that parents were
overdosing their children led many people to
believe that cough medications were no longer
safe to administer to children under 6 years of
age. Pharmaceutical companies responded by
changing the labels on all cough medications,
telling parents to consult with their doctor before
giving a child under 6 years of age the medicine.
FDA recommendations to improve
medication safety
On January 30, 2007, the FDA announced 41
initiatives to improve drug safety based on the
recommendations of the IOM.27 Among them
were:
List all products by generic name.
Do not include the salt of the chemical when
expressing a generic name unless there are
multiple salts available (i.e., hydroxyzine
hydrochloride and hydroxyzine pamoate).
Use brand names in upper case letters (i.e.,
LANOXIN, LASIX) to differentiate them
from their generic cohort.
Express suffixes that are part of the brand
name (i.e., SR, SA, CR) within both the
generic name field and the brand name (i.e.,
diltiazem XR).
Avoid the use of all potentially dangerous
abbreviations and dose expressions. (See
Table 1 – The Do Not Use list.)
Do not use trailing zeros (5 mg, never 5.0
mg).
Use leading zeros for doses that are less than
1 (0.3 mg, never .3 mg).
Spell out the word “units.”
Use the proper, approved standard
abbreviations for dosage units.
Do not abbreviate names (do not use Mso4
for morphine).
Use upper case and lower case letters (ie.,
HydrOXYzine and hydrALAZINE) to help
distinguish look-alike products.
When the drug name, strength, dosage form
and dosage units appear together, avoid
confusion by listing the generic name first
and provide a space between them.62
Page 45
Additional recommendations for
pharmacists to improve medication
safety
In addition to ensuring that the previous
recommendations are implemented, pharmacists
may be able to participate in implementing the
following guidelines to promote patient safety, as
incorporated in JCAHO’s national safety goal.
In 2006, JCAHO initiated the medication
reconciliation form to help prevent medication
errors. The medication reconciliation form is
implemented upon admission, transfer to another
unit, and discharge from the facility to ensure that
all home medications and discharge medications
are clearly stated to avoid an overlap or drugdrug interactions. The requirements for JCAHO’s
national safety goals include:
Implement a process for obtaining and
documenting a complete list of the patient’s
current medications upon the patient’s
admission to the organization, with the
involvement of the patient. This process
includes a comparison of the medications
the organization provides to those on the list.
(Note: While this safety goal does not require
a separate form for the medication list, many
organizations have found it useful to develop
and use one or more forms to support the
medication reconciliation process.)
Ensure that a complete list of the patient’s
medications is communicated to the next
provider of service when a patient is referred
or transferred to another setting, service,
practitioner or level of care within or outside
the organization.1
In the second national standard, JCAHO
recommended the following to prevent a
medication error during the communication
phase.86
Pharmacists are often required to take verbal
orders from a doctor or other prescriber or their
representative over the telephone, or sometimes,
even in person. Before taking a verbal order over
the telephone, the pharmacist should gather all
available data about the patient. When given a
verbal order, the pharmacist must repeat each
component of the order back to the caller, which
includes verbalizing the medication and spelling
it (if appropriate), reiterating the dose and the
frequency of the medication.
Consumers’ role to improve medication
safety
FDA has been diligently attempting to eradicate
or reduce medication errors for patients in a very
complex medical system. To promote medication
safety, FDA recommends that consumers
collaborate with their health care providers to
reduce errors. FDA urges consumers to take the
following steps:66
As a patient, know the most common
type of medication errors that occur. The
most vulnerable populations are children
and elderly patients over 60 years of age.
According to another report in 2007 by FDA,
more than 700,000 people go to emergency
rooms every year because of a medication
interaction. In the same consumer health
information form, the FDA said that the
most commonly implicated drug causing
unexpected medical problems for patients is
Coumadin (warfarin).27
Know the name of your medication and
its purpose. FDA reiterates that the patient
should never take a medication just because
“the doctor said so.”
Always read and understand the directions for
taking each medication safely and properly as
prescribed. According to Weiss (2006), more
than 50 percent of patients do not take their
medications as prescribed.10
Keep a list of all medications, including
OTC, herbals, dietary supplements and any
other substances. In addition, patients should
continuously review their medications with
their primary provider because many people
have more than one physician prescribing
medications to them. Patients should never
assume that their physicians collaborate on
care for an individual patient.
If in doubt, never assume anything. Ask your
health care providers for clarification.
Each health care professional can take the
initiative and rise above the shortcomings
within our health care system to promote patient
safety. The governing bodies have provided
an abundance of research and evidence-based
practice recommendations to prevent and help
eradicate the risk of medication errors.
No one ever wants to be a party in a medication
error, especially knowing that the errors can
be disabling to a patient or even cause death. It
takes just a few extra minutes to ensure that each
medication is safely prescribed, dispensed and
administered to the patient.
Remember: Each patient is an individual who has
a story and a family; do not jeopardize his or her
safety and life. The next time, it could be your
loved one who is the patient.
To promote medication safety for the consumer,
the IOM recommends the following for the
pharmaceutical industry:10
The Food and Drug Administration should
help standardize the text and design of
medication leaflets so that consumers can
easily understand them.
The National Library of Medicine should
create a website that is a comprehensive,
understandable source of information about
drugs and fund a national telephone line for
people who don’t have Internet access.
Health care organizations should tell patients
about medication errors made in their care,
even if they were not hurt by the error.
Goals for the future
Although progress has been made, more
providers need to begin using e-prescribing
systems, and all pharmacies should be able to
receive prescriptions electronically. The Agency
for Healthcare Research and Quality (AHRQ)
should take the lead in fostering improvements in
IT systems used in ordering, administering and
monitoring drug usage.
As pharmacists, it is an exciting time to be
involved in promoting patient safety by reducing
the risks of medication errors. Over the years,
governing bodies have made it apparent that they
want to reduce and eventually eradicate the risk
of patients coming to harm in health care settings.
As pharmacists, we must also do our part!
Conclusion
Although there are many variables that lead
to medication errors in our complex medical
system, there are multiple actions that we can
take as pharmacists to promote patient safety. It is
imperative to understand the legal responsibilities
and obligations that you have to patients you care
for directly or indirectly on a daily basis.
Page 46
Elite
TABLE 1
Official “Do Not Use” List# by JCAHO
Do not use
Potential problem
Use instead
U (unit)
Mistaken for “0” (zero), the number “4” (four) or “cc”
Write “unit”
IU (International Unit)
Mistaken for IV (intravenous) or the number 10 (ten)
Write “International Unit”
Q.D., QD, q.d., qd (daily)
Mistaken for each other
Write “daily”
Q.O.D., QOD, q.o.d, qod
(every other day)
Period after the Q mistaken for “I” and the “O” mistaken for “I”
Write “every other day”
Trailing zero (X.0 mg)*
Decimal point is missed
Write X mg
Lack of leading zero (.X mg)
MS
Write 0.X mg
Can mean morphine sulfate or magnesium sulfate
Write “morphine sulfate”
MSO4 and MgSO4
Write “magnesium sulfate”
Applies to all orders and all medication-related documentation that is handwritten (including free-text computer entry) or on pre-printed forms.32
*Exception: A “trailing zero” may be used only where required to demonstrate the level of precision of the value being reported, such as for laboratory
results, imaging studies that report size of lesions, or catheter/tube sizes. It may not be used in medication orders or other medication-related
documentation.
#
TABLE 2
Drug safety communications
Posted by the FDA January 1, 2012-April 26, 2013
eDate
)Product(s)
Safety issue
April 26, 2013
Anti-seizure drug Potiga (ezogabine)
Linked to retinal abnormalities and blue skin
discoloration
March 14, 2013
Incretin mimetic drugs for type 2 diabetes Byetta,
Bydureon (exenatide); Victoza (liraglutide); Januvia,
Janument, Juvisync (sitagliptin); Onglyza (saxagliptin);
Nesina, Kazano (alogliptin); Tradjenta, Jentadueto
(linagliptin)
Investigating reports of possible increased risk
of pancreatitis and pre-cancerous findings of
the pancreas from incretin mimetic drugs for
type 2 diabetes
March 12, 2013
Zithromax, Zmax (azithromycin)
Risk of potentially fatal heart rhythms
February 26, 2013
Sensipar (cinacalcet)
Pediatric clinical trials suspended after report
of death
February 20, 2013
Codeine
Safety review update of codeine use
in children; new boxed warning and
contraindication on use after tonsillectomy and
adenoidectomy
January 10, 2013
Insomnia drugs containing zolpidem (Ambien, Edluar,
zolpimist)
Risk of next-morning impairment after use
of insomnia drugs; FDA requires lower
recommended doses
References
1.Joint Commission. Sentinel Event Alert. (Issue 35, January 25, 2006). Accessed online
April 28, 2013 at http://www.jointcommission.org/assets/1/18/SEA_35.PDF
2.Institute of Medicine: To err is human: Building a safer healthcare system (November,
1999). Accessed online April 28, 2013 at http://www.iom.edu/~/media/Files/
Report%20Files/1999/To-Err-is-Human/To%20Err%20is%20Human%201999%20
%20report%20brief.pdf
3.FDA: Consumer health information. Strengthening drug safety. (May 31,
2007) Accessed online April 28, 2013 at http://www.fda.gov/ForConsumers/
ConsumerUpdates/ucm107769.htm
4.Institute of Medicine of the National Academies (2006) Preventing Medication
Errors: Quality Chasm series. Accessed online April 28, 2013 at http://www.iom.edu/
Reports/2006/Preventing-Medication-Errors-Quality-Chasm-Series.aspx
5.Ernst, F.R., & Grizzle, A.J. (2001). Drug related morbidity and mortality: updating
the cost of illness model. Journal of the American Pharmaceutical Association. 41(2),
192-199
6.Institute of Medicine: Identifying and preventing medication errors (2013). Accessed
online April 28, 2013 at www.iom.edu/CMS/3809/22526.aspx?printerfriendly=true
7.National Coordinating Council for Medication Error Reporting and Prevention.
What is a Medication Error? Accessed online April 28, 2013 at www.nccmerp.org/
aboutMedErrors.html?USP_Print=true&frame=lowerfrm
8.National Coordinating Council for Medication Error Reporting and Prevention. Types
of Medication Errors. Accessed online April 28, 2013 at http://www.nccmerp.org/
medErrorCatIndex.html
9.National Academies. Medication errors injure 1.5 million people and costs billions of
dollars annually. Accessed online April 28, 2013 at http://www8.nationalacademies.
org/onpinews/newsitem.aspx?recordid=11623
10. Weise, E. Study: Medication Errors harm 1.5m a year (USA Today, July 21, 2006)
- Accessed online April 28, 2013 at http://www.usatoday.com/money/industries/
health/2006-07-20-drug-errors_x.htm
11. Oren, E., Shaffer, E.R., & Guglelmo, B.J. (2003) Impact of Emerging Technologies
on Medication Errors and Adverse Drug Events Am J Health-Syst Pharm 60(14):
1447-1458). Accessed online April 28, 2013 at http://www.medscape.com/
viewarticle/458906_print
12. Reducing and Preventing Adverse Drug Events To Decrease Hospital Costs.
Research in Action, Issue 1. AHRQ Publication Number 01-0020, March 2001. Agency
for Health Care Research and Quality, Rockville, MD. Accessed online April 28, 2013
at http://www.ahrq.gov/qual/aderia/aderia.htm
13. Institute of Medicine: Preventing Medication Errors. (Report brief, July 2006).
Accessed online April 30, 2013 at http://www.iom.edu/~/media/Files/Report%20
Files/2006/Preventing-Medication-Errors-Quality-Chasm-Series/medicationerrorsnew.
pdf
14. HHS. Fiscal year 2014: Budget in Brief (2013). Accessed online April 30, 2013 at
http://www.hhs.gov/budget/fy2014/fy-2014-budget-in-brief.pdf
15. United States Department of Health and Human Services (HHS). What We Do.
(2013) Accessed online April 28, 2013 at http://www.hhs.gov/about/whatwedo.html/
16. Swann, J. (1998). History of the FDA. Oxford: University Press. Accessed online
on April 28, 2013 at http://www.fda.gov/AboutFDA/WhatWeDo/History/Origin/
ucm124403.htm
17. FDA. FDA’s Mission Statement. Accessed online on April 28, 2013 at http://www.
fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/BudgetReports/
UCM202307.pdf
18. FDA: U.S. Food and Drug Administration. FDA Statement on Institute of Medicines
Report on Preventing Medication Errors. Accessed online April 28, 2013 at http://www.
fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108695.htm
19. MedWatch: The FDA Safety Information and Adverse Event Reporting Program
(2013). Accessed online on April 28, 2013 at http://www.fda.gov/Safety/MedWatch/
default.htm
20. AHRQ. About us (2013). Accessed online on April 28, 2013 at http://www.ahrq.gov/
about/index.html
21. Institute of Medicine, About the IOM (2013). Accessed online on April 28, 2013 at
http://www.iom.edu/About-IOM.aspx
22. Institute of Medicine. About the Institute of Medicine: Advising the nation.
Improving Health. Accessed online on April 28, 2013 at http://www.iom.edu/AboutIOM/~/media/Files/About%20the%20IOM/IOM-brochure-website.pdf
23. Institute of Medicine of the National Academies (April 2007). Preventing Medication
Errors. Accessed online on April 28, 2013 at http://www.nap.edu/openbook.
php?record_id=11623&page=R1
24. Institute of Medicine. The Future of Drug Safety: Promoting and Protecting the
Health of the Public. (2006). Accessed online April 28, 2013 at www.iom.edu/
CMS/3793/26341/37329.aspx?printerfriendly=true
25. United States Pharmacopeia. About USP. Accessed online April 28, 2013 at http://
www.usp.org/aboutUSP/
26. National Coordinating Council for Medication Error Reporting and Prevention.
Elite
Home Page. Accessed online April 28, 2013 at http://www.nccmerp.org/
27. National Coordinating Council for Medication Error Reporting and Prevention.
About NCC MERP. Accessed online April 28, 2013 at http://www.nccmerp.org/
aboutNCCMERP.html
28. Institute for Safe Medication Practice. About ISMP. Accessed online April 28, 2013
at www.ismp.org/about/Default.asp
29. Institute for Safe Medication Practice: USP-ISMP Medication Errors Reporting
Program (MERP). Accessed online April 30, 2013 at https://www.ismp.org/
orderForms/reporterrortoISMP.asp
30. JCAHO. The Joint Commission History. Accessed online April 28, 2013 at http://
www.jointcommission.org/assets/1/6/Joint_Commission_History.pdf
31. McLeod, P. (2007). Learning to block and tackle. Med3000 Connection Newsletter
(Page 6). Accessed online May 1, 2013 at http://med3000.com/UserFiles/File/PDF/
Connection%20Newsletters/MED3OOO%20Connection%20Newsletter%20Fall%20
2007%20Edition.pdf
32. Joint Commission. The Official Do Not Use List. Accessed online on April 28, 2013
at http://www.jointcommission.org/assets/1/18/Do_Not_Use_List.pdf
33. ISMP’s. List of Error- Prone Abbreviations, symbols, and dose designations.
Accessed online April 30, 2013 at http://www.ismp.org/tools/errorproneabbreviations.
pdf
35. Stoppler, M (2006). The most common medication errors. Accessed online April 28,
2013 at http://www.medicinenet.com/script/main/art.asp?articlekey=55234
36. FDA. FDA-101: Medication Errors. Accessed online April 28, 2013 at http://www.
fda.gov/ForConsumers/ConsumerUpdates/ucm048644.htm
37. Medication Errors Harm 1.5m U.S. Residents Annually: New Institute of Medicine
Report Says Medical News Today (25 July 2006).Accessed online April 28, 2013 at
http://www.medicalnewstoday.com/articles/47931.php
38. Youngkin, E., Sawin, K., Kissinger, J., & Israel, D. (2005). Pharmacotherapuetics; A
primary care guide. (2nd ed.) Pearsons: NJ.
39. WHO. The role of the pharmacist in self-care and self-medication (2013). Accessed
online, April 28, 2013 at http://apps.who.int/medicinedocs/en/d/Jwhozip32e/3.3.html
#Jwhozip32e.3.3
40. CBS News. Few Americans Buy Drugs Online (February, 2009). Washington.
Accessed online, April 29, 2013 at http://www.cbsnews.com/2100-204_162-648495.
html
41. FDA: FDA Says consumers continue to buy risky drugs online. Self-medication a
concern; FDA approved generics may be cheaper alternative. (November 1, 2007).
Page 47
Accessed Online April 29, 2013 at http://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/2007/ucm109018.htm
42. FDA. FDA Consumer Safety Alert: Don’t Buy these Drugs Online or From
Foreign Countries. (March 2010) Accessed online April 30, 2013 at http://www.
fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/
BuyingMedicinesOvertheInternet/ucm202893.htm
43. Meadows M. Strategies to reduce medication errors. How the FDA is working to
improve medication safety and what you can do to help. FDA Consum. 2003 MayJun;37(3):20-7
44. The National Medication Errors Reporting Program (ISMP MERP) (2013). Accessed
online April 29, 2013 at https://www.ismp.org/orderforms/reporterrortoismp.asp
45. Quantros- MEDMARX ADE Data Repository (2013). Accessed online April 29,
2013 at http://quantros.com/our-products/safety-and-risk-management-srm/medmarxmedication-database
46. National Coordinating Council for Medication Error Reporting and Prevention.
Report a Medication Error. Accessed online November 8, 2007 at http://www.nccmerp.
org/reportMedError.html
47. Thomas, M., Holquist, C., & Phillips, J. (October 2001). FDA Safety Page: Med
error reports to FDA show a mixed bag. Accessed online on April 29, 2013 at http://
www.fda.gov/downloads/Drugs/DrugSafety/MedicationErrors/ucm115775.pdf
48. FDA. FDA 101: Medication Errors. Accessed online on April 29, 2013 at http://
www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM143038.pdf
49. FDA. What is a serious adverse event? (4/2013). Accessed online April 29, 2013 at
http://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm
50. FDA. 2013 Drug Safety Communications. Accessed online April 29, 2013 at http://
www.fda.gov/Drugs/DrugSafety/ucm334024.htm
51. Institute of Medicine. FDA acts on drug safety recommendation in IOM report
(2008). Accessed online April 29, 2013 at http://www.iom.edu/Reports/2006/TheFuture-of-Drug-Safety-Promoting-and-Protecting-the-Health-of-the-Public/ChangeDrug-Safety-Policy-FDA.aspx
52. The Office of the National Coordinator for Health Information Technology.
(November, 2012). Accessed online on April 29, 2013 at http://www.healthit.gov/sites/
default/files/us_e-prescribingtrends_onc_brief_4_nov2012.pdf
53. U.S. National Library of Medicine. Drug information from the National Library of
Medicine (2013). Accessed online April 29, 2013 at http://www.nlm.nih.gov/learnabout-drugs.html
54. FDA. Division of Drug Information (2013). Accessed online April 29, 2013 at http://
www.fda.gov/AboutFDA/CentersOffices/
55. Ross GS, Gross CP, Krumholz HM. Promoting transparency in pharmaceutical
industry sponsored research. Am J Public Health. 2012; 102:72-80
56. AHRQ. Standardizing Medication Error Event Reporting in the U.S. Department of
Defense. Accessed online on April 29, 2013 at http://www.ahrq.gov/news/ulp/ptsafety/
ptsafety4.htm
57. Joint Commission. National Patient Safety Goals: Facts About the 2008 National
Patient Safety Goals. (2007). Accessed April 29, 2013 at http://www.jointcommission.
org/PatientSafety/NationalPatientSafetyGoals/08_npsg_facts.htm
58. HHS. HHS Announces New Requirements for Bar Codes on Drugs and Blood
to Reduce Risks of Medication Errors (February, 2004). Accessed online on May
1, 2013 at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/
ucm108250.htm
59. FDA. Guidance for Industry: Bar code label requirements. Questions and
answers (August, 2011). Accessed April 29, 2013 at http://www.fda.gov/downloads/
BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/
UCM267392.pdf
60. Premiere, Inc.. FDA Rule Requires Barcodes on Drug and Blood Products to Help
Reduce Errors (2006). Accessed online April 29, 2013 at https://www.premierinc.com/
safety/topics/bar_coding/
61. JCAHO. Electronic prescribing within an electronic health record reduces
ambulatory prescribing errors (October, 2011). Accessed online April 29, 2013 at http://
www.ingentaconnect.com/content/jcaho/jcjqs/2011/00000037/00000010/art00007
62. FDA Statement: FDA Statement on Institute of Medicine’s Report on Preventing
Medication Errors (July, 2006). Accessed online April 29, 2013 at: http://www.fda.gov/
NewsEvents/Newsroom/PressAnnouncements/2006/ucm108695.htm
63. Institute for Safe Medication Practices. It’s Time for Standards to Improve Safety
with Electronic Communication of Medication Orders. (Feb 2003). Accessed online
April 29, 2013 at www.ismp.org/Newsletters/acutecare/articles/20030220.asp?ptr=y
PATIENT SAFETY AND MEDICATION
ERRORS
Final Examination Questions
Choose the best answer for questions
26 through 30, mark your answer on the final
examination answer sheet found on page 75
or complete your final examination online at
pharmacy.elitecme.com.
30.Which of the following was not an FDA
recommendation to improve medication
safety?
a. List all products by generic name.
b. Spell out brand names in lower case to
distinguish them from generic names.
c. Spell out the word “units.”
d. Do not abbreviate names.
26. Which of the following is not a component
of a safe medication system?
a. Administration of the drug.
b. Preparation and dispensation of the
drug.
c. Selecting the generic equivalent that
provides the best profit margin.
d. Selection and procurement of the drug
by a pharmacy.
27. According to the ISMP MERP program,
all health care professionals should report
actual or potential medication errors that
occur due to all of the following factors,
except:
a. Staff misconduct.
b. Wrong drug, wrong strength, wrong
dose.
c. Errors in transcription.
d. Calculation errors.
28. Assume the scenario where a prescriber
has written an order for three daily doses
of lorazepam, 0.5 mg, to be administered
at bedtime, with discontinuation after the
third dose. When visiting the floor on the
fourth night, the pharmacist notes that
the nurse has taken a dose of lorazepam
from the floor stock, and is preparing to
administer it to the patient. The pharmacist
immediately recognizes the potential error
and stops the nurse from administering the
dose. This situation could be described as:
a. Lucky.
b. A near-miss.
c. A pharmacist overstepping his or her
responsibility.
d. A safe and efficient way to run a
nursing unit.
29. When determining whether an adverse
event is to be considered “serious,” FDA
requires it to include at least one of the
following attributes?
a. Fatal.
b. Life-threatening.
c. Requires a hospitalization.
d. All of the above.
RPCO03PSE13
Page 48
Elite
CHAPTER 5
PHARMACIST RESPONSIBILITIES IN
THE MANAGEMENT OF
CONTROLLED SUBSTANCES
(1 CONTACT HOUR)
Keywords
Controlled Substances Act (CSA), Drug
Enforcement Administration (DEA), controlled
substance.
Learning objectives
After the pharmacist has concluded this
knowledge-based activity, he or she will be
qualified and able to:
!! Understand the role of the Drug Enforcement
Author Disclosure: Bradley Gillespie and Elite
Professional Education do not have any actual or
Administration in regulating the use of
potential conflicts of interest in relation to this lesson.
controlled substances.
!! Appreciate the importance of a controlled
Universal Activity Number (UAN):
system of distribution to best manage
0761-9999-13-221-H01-P
Activity Type: Application-based
transactions involving controlled substances.
Initial Release Date: June 12, 2013
!! Develop a general understanding of how to
Expiration Date: June 30, 2015
schedule controlled substances.
!! Become familiar with the appropriate DEA
Target Audience: Pharmacists in a community-based
setting.
forms needed to document the transaction of
controlled substances.
To Obtain Credit: A minimum test score of 70 percent
is needed to obtain a credit. Please submit your answers !! Describe the requirements of both electronic
and paper-based controlled substance record
either by mail, fax, or online at
pharmacy.elitecme.com.
keeping systems.
!
!
Understand the requirements for inventorying
Questions regarding statements of credit and other
controlled substances.
customer service issues should be directed to 1-888!! Understand that there are requirements for
666-9053. This lesson is $5.00.
Internet pharmacies dispensing controlled
Educational Review Systems is accredited
substances that are unique and apart from
by the Accreditation Council of Pharmacy
those needed to dispense non-controlled
Education (ACPE) as a provider of
substances.
continuing pharmaceutical education. This
By Brad Gillespie, PharmD who has over 20 years’
experience spanning the regulatory, pharmaceutical
biotech and human nutritional supplement industries.
program is approved for 1 hour (0.1
CEU’s) of continuing pharmacy education credit. Proof
of participation will be posted to your NABP CPE
profile within 4 to 6 weeks to participants who have
successfully completed the post-test. Participants must
participate in the entire presentation and complete the
course evaluation to receive continuing pharmacy
education credit.
Abstract
Objective
To increase pharmacist awareness about the
requirements necessary to remain compliant with
the federal Controlled Substance Act.
Summary
As practicing pharmacists, it is critical that we
remain totally aware and compliant with all of the
laws governing our practice. Because dispensing
controlled substances is a major part of our work,
and because they are susceptible to abuse, it is
critical that we are well versed in all applicable
laws governing the role of pharmacists in safely
administering controlled substances to patients.
Conclusion
Evolving national trends in the abuse of
controlled substances and the development of
new regulations to combat this practice have
created an ever-changing clinical practice
environment as well as laws to govern it. It is
critical that all practicing pharmacists understand
how controlled substances are scheduled
by the Controlled Substance Act and their
responsibilities in ensuring that these potentially
dangerous medications are managed throughout
the prescribing system.
Pre-assessment questions
Before beginning this activity, test your precourse knowledge by answering the following
questions. Please be aware that these questions
will also be included as part of the CPE final
examination.
1. Jim Walters, PharmD, has completed his
residency in community practice and is
preparing to open his own pharmacy.
Before he can begin to dispense controlled
substances in his pharmacy, he will need to
complete which of the following tasks?
a. Register his pharmacy with the DEA,
using DEA Form 224.
b. Display a certificate indicating this
registration in a prominent place.
c. Order schedule II controlled substances
for inventory using DEA Form 222.
d. All of the above.
2. When opening the pharmacy one morning,
Jennifer Carlson, RPh, is horrified to find
that the window of the front door to the
store was broken, and that the lock had been
forcibly opened. When she entered the actual
pharmacy area, she was further distressed to
find that the shelves had been ransacked, and
it appeared that a number of units of anabolic
steroids, narcotics and benzodiazepines were
missing. In addition to calling the local police
authorities, Jennifer will also be required to
do which of the following:
a. File DEA Form 106 within one business
day with the DEA.
b. Immediately replace all missing stock.
c. Consider a more secure alarm system.
d. Complete full interviews with all
employees to rule out their involvement.
Elite
3. Davies’ Community Pharmacy is preparing
for its biennial inventory of controlled
substances. While Steen Davies, PharmD,
has an idea of how this should be conducted,
there are a few key things that he should
keep in mind when completing this important
count of all controlled substances. Some
of things that he should think about when
planning the specifics of the inventory
include which of the following?
a. An exact count of all schedule IV
substances, regardless of bottle size, is
critical.
b. All schedule II substances must be
manually counted.
c. All documents created summarizing the
inventory must be stored for a period of
at least five years.
d. All papers created documenting the
inventory of controlled substances must
be stored together to facilitate their
simple retrieval.
Introduction
This course is designed to provide an overview
of the Controlled Substances Act and allow
practicing pharmacists the opportunity to test
their knowledge by evaluating relevant case
studies and applying information they have
learned in this course to answer questions specific
to those cases.
This course is not designed to cover all situations.
A more detailed and exhaustive program would
be required to cover all eventualities that may
be encountered by a pharmacist navigating the
Controlled Substances Act. Further to that, this
course covers only federal law. Pharmacists must
also be familiar with the requirements laid out by
their respective state pharmacy laws.
What is the DEA, and what is the purpose
of the Controlled Substances Act (CSA)?
In 1973, the Drug Enforcement Administration
(DEA) was formed. Its role was primarily to
enforce all federal drug laws. The Controlled
Substances Act (CSA) and associated regulations
formed its backbone, implementing federal
requirements governing the disposition of both
legal and illicit drugs.
In the context of pharmacy, the DEA has two
major jobs: prevention of the diversion and
abuse of controlled substances and at the same
time, ensuring that the supply of legal controlled
substances remain available to meet legitimate
needs for these drugs. To carry out this important
mission, DEA works hand-in-hand with state,
local and other federal authorities.
Key concepts
Within the confines of the CSA, it is critical that
all transactions involving controlled substances
occur within a “closed system” of distribution.
Within this controlled loop, all entities authorized
to “touch” controlled substances – manufacturers,
distributors, doctors, and pharmacies – must hold
the proper DEA registration applicable to their
practice. Further, all parties must maintain a strict
accounting for all transactions, and maintain
Page 49
their records in such a way that they are kept
separate from other documents and are readily
retrievable.1
Scheduling
Substances that fit under the CSA are currently
divided into five schedules based on whether they
have an acceptable medical use and their relative
potential for abuse and likelihood of causing
dependence.
Schedule I: Schedule I drugs either have no
currently medically acceptable use or have a
high potential for abuse. Schedule 1 substances
include: MPPP, heroin, marijuana, LSD and
methaqualone. Additionally, some materials can
be temporarily included in Schedule I subject to
emergency scheduling.2
Schedule II: Substances categorized as schedule
II all have a high potential for abuse. Further
to that, the use of these drugs can lead to
severe psychological or physical dependence.
Schedule II drugs include codeine, morphine,
cocaine, amphetamine, methylphenidate and
phenylacetone.3
Schedule III: Substances in this schedule
generally are considered to have a potential for
abuse less than substances listed in schedules
I or II. The abuse of these drugs may lead to
moderate or low physical dependence or high
psychological dependence. Schedule II drugs
include chlorphentermine; secobarbital; products
containing not more than 1.8 grams of codeine
per 100 milliliters or not more than 90 milligrams
per dosage unit with one or more active, nonnarcotic ingredient in recognized therapeutic
amounts; and anabolic steroids.4
Schedule IV: Compared to substances
categorized in schedule II and III, substances
in schedule IV have a low potential for abuse
or dependence. Schedule IV items include
preparations containing not more than 1
milligram of difenoxin and not less than 25
micrograms of atropine sulfate per dosage unit,
alprazolam, fenfluramine, pentazocine and
sibutramine.5
Schedule V: Compared to substances categorized
into schedules I, II, III and IV, substances in
this schedule have a low potential for abuse and
consist primarily of preparations containing
limited quantities of certain narcotics. In most
cases, preparations appearing in schedule V
are used for their antitussive, antidiarrheal and
analgesic properties. Examples of Schedule V
products include preparations containing not
more than 200 milligrams of codeine per 100
milliliters or per 100 grams, pyrovalerone and
ezogabine.6
Registration requirements
Before any controlled substances can be
dispensed by a pharmacy, that pharmacy needs to
be registered with the DEA. This is accomplished
online using DEA Form 224.7 A certificate of this
registration must be publically displayed at each
pharmacy. This registration must be renewed
every three years using DEA Form 224a.8
Transfer or disposal of controlled
substances
If a pharmacy should ever need to transfer or
dispose of controlled substances to another
properly registered facility, this transaction
must be documented. These records must be
maintained and kept available for inspection by
DEA for a period of two years.
For the transfer of schedule II products, a DEA
Form 222 must be completed.9 For Schedule
III-V controlled substances, the transfer must be
documented, including the drug name, dosage
form, strength, quantity and date transferred.
Additionally, the document must include the
names, addresses, and DEA registration numbers
of all parties involved in the transfer.
How to manage a significant loss or theft
of controlled substances
The theft of a controlled substance is a criminal
event that must be reported to the police
and DEA within one business day. Should
there be any question of whether a crime has
occurred, pharmacists should err on the side of
conservatism and report the event.1 The theft of
a controlled substance is documented using DEA
Form 106. This documentation will describe the
actual circumstances of the diversion and include
all relevant details.10
Prescription records
Should the pharmacy determine there is a conflict
between the requirements of federal and state
requirements for record keeping, the pharmacy
will need to develop a filing system that complies
with both federal and state law. Regardless of
the filing system chosen, all prescriptions and
supporting documents need to be stored in a way
that makes them readily retrievable for DEA
inspection. If a paper-based system is used, all
schedule II prescriptions must be kept separate
from all other documents.1
The requirements governing the use of electronic
prescriptions for controlled substances are
outlined in 21 C.F.R. §1311. Briefly, all electronic
records must be maintained for two years
(although this time requirement does not preempt any longer periods of retention that may be
required by other applicable laws or regulations).
The electronic system must allow the records
to be separated from other prescriptions and
must be easily rendered into a readable format.
Lastly, prescription records must be sortable
by prescriber name, patient, drug and date
dispensed.11
Controlled substances inventory
requirements
An inventory is a comprehensive and accurate
count of all controlled substances on hand. This
accounting will be based on an actual count
of schedule II controlled substances and a
reasonable estimate of schedule III-V controlled
substances (except in case of containers holding
1,000 or more dosage units, in which case an
actual count is required). The CSA dictates that
all inventory records be maintained for at least
two years. Schedule II inventory records must be
kept separate from all other inventory documents.
When are inventories required?
At the time of initial DEA registration.
Biennially (every two years following initial
inventory).
For newly scheduled controlled substances,
they must be completed as of the effective
date of scheduling or change in schedule.1
Ordering controlled substances
Only schedule II controlled substances require
a specific ordering protocol. DEA Form 222
is required on each occasion that a schedule II
controlled substance is distributed, purchased or
transferred between properly registered facilities.9
For schedule III-V controlled substances,
pharmacists are required to maintain an invoice
or packing slip stating the date that the products
were received and confirmation of the order’s
accuracy. Additionally, these receipts must also
document the name of the controlled substance,
the formulation, the number of dosage units, and
the total number of containers received. These
receipts must be maintained using a system that
allows them to be readily retrieved for inspection
by DEA.1
Prescription requirements
The basic elements for a controlled substance
prescription do not vary greatly from those
needed for any other prescription based on the
CSA, although states may have their own laws
governing the prescription of these products.
With that said, pharmacists must be cognizant
of their responsibility to ensure that every
prescription they fill is legitimate within the
meaning and intent of the CSA. If a pharmacist
has any doubt about the authenticity or validity
of a prescription, he or she is under no obligation
to fill it.12 To the contrary, any pharmacist who
knowingly fills a questionable prescription for
a controlled substance is committing a felony
offense.13
The use of electronic prescriptions for controlled
substances is permitted only after their system
has obtained a third party audit or certification
review, determining that the application meets
DEA requirements. Refills are not permitted
for schedule II controlled substances. Up to
five refills may be obtained for a schedule III-V
controlled substances within six months of
issuance of the original prescription.1
Dispensing requirements
Labeling requirements for controlled substances
are generally the same as for other prescription
medications. When actually dispensing, though,
controlled substances may be received only by
the actual patient or a member of the patient’s
household. Schedule II controlled substances
may be dispensed only pursuant to a written
prescription, except in cases of a bona fide
emergency, in which case the prescription can
be transmitted to the pharmacy telephonically. In
this case, the prescriber must provide a written
prescription to the pharmacy within seven days.
Prescriptions for schedule III-V controlled
Page 50
Elite
substances can be delivered by paper, facsimile,
orally or electronically, so long as they meet the
DEA requirements for such prescriptions.1
The Ryan Haight Online Pharmacy
Consumer Protection Act of 2008
The Ryan Haight Online Pharmacy Consumer
Protection Act of 2008 Amended the CSA by
including a number of new provisions designed
to prevent the illegal distribution and dispensing
of controlled substances over the Internet. This
act, designed to counteract “rogue” Internet sites,
applies to all controlled substances.
Under this act, it is illegal to deliver, distribute
or dispense a controlled substance by means of
the Internet unless the online pharmacy holds
a modified DEA registration authorizing it to
operate as an online pharmacy. Operating counter
to this act is in violation of 21 U.S.C. § 841(h)(1)
and subject to potential criminal prosecution.14
Before he can begin to dispense controlled
substances in his pharmacy, he will need to
complete which of the following tasks:
a. Register his pharmacy with the DEA,
using DEA Form 224.
b. Display a certificate indicating this
registration in a prominent place.
c. Order schedule II controlled substances
for inventory using DEA Form 222.
d. All of the above.
Answer: Although many procedures must
be followed to properly open a pharmacy, if
that pharmacy chooses to dispense controlled
substances, the CSA requires that additional
tasks must also be completed. The first task for
Dr. Walters is to properly register his pharmacy
with the DEA, using DEA Form 224. After he
receives this registration, the certificate indicating
his registration needs to be prominently displayed
in the pharmacy. In order to procure schedule
II controlled substances, Dr. Walters must
do so using DEA Form 222. This form is not
required for acquiring schedule III-V controlled
substances.
The information contained in this section above
is included only as a brief summary. A full
description of the requirement of this act is
beyond the scope of this course. Pharmacists
and pharmacies needing more complete and
Scenario 3
comprehensive information describing the act
After Dr. Walters has been in business for
should access the actual text of the CSA and DEA
some time, he realizes that due to poor
regulations.
inventory control, he has a number of
dosages of oxycodone that have reached their
Controlled Substance Act scenarios
expiry date and are thus not suitable for sale
Scenario 1
to patients. In response to this finding, Dr.
Winter Pharmacy is preparing a record
Walters should:
keeping system to account for the acquisition,
a. Mail them back to his wholesaler without
storage and dispensing of controlled
documentation.
substances. To accomplish this within
b. Discard the expired pills in an approved
the guidelines set out by the Controlled
refuse receptacle.
Substances Act, its owners wisely choose to
c.
Complete DEA Form 222 and transfer
design a “closed” system. Critical elements
to a properly licensed facility.
of this inventory control system will include
d. Contact the manufacturer to request an
which of the following?
extension on the expiry date.
a. For sake of simplicity, make sure that
all prescriptions (non-controlled and
controlled substances) are filed in a single
location.
b. Maintain a strict accounting of all
transactions of controlled substances.
c. Ensure that only the pharmacy has the
proper DEA registration permits.
d. None of the above.
Answer: To comply with all provisions of the
CSA, any pharmacy that dispenses controlled
substances must operate within the confines of
a “closed system.” In essence, this means that
every entity that comes into contact with the
controlled substance must be properly licensed,
registered, and follow proper guidelines. One
such guideline stipulates that all involved parties,
including Winter Pharmacy, must provide a
comprehensive and thorough accounting of all
transactions involving controlled substances.
Further, all documents on controlled substances
must be kept separate and readily retrievable
from other records.
Scenario 2
Jim Walters, PharmD, has completed his
residency in community practice and is
preparing to open his own pharmacy.
authorities, Jennifer will also be required to
which of the following:
a. File DEA Form 106 within one business
day with the DEA.
b. Immediately replace all missing stock.
c. Consider a more secure alarm system.
d. Complete full interviews with all
employees to rule out their involvement.
Answer: While there may be a number of
business-related responses to a theft of controlled
substances that Jennifer may elect to accomplish,
the CSA is clear that a DEA Form 106 needs to
be filed with DEA within one business day. DEA
Form 106 describes the circumstances and details
of the theft. Although items b, c and d, may be
reasonable responses, they are not mandated by
the CSA.
Scenario 5
Mammoth Lakes Community Pharmacy,
in an effort to create greater levels of
patient safety and improve efficiencies, is
considering replacing its antiquated paper
record keeping system with a state-of-theart electronic system. Unfortunately, the
pharmacy manager, Jim Edwards, PharmD,
finds that the more vendors he speaks to, the
more confused he gets about the requirements
of such a system. Whichever system
Mammoth Lakes ends up using, it is critical
that it addresses which of the following key
elements?
a. The selected system complies only
with federal DEA regulations, as these
supersede state laws.
b. The system should simplify its approach
to filing by making sure that all
prescriptions for controlled substances
remain together.
c. To comply with DEA regulations, all
schedule II prescriptions need to be
maintained in a readily retrievable
state for a period of at least two years.
d. None of the above elements are needed.
Answer: The CSA makes it clear that any
change in disposition of schedule II controlled
substances, including oxycodone, needs to be
documented using DEA Form 222. To either
return to the wholesaler without documentation
or simply discard the doses would be a clear
violation of the CSA. It would not be appropriate
for Dr. Walters to request an extension on the
expiry date. To move these schedule II controlled
substances from his inventory, the only legal way
to accomplish this, is to send them to another
properly licensed facility. This transaction will
need to be appropriately documented using DEA
Form 222.
Answer: Electronic pharmacy data systems can
be complex, creating confusion for the people
who need to select an appropriately designed
system. Nonetheless, whether a paper, or
electronic structure is employed, the CSA is clear
that prescriptions for all schedule II controlled
substances need to be kept separate from other
documents in a readily retrievable state for no
less than two years. Further to that, systems need
to be designed to be compliant with all laws, both
state and federal.
Scenario 4
Scenario 6
When opening the pharmacy one morning,
Jennifer Carlson, RPh, is horrified to find
that the window of the front door to the
store was broken, and that the lock had been
forcibly opened. When she entered the actual
pharmacy area, she was further distressed to
find that the shelves had been ransacked, and
it appeared that a number of units of anabolic
steroids, narcotics and benzodiazepines were
missing. In addition to calling the local police
Elite
Davies’ Community Pharmacy is preparing
for its biennial inventory of controlled
substances. While Steen Davies, PharmD,
has an idea of how this should be conducted,
there are a few key things that he should
keep in mind when completing this important
count of all controlled substances. Some
of things that he should think about when
planning the specifics of the inventory
include which of the following?
Page 51
a. An exact count of all schedule IV
substances, regardless of bottle size, is
critical.
b. All schedule II substances must be
manually counted.
c. All documents created summarizing the
inventory must be stored for a period of
at least five years.
d. All papers created documenting the
inventory of controlled substances must
be stored together to facilitate their
simple retrieval
Answer: The inventorying of all controlled
substances is critical to maintaining compliance
with the CSA. Exact counts are required only
for schedule II controlled substances and other
controlled substances in bottles containing 1,000
or more dosage units. All documents must be
maintained for at least two years, with schedule II
records kept separate from the others.
Scenario 7
Kim Maxon, PharmD, the pharmacist in
charge of Arrow Community Pharmacy,
is working with her pharmacy technician
to prepare its regular medication order.
In addition to non-controlled substances,
this order will also call for a number
of medications that are categorized as
schedule III-V, as well as for some ADHD
medications, which fall under schedule II. To
complete the submission and receipt of this
order, Kim will need to ensure that which of
the following tasks is accomplished?
a. All of the ADHD medications will need
to be ordered using DEA Form 222.
b. DEA Form 222 will need to be
completed, including all of the controlled
substances.
c. For the schedule III-V controlled
substances, Kim is required to maintain
an invoice or packing slip stating the date
that the products were ordered from the
wholesaler.
d. The receipts or invoices that are included
with the shipment must be accounted for
and signed by Dr. Maxon, as she is the
pharmacist in charge
Answer: According to ordering provisions
laid out in the CSA, all orders for schedule II
controlled substances will need to be made using
DEA Form 222. The other controlled substances
can be ordered using regular order forms. The
CSA does not require that receipts or invoices
documenting the orders are signed for by the
pharmacist in charge, but does require that the
receipt date is noted on the invoice and that it is
filed in a way that they can be readily retrieved
by DEA.
Scenario 8
Lawrence Campbell, RPh, is nearing the
end of his shift at the Eagle Community
Pharmacy when a man approaches the
prescription drop-off area. The well-dressed
man presents a prescription to Lawrence
for a total of 30 10-milligram oxycodone
tablets. While at first glance, the prescription
appears legitimate, upon closer examination,
Lawrence notes that the patient’s name
is slightly smeared. To try to validate the
prescription, Lawrence asks the man why he
was being prescribed the medication. The
customer hesitates slightly, and then, without
making eye contact, states that it is for back
pain. Based on these series of events, the best
initial approach to managing this situation is
for Mr. Campbell to:
a. Dispense the medication.
b. Contact the prescribing physician to
verify the prescription.
c. Detain the customer and call the police.
d. Ask the customer whether the
prescription is authentic.
Answer: Lawrence was wise to question the
validity of the prescription. Based on the
response to his additional inquiry, the patient
gave the impression that there may be a problem
with the authenticity of the prescription. Based
on this, Lawrence had an obligation to ensure that
the prescription was genuine before filling it.
The proper next steps are subjective, but there
are some basic ideas to keep in mind when
considering this situation. Dispensing the
prescription under these circumstances would
be wrong, and a potential violation of the CSA.
Detention of the patient, and calling the police,
may be appropriate, but is likely not the best
initial approach. The best tactic would be to
simply contact the physician who allegedly wrote
the prescription and ask him or her to verify that
it is bona fide.
Scenario 9
Jeanna Andrew, pharmacist in charge of
Century City Pharmacy, is putting together
a list of special requirements specific to
the dispensing of schedule II controlled
substances. Some of the key elements that
must be discussed in her checklist include
which of the following?
a. The transfer of schedule II substances
must be documented using DEA Form
222.
b. Schedule II inventory records must be
kept separate from all other pharmacy
documents.
c. If schedule II substances are dispensed
under an emergency situation without a
written prescription, a paper prescription
from the prescriber must be provided to
the dispensing pharmacy within seven
days.
d. All of the above.
Answer: The CSA is especially clear on the
guidelines for handling schedule II controlled
substances. All changes in disposition of schedule
II controlled substances must be documented
using DEA Form 222. Regular inventorying of
schedule II controlled substances is also required,
and resultant documents must be kept separate
from all other pharmacy records in an easily
retrievable state. While telephonic emergency
prescriptions for schedule II controlled
substances are allowed in some circumstances,
it is incumbent on the prescribing physician to
provide a supportive written prescription within
seven days.
Scenario 10
James Gilbert, PharmD is realizing his career
goals by establishing a large, Internet-based
pharmacy. He believes that by opening this
service, he can provide excellent service to
his customers at competitive prices because
of the efficiencies of scale and reduced
overhead costs. In addition to regulations and
laws governing all pharmacies, though, he
should be especially concerned with the rules
included in which of the following acts?
a. The Ryan Haight Online Pharmacy
Consumer Protection Act of 2008.
b. The Consumer Protection Act.
c. The 1962 Kefauver Harris Amendment.
d. The 1952 Durham-Humphrey
Amendment.
Answer: To remain current and relevant, the
CSA was amended in 2008 to more closely
govern the dispensing of controlled substances
over the Internet. Under the provisions of this
act, it is illegal to sell controlled substances over
the Internet without proper DEA registration
(in addition to the requirements of traditional
pharmacies). The acts identified in items b, c
and d, while important to pharmacy practice,
in general, are not as closely aligned with the
dispensing of controlled substances over the
Internet as that described in item a.
References
1.U.S. Department of Justice (2010). Pharmacist’s Manual: An Informational Outline
of the Controlled Substances Act. Accessed online 26 May 2013 at: http://www.
deadiversion.usdoj.gov/pubs/manuals/pharm2/pharm_manual.pdf
2.Code of Federal Regulations (2013). § 1308.11. Accessed online 26 May 2013 at http://
www.ecfr.gov/cgi-bin/text-idx?c=ecfr&rgn=div5&view=text&node=21:9.0.1.1.9&id
no=21#21:9.0.1.1.9.0.26.4
3.Code of Federal Regulations (2013). § 1308.12. Accessed online 26 May 2013 at http://
www.ecfr.gov/cgi-bin/text-idx?c=ecfr&rgn=div5&view=text&node=21:9.0.1.1.9&id
no=21#21:9.0.1.1.9.0.26.4
4.Code of Federal Regulations (2013). § 1308.13. Accessed online 26 May 2013 at http://
www.ecfr.gov/cgi-bin/text-idx?c=ecfr&rgn=div5&view=text&node=21:9.0.1.1.9&id
no=21#21:9.0.1.1.9.0.26.4
5.Code of Federal Regulations (2013). § 1308.14. Accessed online 26 May 2013 at http://
www.ecfr.gov/cgi-bin/text-idx?c=ecfr&rgn=div5&view=text&node=21:9.0.1.1.9&id
no=21#21:9.0.1.1.9.0.26.4
6.Code of Federal Regulations (2013). § 1308.15. Accessed online 26 May 2013 at http://
www.ecfr.gov/cgi-bin/text-idx?c=ecfr&rgn=div5&view=text&node=21:9.0.1.1.9&id
no=21#21:9.0.1.1.9.0.26.4
7.U.S. Department of Justice: Drug Enforcement Administration (2013). DEA Form
224. Accessed online 26 May 2013 at: http://www.deadiversion.usdoj.gov/drugreg/
reg_apps/224/224_instruct.htm
8.U.S. Department of Justice: Drug Enforcement Administration (2013). DEA Form
224a. Accessed online 26 May 2013 at: http://www.deadiversion.usdoj.gov/fed_regs/
notices/2009/fr08212.htm
9.U.S. Department of Justice: Drug Enforcement Administration (2013). DEA Form 222.
Accessed online 26 May 2013 at: http://www.deadiversion.usdoj.gov/faq/dea222.htm
10. U.S. Department of Justice: Drug Enforcement Administration (2013). DEA Form
106. Accessed online 26 May 2013 at: http://www.deadiversion.usdoj.gov/21cfr_
reports/theft/
11. U.S. Department of Justice: Drug Enforcement Administration (2013). Part 1311
digital certificates- Subpart C—electronic prescriptions. Accessed online 26 May 2013
at: http://www.deadiversion.usdoj.gov/21cfr/cfr/1311/subpart_c100.htm
12. U.S. Department of Justice: Drug Enforcement Administration (2013). Title 21
United States Code (USC) Controlled Substances Act: Section 829. Prescriptions.
Accessed online 26 May 2013 at: http://www.deadiversion.usdoj.gov/21cfr/21usc/829.
htm
13. United States v. Kershman, 555 F.2d 198 (United States Court Of Appeals, Eighth
Circuit, 1977). Accessed on 26 May 2013 line at: https://bulk.resource.org/courts.
gov/c/F2/555/555.F2d.198.76-2075.html
14. Department Of Justice, Drug Enforcement Administration. 21 CFR Parts 1300, 1301,
1304, 1306, Implementation of the Ryan Haight Online Pharmacy Consumer Protection
Act of 2008 (2008). Accessed on 26 May 2013 line at: http://www.deadiversion.usdoj.
gov/fed_regs/rules/2009/fr0406.pdf
(Final examination questions on next page)
Page 52
Elite
PHARMACIST RESPONSIBILITIES IN
THE MANAGEMENT OF
CONTROLLED SUBSTANCES
Final Examination Questions
Choose the best answer for questions
31 through 35, mark your answer on the final
examination answer sheet found on page 75
or complete your final examination online at
pharmacy.elitecme.com.
31.Critical elements of a “closed” inventory
control system will include which of the
following?
a. For sake of simplicity, make sure that
all prescriptions (non-controlled and
controlled substances) are filed in a
single location.
b. Maintain a strict accounting of all
transactions of controlled substances.
c. Ensure that only the pharmacy has the
proper DEA registration permits.
d. None of the above.
35. What is one of the inventory requirements
of the inventory of controlled substances?
a. An exact count of all schedule IV
substances, regardless of bottle size is
critical.
b. All schedule II substances must be
manually counted.
c. All documents created summarizing
the inventory must be stored for a
period of at least five years.
d. All papers created documenting the
inventory of controlled substances
must be stored together to facilitate
their simple retrieval.
32.Before a new pharmacy can begin dispense
controlled substances, which task must the
pharmacy complete?
a. Register his pharmacy with the DEA,
using DEA Form 224.
b. Display a certificate indicating this
registration in a prominent place.
c. Order schedule II controlled substances
for inventory using DEA Form 222.
d. All of the above.
33.If a pharmacy should ever need to transfer
or dispose of controlled substances to
another properly registered facility, the
pharmacy must:
a. Mail back the controlled substances
without documentation.
b. Discard the expired pills in an
approved refuse receptacle.
c. Complete DEA Form 222 and transfer
to a properly licensed facility.
d. Contact the manufacturer to request an
extension on the expiry date.
34.According to the Controlled Substance
Act, what is the procedure when a theft of a
controlled substance occurs?
a. Report to the police and file DEA Form
106 within one business day with the
DEA.
b. Immediately replace all missing stock.
c. Consider a more secure alarm system.
d. Complete full interviews with
all employees to rule out their
involvement.
RPCO01PRE13
Elite
Page 53
medications used to treat schizophrenia.
!! Recommend a treatment plan for treatment
of schizophrenia based on patient-specific
characteristics.
(7 CONTACT HOURS)
By Katie Ingersoll, RPh, PharmD, and Staff Pharmacist !! Discuss counseling points for medications
used in the treatment of schizophrenia.
for national chain
!! Determine differences in drug classifications,
Author Disclosure: Katie Ingersoll and Elite
side effects, mechanism of action, and drug
Professional Education do not have any actual or
interactions between medications used to
potential conflicts of interest in relation to this lesson.
treat alcoholism.
Universal Activity Number (UAN):
!! Design a treatment plan for treatment
0761-9999-13-167-H01-P
of alcoholism based on patient-specific
Activity Type: Knowledge-based
characteristics.
Initial Release Date: May 18, 2013
!
!
Discuss counseling points for medications
Expiration Date: May 23, 2015
used in the treatment of alcoholism.
Target Audience: Pharmacists in a community-based
!! Determine appropriateness of treatment
setting
of mental health disorders in special
To Obtain Credit: A minimum test score of 70 percent
populations, such as pregnant patients.
CHAPTER 6
PHARMACOLOGY: mENTAL hEALTH
mEDICATIONS
is needed to obtain a credit. Please submit your answers
either by mail, fax, or online at
pharmacy.elitecme.com.
Questions regarding statements of credit and other
customer service issues should be directed to 1-888666-9053. This lesson is $29.00.
Educational Review Systems is accredited
by the Accreditation Council of Pharmacy
Education (ACPE) as a provider of
continuing pharmaceutical education. This
program is approved for 7 hours (0.7
CEU’s) of continuing pharmacy education credit. Proof
of participation will be posted to your NABP CPE
profile within 4 to 6 weeks to participants who have
successfully completed the post-test. Participants must
participate in the entire presentation and complete the
course evaluation to receive continuing pharmacy
education credit.
Learning objectives
!! Differentiate the drug classifications, side
effects, mechanisms of action, and drug
interactions of antidepressant medications.
!! Recommend a treatment plan for
antidepressant therapy based on patientspecific characteristics.
!! Discuss counseling points for medications
used in the treatment of major depression.
!! Distinguish differences in drug
classifications, side effects, mechanism
of action, and drug interactions between
antianxiety medications.
!! Design a treatment plan for antianxiety
therapy based on patient-specific
characteristics.
!! Discuss counseling points for medications
used in the treatment of anxiety disorders.
!! Differentiate the side effects, mechanism
of action, and drug interactions between
medications used to treat bipolar disorder.
!! Develop a treatment plan for bipolar therapy
to prevent deterioration and stabilize the
patient’s condition based on patient-specific
characteristics.
!! Discuss counseling points for medications
used in the treatment of bipolar disorders.
!! Distinguish differences in drug
classifications, side effects, mechanism
of action, and drug interactions between
Summary
This course will review the pharmacology of
medications used to treat depression, anxiety,
alcoholism, bipolar disorder and schizophrenia.
After reviewing the diagnosis of each disease
state, the mechanism of action, side effects, drug
interactions, black box warnings and applications
will be reviewed for each medication class.
Considerations for special populations will be
reviewed as applicable, as well as any effects
on lab results. A discussion of counseling points
for each class or type of medication will also be
provided.
Conclusion
This course will allow pharmacists to review the
pharmacology of mental health medications to
apply this information to clinical practice.
Pre-assessment questions
Prior to beginning work on this activity, test your
baseline knowledge by answering the following
questions. These questions may be repeated in the
final examination.
1. Jackie Robinson has been diagnosed with
depression, and he has been suicidal for the
past few weeks after losing several baseball
games in a row. Which of the following
antidepressants would be the most dangerous
to dispense to Jackie in a one-month supply?
a. Sertraline.
b. Nortriptyline.
c. Duloxetine.
d. St. John’s Wort.
2. Which of the following medications is
considered a short-acting benzodiazepine?
a. Alprazolam.
b. Diazepam.
c. Chlordiazepoxide.
d. Clonazepam.
3. Genevive has bipolar disorder and
has recently been diagnosed with
hypothyroidism. Which of the following
medications has the most negative effects on
thyroid hormone levels?
a. Lamotrigine.
b. Carbamazepine.
c. Lithium.
d. Valproic acid.
Introduction
Mental illness, defined as diagnosable mental
disorders, causes more disability in developed
countries than any other group of illnesses,
including cancer and cardiac disease. In fact, it
is estimated that 25 percent of all adults in the
United States will develop at least one mental
illness during their lives.1
The prevalence of mental illness makes it almost
a certainty that pharmacists, no matter their
practice setting or specialty, will care for patients
who are currently experiencing a mental illness.
It also makes it likely that these patients are
taking medications for such illnesses or will need
to be prescribed appropriate pharmacotherapy.
Therefore, it is imperative that all pharmacists be
knowledgeable about the treatments available for
various mental illnesses, their actions, dosage,
side effects and potential drug interactions. This
education program will provide information
about the pharmacological interventions for
several of the most commonly encountered
mental illnesses.
Antidepressant pharmacology
The reported incidence of depression has risen
every year since early in the 20th century. In
the United States, it is estimated that one in six
people will experience a depressive episode at
some point in their life. However, only half of the
people who meet the criteria for diagnosis seek
treatment for their depression.2
According to the DSM-IV, a primary diagnosis
of depression is made when a patient has
either anhedonia (loss of interest in previously
pleasurable activities) or consistently depressed
mood and at least five of the following symptoms
that last at least two weeks:36
Changes in sleep: either hypersomnia or
insomnia.
Feelings of guilt or worthlessness.
Fatigue or loss of energy.
Decreased ability to concentrate or focus.
Significant weight loss or gain.
Psychomotor symptoms of retardation or
agitation.
Suicidal attempt or thoughts.
Prescription antidepressant medication is
a common treatment modality for major
depression. Treatment length varies among
patients. Treatment for an initial depressive
episode may last from six months to a year,
and recurrent episodes may require two years
of treatment or more. Chronic depression may
necessitate lifelong treatment.3
Drugs are generally prescribed initially at a low
dose, which is gradually increased according
to the patient’s tolerance and response to the
drug. It may take from one to eight weeks for
antidepressant medication to become effective,
depending on the medication, dosage, and patient.
Therapeutic effects are not immediately apparent,
and patients should be counseled on this point.3,4
Page 54
Elite
Classes of antidepressant medications include:3,4
SSRIs: selective serotonin reuptake
inhibitors.
TCAs: tricyclic and tetracyclic
antidepressants.
MAOIs: monoamine oxidase inhibitors.
SNRIs: serotonin and norepinephrine
reuptake inhibitors.
Atypical antidepressants.
Drug alert! Antidepressants are sometimes
prescribed to treat conditions other than
depression, such as panic disorder, post-traumatic
stress disorder (PTSD), anxiety disorders,
obsessive-compulsive disorder, and premenstrual
syndromes.
Antidepressant use in children and
adolescents
Antidepressant use in children and adolescents
requires meticulous monitoring. The Food and
Drug Administration (FDA) mandates that
all antidepressants carry a warning that some
children, adolescents and young adults may be at
increased risk for suicidal ideation. All patients,
however, should be monitored meticulously for
any increase in depression or unusual behavior,
particularly during the first few weeks after
antidepressant therapy is initiated.4,5
Selective serotonin reuptake inhibitors
(SSRIs)
The most commonly prescribed antidepressants,
SSRIs, work by blocking the reuptake of
serotonin into the presynaptic cell, increasing
the serotonin in the synapse available to bind to
receptors on the postsynaptic cell. These drugs
are referred to as selective because they primarily
have an impact on serotonin, not on other types
of neurotransmitters.3,4,5,36
The following SSRIs and doses are used for the
treatment of depression:4,5,36
Citalopram (Celexa) 10-40 mg. per day.
Escitalopram (Lexapro) 5-20 mg. per day.
Fluoxetine (Prozac, Prozac Weekly, Sarafem)
20-60 mg. per day
ŠŠ Longer half-life, generally has fewer
withdrawal symptoms.
ŠŠ Considered to be the most activating of
the SSRIs.
Paroxetine (Paxil, Paxil CR) 10-60 mg. per
day.
ŠŠ Relatively short acting, generally has the
most withdrawal symptoms.
Sertraline (Zoloft) 25-200 mg. per day.
Fluvoxamine (Luvox) 50-300 mg. per day.
Drug interactions
There are a number of drugs that can cause
harmful effects if taken in conjunction with
antidepressants. That is why it is so important
to explain to patients that they must inform their
health care providers of all of the medications
they take, including not only prescription
drugs, but over-the-counter medications, herbal
preparations, vitamins, minerals and even
nutrition supplements and weight-loss products.
Many patients assume that non-prescription
medications and substances such as aspirin,
herbal preparations and vitamins are not
medications, so they do not bother to inform
their health care providers that they are taking
them. Patients must be counseled that any or all
of these substances may interact negatively with
antidepressants.
Aspirin products, other non-steroidal antiinflammatory drugs (NSAIDs), Coumadin
and other drugs that increase coagulation time
may increase the risk of bleeding if taken in
conjunction with SSRIs. Patients who take such
drugs should be cautioned about this risk and
monitored closely.4,5 When possible, alternatives
to these types of drugs should be investigated
while the patient is taking SSRIs.
Monoamine oxidase inhibitors (MAOIs), such as
phenelzine (Nardil) and isocarboxazid (Marplan),
are also used in the treatment of depression.
However, they must not be used in conjunction
with SSRIs, nor should SSRIs be used within 14
days of MAOI therapy.
Use of MAOIs in too-close conjunction
with SSRIs can cause neuroleptic malignant
syndrome. This syndrome can be fatal and is
characterized by hyperthermia, rigidity and
autonomic dysregulation.4,5,6
Serotonin syndrome is also a serious
adverse reaction to antidepressant therapy.
It is more likely to occur when two or more
medications that raise serotonin levels are
used in combination. Serotonin syndrome is
characterized by confusion, hallucinations,
restlessness, loss of coordination, vomiting,
tachycardia, irregular heart rates, dilated
pupils, fever, changes in blood pressure and
unconsciousness.4,5
When starting a patient on SSRIs, it is important
to check whether the patient is taking other
medications that can increase serotonin levels.
If a patient is taking several medications that
increase serotonin levels, the person is at risk
of developing serotonin syndrome, a potentially
fatal condition. Examples of serotonergic
medications are linezolid (contraindicated within
14 days of taking SSRIs), MAO inhibitors
(contraindicated within 14 days of taking SSRIs),
triptans (such as sumatriptan, frovatriptan, and
zolmitriptan), tramadol, and St. John’s Wort.36
Fluoxetine and paroxetine are inhibitors of
the cytochrome P450 enzyme 2D6, and can
increase the levels and incidence of side effects
of CYP2D6 substrates, such as aripiprazole,
clozapine, codeine, donepezil, flecanide,
hydrocodone, meperidine, propafenone and
tamoxifen.36
Fluvoxamine is an inhibitor of the cytochrome
P450 enzymes 1A2 and 3A4, and can increase
the levels and incidence of side effects of
CYP1A2 and 3A4 substrates, such as haloperidol,
theophylline, tizanidine, methadone, warfarin,
and carbamazepine; statin drugs, such as
simvastatin, lovastatin, atorvastatin, and
triazolam; and prostate medications, such as
tamsulosin, alfuzosin, dutasteride, eplerenone,
Elite
amiodarone,clarithromycin, erythromycin,
sirolimus and tacrolimus.
Other drug interactions with SSRIs include
pimozide (combination contraindicated due to
increased pimozide levels, increased risk of
QT prolongation), thioridazine (combination
contraindicated due to increased thioridazine
levels), and diuretics (when used in combination,
patients should be monitored for excessive
electrolyte loss).
Side effects
Side effects commonly associated with SSRIs
include:3,4,5
Fatigue.
Headache.
Tremor.
Dizziness.
Insomnia.
Dry mouth.
Nausea.
Diarrhea.
Agitation or restlessness.
Reduced libido.
Difficulty reaching orgasm.
Erectile dysfunction.
Rash.
Diaphoresis.
Weight gain.
Drowsiness.
Pregnancy
Some antidepressants may place the fetus at
risk during pregnancy or the drugs may pass
to the baby during breastfeeding. Paroxetine
(Paxil) in particular seems to be linked to an
increased risk of birth defects, including cardiac
and respiratory problems.5 Women who are
considering becoming pregnant should discuss
depression treatment options with their doctor
before becoming pregnant.
Discontinuing the drug
Patients must be instructed to avoid missing
several doses and must not discontinue using
the drug abruptly. When discontinuing SSRIs,
the dosage must be tapered gradually under
the supervision of the prescriber. Abrupt
discontinuation can cause withdrawal-like
symptoms that include:4,5
Nausea.
Headache.
Dizziness.
Lethargy.
Flu-like symptoms.
Counseling Points for SSRIs36
Patients should be told to take SSRIs as
directed by their doctor, and to not miss doses
or discontinue the medication abruptly.
Counsel patients on symptoms and severity
of serotonin syndrome, and tell them to notify
their pharmacist or doctor if they start new
medications, herbs, or supplements.
Notify patients of potential side effects and
when to contact a doctor or seek emergency
care.
Inform patients of black box warnings on
antidepressants and instruct them to contact
Page 55
their doctor if they experience severe mood
changes.
Tricyclic antidepressants (TCAs) and
tetracyclics
TCAs and tetracyclics are among the earliest
identified antidepressants and are sometimes
referred to as cyclics. Although effective, they
have been largely replaced by antidepressants
that cause fewer side effects. However, TCAs and
tetracyclics may still be prescribed for patients
who do not respond to other classifications of
antidepressants.7
These drugs work by increasing the amount
of norepinephrine and serotonin in the
CNS by blocking their reuptake by the
presynaptic neurons.4 These actions make more
norepinephrine, serotonin, or both available in
the brain, which, in turn, enhances the ability of
neurons to send and receive messages. They also
affect other types of neurotransmitters, which can
cause a number of side effects.4,7
Cyclics and doses used in the treatment of
depression include:3,4,7,36
Tertiary TCAs
ŠŠ Amitriptyline (Elavil), 10-300 mg. per
day, divided into 1-3 doses per day.
ŠŠ Doxepin (Sinequan) 25-300 mg. per day,
divided into 1-3 doses per day.
ŠŠ Clomipramine (Anafranil) 75-250 mg.
per day, divided into 3 doses per day.
ŠŠ Imipramine (Tofranil) 100-300 mg. per
day, divided into 1-3 doses per day.
ŠŠ Trimipramine (Surmontil) 75-300 mg.
per day, divided into 1-3 doses per day.
Secondary TCAs
ŠŠ Desipramine (Norpramin) 100-300 mg.
per day, divided into 1-3 doses per da).
ŠŠ Nortriptyline (Pamelor) 50-150 mg.
per day, divided into 1-3 doses per day;
*max. 150 mg./day.
ŠŠ Protriptyline (Vivactil) 15-60 mg. per
day, divided into 3-4 doses per day.
Tetracyclic antidepressants
ŠŠ Amoxapine (Asendin) 50-600 mg. per
day, divided into 2-3 doses per day.
Drug alert! Tricyclic antidepressants should
be used with caution in patients who are
suicidal. Overdose on tricyclic antidepressants
can be potentially fatal from cardiovascular
complications. Consider dispensing smaller
quantities to suicidal patients.36
Photophobia.
Blurred vision.
Constipation.
Dizziness.
Delayed orgasm.
Decreased sex drive.
Tachycardia.
Confusion.
Increased appetite and weight gain.
Fatigue.
Headache.
Nausea.
Seizures, especially with maprotiline
(Ludiomil).
Drug alert! Tricyclic antidepressants are often
used to treat insomnia because of the adverse
effects of drowsiness.36
Pregnancy
There are a number of safety concerns associated
with TCAs and tetracyclics. As with SSRIs,
some cyclics may harm a fetus and may pass
to the baby during breast-feeding. Women of
childbearing age should be counseled about the
potential benefits versus risks to the unborn child
and to the baby during breast-feeding before
becoming pregnant.7
Drug interactions
Adverse drug interactions are also problematic.
Serotonin syndrome is a possibility as it is with
SSRIs. There are specific types of drugs that,
if taken in conjunction with cyclics, can cause
specific, severe problems. These include: 4,7,36
CYP2D6 inhibitors: Can alter hepatic
metabolism of antidepressant.
Barbiturates, alcohol and other CNS
depressants: Can significantly increase CNS
depression and drowsiness.
Serotonergic medications, such as
linezolid, MAO inhibitors, SSRIs, triptans,
and St. John’s wort: Can cause serotonin
syndrome.
Evening primrose: Can cause additive
effects and lower seizure threshold.
Cimetidine: May increase TCA levels.
Clonidine (Catapres): May decrease the
anti-hypertensive effect of Catapres and
cause severe, life-threatening hypertension.
Quinolones (broad-spectrum antibiotics):
May increase the risk of life-threatening
arrhythmias.
Side effects
Lab studies and concurrent health
problems
Other common side effects of cyclic
antidepressants include: 4,7,36
Cyclics can also exacerbate certain chronic health
problems. They are contraindicated in patients
who have received an MAO inhibitor within the
last 14 days or who are in the acute recovery
phase following a myocardial infarction. They
are to be used with caution in patients who have
narrow-angle glaucoma, enlarged prostate, or
Side effects of cyclic antidepressants can vary
depending on the subclass. Tertiary TCAs are
more likely to cause anticholinergic symptoms,
such as dry mouth, urinary retention, orthostatic
hypotension, and drowsiness because of the
strong antagonism of acetylcholine and histamine
receptors. Secondary TCAs are less likely to
cause these effects because they cause less strong
antagonism of acetylcholine and histamine
receptors.4,7,36
Cyclics may alter blood glucose levels. Blood
glucose levels should be monitored, especially
if the patient is diabetic. Liver function should
also be monitored as well as white and red blood
counts.4
a history of seizures, cardiac problems, thyroid
problems, diabetes or impaired liver function.4,7
There are some environmental factors that
can have an impact on patients taking cyclics.
Smoking may lower drug levels. Patients who
smoke must be particularly monitored for lack of
drug effectiveness. Additionally, exposure to the
sun may increase photophobia. Patients should be
advised to avoid excessive exposure to sunlight.4
As with SSRIs, cyclics should never be abruptly
discontinued. Such abrupt discontinuation can
cause withdrawal symptoms, including nausea,
headache, dizziness, lethargy and flu-like
symptoms.4,7
Counseling points for TCAs36
Patients should be told to take TCAs as
directed by their doctor, and to not miss doses
or discontinue the medication abruptly.
Counsel patients on symptoms and severity
of serotonin syndrome, and tell them to notify
their pharmacist or doctor if they start new
medications, herbs, or supplements.
Notify patients of potential side effects
and when to contact their doctor or seek
emergency care.
Inform patients of black box warnings on
antidepressants and tell them to contact
their doctor if they experience severe mood
changes.
Patients who are suicidal should be dispensed
smaller quantities of tricyclic antidepressants
because of the dangerous cardiovascular
complications related to overdose.
Discuss timing of dosing; generally these
are taken at bedtime because they can cause
drowsiness.
Monoamine oxidase inhibitors (MAOIs)
MAOIs were the first type of antidepressant
drug developed, and although effective, they,
like TCAs, have been replaced by other types
of antidepressants that are safer and cause
fewer side effects.8 One of the major concerns
with MAOIs is that they generally necessitate
dietary restrictions. If these drugs are taken
in conjunction with a diet high in tyraminecontaining foods, life-threatening hypertension
may occur.4,8 However, MAOIs may still be
prescribed if the patient does not respond to other
types of antidepressants.
Monoamine oxidase is an enzyme that helps
to remove the neurotransmitters serotonin,
dopamine and norepinephrine from the brain.
MAOIs work by nonselectively inhibiting this
removal, increasing the availability of these
neurotransmitters in the brain and enhancing
neuron communication. However, MAOIs also
affect other neurotransmitters in the brain and
in the digestive system, such as 5HT,3 causing
significant side effects.8
MAOIs and doses used in the treatment of
depression include:4,8
Isocarboxazid (Marplan) 20-60 mg. per day,
divided into 2-4 doses per day.
Page 56
Elite
Phenelzine (Nardil) 45-90 mg. per day,
divided into 3-4 doses per day.
Tranylcypromine (Parnate) 30-60 mg. per
day, divided into 2-4 doses per day.
Drug alert! Selegiline (Emsam) is a transdermal
MAOI mainly used to treat Parkinson’s disease,
minimizing side effects by bypassing the
stomach.36
MAOIs should be avoided in patients with
cardiovascular or cerebrovascular disorders,
hypertension, those undergoing general
anesthesia, and patients with severe renal
impairment.
Side effects
Side effects of MAOIs include:4,8
Headache.
Insomnia.
Dizziness.
Nausea.
Arrhythmias.
Low blood pressure.
Diarrhea.
Dry mouth.
Changes in sense of taste.
Nervousness.
Muscle aches.
Weight gain.
Difficulty urinating.
Paresthesia.
Erectile dysfunction.
Reduced sexual desire.
Difficulty reaching orgasm.
Pregnancy
There are significant safety concerns associated
with the use of MAOIs. As with other
classifications of antidepressants, MAOIs may
place a fetus at risk and may pass to the infant
during breast-feeding. Women of childbearing
age should be counseled about the potential
benefits versus risks to the child before becoming
pregnant.4,8
Drug and food interactions
MAOIs should never be taken in conjunction
with other types of antidepressants or with St.
John’s wort because of the risk of serotonin
syndrome. Ginseng in combination with
MAOIs may cause headache, tremors or mania.
Concurrent use should be avoided.4
Patients taking MAOIs must restrict foods that
contain high levels of tyramine. Tyramine is an
amino acid found naturally in the body and in
certain foods and is involved in the regulation
of blood pressure. Interaction of tyramine
and MAOIs can cause dangerous, even lifethreatening hypertension.8
Tyramine is found in especially large amounts
in aged foods or foods that contain significant
amounts of yeast. Foods that have moderate to
large amounts of tyramine include:9
All tap beers.
Bottled or canned beer, including
nonalcoholic beer.
Aged cheeses, such as cheddar, Brie and
Camembert.
Aged, smoked, fermented and pickled meats,
such as pepperoni, salami and meat jerky.
Banana peel.
Breads or crackers that contain cheese.
Soy products.
Pickled herring.
Smoked fish.
Red and white wine.
Yeast extracts.
Patients should be provided with a list of foods
that are high in tyramine and that should be
avoided. A dietary consult is recommended to
help patients modify their diets to reduce their
intake of tyramine.
Drug alert! As with any antidepressant, MAOIs
should never be discontinued abruptly.
Counseling points for MAOIs36
Patients should be told to take MAOIs as
directed by their doctor, and to not miss doses
or discontinue the medication abruptly.
Counsel patients on the symptoms and
severity of serotonin syndrome, and tell them
to notify their pharmacist or doctor if they
start new medications, herbs, or supplements.
Notify patients of potential side effects and
when they should contact their doctor or seek
emergency care.
Inform patients of black box warnings on
antidepressants and tell them to contact
their doctor if they experience severe mood
changes.
Discuss dietary restrictions with patients
and provide them with a list of foods to
avoid, and discuss when they should call for
emergency assistance if they eat the problem
foods.
Serotonin and norepinephrine reuptake
inhibitors (SNRIs)
SNRIs work by increasing neural concentrations
of the neurotransmitters serotonin and
norepinephrine by preventing their reuptake
by the presynaptic neuron. They are also used
to treat other mental health issues, such as
anxiety.4,13,36
SNRIs and doses used to treat depression
include:4,13,36
Duloxetine (Cymbalta) 30-120 mg. per day,
given once daily.
Venlafaxine (Effexor, Effexor XR) 25-375
mg. per day, divided into 1-3 doses per day.
Desvenlafaxine (Pristiq) 50-100 mg. per day,
given once daily.
Drug alert! Duloxetine can also be used to treat
neuropathic pain.36
Side effects
SNRI side effects include:4,13
Nausea (especially with duloxetine).
Dizziness.
Fatigue.
Headache.
Insomnia.
Constipation.
Diaphoresis.
Hypertension (with venlafaxine).
Elite
Tachycardia.
Decreased sexual desire.
Blurred or double vision.
Arrhythmias.
Erectile dysfunction.
Difficulty urinating.
Drug interactions
Duloxetine is an inhibitor of the cytochrome
P450 enzyme 2D6, and can increase the levels
and incidence of side effects of CYP2D6
substrates, such as aripiprazole, clozapine,
codeine, donepezil, flecanide, hydrocodone,
meperidine, propafenone and tamoxifen.
Venlafaxine is a weak inhibitor and substrate of
CYP2D6, and should be used with caution with
other 2D6 medications.36
Other drug interactions for the SNRI class
include:4
MAOIs: Avoid use within 14 days of each
other.
Alcohol: May cause liver damage if used in
conjunction with some SNRIs.
SSRIs and other seroronergic agents,
such as tramadol and triptans: May lead to
serotonin syndrome.
Pregnancy
There are significant safety concerns associated
with the use of SNRIs. As with other
classifications of antidepressants, SNRIs may
place a fetus at risk and may pass to the infant
during breast-feeding. SNRIs should not be used
in the third trimester of pregnancy. Women of
childbearing age should be counseled about the
potential benefits versus risks to the child before
becoming pregnant.4,8
Counseling points for SNRIs36
Patients should be told to take SNRIs as
directed by their doctor and to not miss doses
or discontinue the medication abruptly.
Counsel patients on the symptoms and
severity of serotonin syndrome, and tell them
to notify their pharmacist or doctor if they
start new medications, herbs, or supplements.
Notify patients of potential side effects and
when they should contact their doctor or seek
emergency care.
Inform patients of black box warnings on
antidepressants and tell them to contact
their doctor if they experience severe mood
changes.
Practice question
Harry Houdini has been treated for depression
for several years with sertraline. It is no longer
working for him, and his doctor would like to
switch him to a different antidepressant. His
medical conditions include residual nerve pain
from a past incident with a complicated magic
trick that did not go as planned, high blood
pressure, and he is taking ketoconazole for a
fungal infection. He would prefer to have a
medication that does not make him drowsy, as
he needs to be alert when performing. What
antidepressant would be best for Harry to try?
a. Venlafaxine.
b. Amitriptyline.
Page 57
c. Duloxetine.
d. Nefazodone.
Answer: C – Duloxetine would be the most
appropriate option for Harry to try because
it helps treat both depression and nerve pain.
Venlafaxine is not advised because Harry has
high blood pressure. Amitriptyline causes
sedation, which Harry would like to avoid at
this time. Nefazodone should not be used with
ketoconazole because they are both metabolized
through CYP3A4.
Atypical antidepressants
Atypical antidepressants are referred to as
atypical because they do not fit into other
classifications of antidepressants. Each is unique
and works in different ways, with different side
effects and safety concerns.10
Atypical antidepressants used in the treatment of
depression include:10
Bupropion (Wellbutrin, Wellbutrin SR,
Wellbutrin XL).
Mirtazapine (Remeron, Remeron SolTab).
Nefazodone (Serzone).
Trazodone (Desyrel, Oleptro).
Bupropion (Wellbutrin, Wellbutrin SR,
Wellbutrin XL)
Bupropion’s exact action is unknown, but it
is thought to weakly inhibit norepinephrine
and dopamine reuptake, increasing available
concentrations of these neurotransmitters in the
brain. Its noradrenergic mechanisms are thought
to cause the drug’s antidepressive effect.4,36
Bupropion is used in doses of 100-450 mg. per
day, divided into 1-3 doses per day, depending
on the product chosen. It is believed to be a
good choice for patients who have low energy
caused by depression, but it can exacerbate or
cause anxiety for some people. This is due to the
amphetamine-like structure of the drug molecule.
Bupropion is not associated with sexual
side effects or weight gain as often as other
antidepressants.10, 36
Drug alert! Bupropion is also prescribed as an
aid to smoking cessation treatment.4
Side effects of bupropion include:4,10
Confusion.
Abnormal dreams.
Insomnia.
Headache.
Tremor.
Sedation.
Agitation.
Dizziness.
Seizures.
Tachycardia.
Arrhythmias.
Blurred vision.
Sore throat.
Rhinitis.
Dry mouth.
Constipation.
Nausea.
Vomiting.
Fluctuations in weight.
Excessive sweating.
Contraindications include:4
Patients who have taken MAOIs or linezolid
within the previous 14 days.
Patients with seizure disorders.
Patients with history of eating disorders
(increases the risk of seizures).
Patients in alcohol withdrawal (increases risk
of seizures).
There are a number of potential drug interactions
with bupropion use. Bupropion is an inhibitor
of the cytochrome P450 enzyme 2D6, and can
increase the levels and incidence of side effects
of CYP2D6 substrates such as aripiprazole,
clozapine, codeine, donepezil, flecanide,
hydrocodone, meperidine, propafenone and
tamoxifen.36 Other drug interactions include:4
Other antidepressants: May lower seizure
threshold.
Beta-blockers: Levels of beta blockers may
be increased and cause adverse reactions.
Nicotine replacement agents: May cause
hypertension.
Alcohol: May alter seizure threshold.
Drug alert! Excessive sun exposure may increase
the risk of photosensitivity.4
Counseling points for bupropion36
Patients should be told to take bupropion as
directed by their doctor, and to not miss doses
or discontinue the medication abruptly.
Counsel patients on the symptoms and
severity of serotonin syndrome, and tell them
to notify their pharmacist or doctor if they
start new medications, herbs, or supplements.
Notify patients of potential side effects
and when to contact their doctor or seek
emergency care.
Inform patients of black box warnings on
antidepressants and tell them to contact
their doctor if they experience severe mood
changes.
Discuss the importance of using sunscreen
during periods of sun exposure because of
photosensitivity.
Drug alert! Bupropion is not approved for use in
children.4
Mirtazapine (Remeron, Remeron SolTab)
Mirtazapine is believed to act by enhancing
central noradrenergic and serotonergic activity.
Like bupropion, mirtazapine does not cause
sexual side effects that are caused by other
antidepressants. It is used in doses of 15-45 mg.,
and because it often causes drowsiness, it is
usually taken at bedtime.10
Side effects include:4,10
Somnolence.
Dizziness.
Increased appetite.
Weight gain.
Increased cholesterol levels.
Increase or decrease in blood pressure.
Decreased white blood cell count.
Weakness.
Drug interactions include:4
MAOIs: Avoid use within 14 days of MAOI
therapy.
CNS depressants, including alcohol: May
cause additive CNS effects.
CYP1A2, 2D6 and 3A4 inhibitors or
inducers: May alter hepatic metabolism of
mirtazapine.
Mirtazapine should be used with caution
in patients with cardiovascular disease,
cerebrovascular disease, seizure disorders,
hepatic or renal impairment or history of mania
or hypomania.4
Counseling points for mirtazapine36
Patients should be told to take mirtazapine as
directed by their doctor, and to not miss doses
or discontinue the medication abruptly.
Counsel patients on the symptoms and
severity of serotonin syndrome, and tell them
to notify their pharmacist or doctor if they
start new medications, herbs, or supplements.
Notify patients of potential side effects and
tell them when to contact their doctor or seek
emergency care.
Inform patients of black box warnings on
antidepressants and tell them to contact
their doctor if they experience severe mood
changes.
Discuss timing of dosing; mirtazapine is
generally taken at bedtime due to drowsiness.
Nefazodone (Serzone)
Nefazodone is thought to work by blocking
serotonin type 2A receptors as well as mildly
inhibiting the reuptake of serotonin, dopamine
and norephinephrine. It may help to decrease
anxiety in addition to alleviating depression.
Nefazodone is given in doses of 100-600 mg. per
day, divided into 1-2 doses per day. It is likely to
cause drowsiness but is less likely to cause sexual
side effects than other types of antidepressants.10
Side effects include:10,11
Orthostatic hypotension. (Patients should be
taught to change positions slowly, especially
when they first start taking the drug.)
Dizziness.
Headache.
Dry mouth.
Blurred vision.
Confusion.
Nausea.
Sleepiness.
Weakness.
Flushing.
Heartburn.
Constipation.
Pain, burning, numbness, or tingling in the
hands or feet.
Drug alert! Nefazodone has been associated with
liver failure in some patients. Patients who have
compromised hepatic function should not take
this drug.10
There are many drug interactions with
nefazodone because it is a potent inhibitor of
CYP3A4. Among these interactions are:4
Page 58
Elite
Carbamazepine – May increase
carbamazepine levels and decrease
nefazodone levels.
Statin drugs, such as simvastatin,
lovastatin, and atorvastatin – Can increase
simvastatin levels and increase risk of
rhabdomyolysis.
Benzodiazepines, such as triazolam – Can
increase triazolam levels and increase CNS
depression.
MAOIs and linezolid – Avoid use within 14
days of MAOI therapy.
Prostate medications, such as tamsulosin,
alfuzosin, dutasteride – Can increase drug
levels and adverse effect risk.
Eplerenone – Increases eplerenone levels
and risk of hyperkalemia and arrhythmias.
Amiodarone – Can increase amiodarone
levels and risk of arrhythmias.
Clarithromycin, erythromycin – Can
increase clarithromycin and erythromycin
levels and risk for QT prolongation and
arrhythmias.
Sirolimus, tacrolimus – Can increase levels
and increase risk of toxicity.
Counseling points for nefazodone36
Patients should be told to take nefazodone as
directed by their doctor, and to not miss doses
or discontinue the medication abruptly.
Counsel patients on the symptoms and
severity of serotonin syndrome, and
emphasize that because of the number of
drug interactions with this medication, it is
very important to notify their pharmacist or
doctor if they start new medications, herbs, or
supplements.
Notify patients of potential side effects and
when they should contact doctor or seek
emergency care.
Inform patients of black box warnings on
antidepressants and tell them to contact
their doctor if they experience severe mood
changes.
Trazodone (Desyrel, Oleptro)
Trazodone is a rather weak antidepressant
thought to work by inhibiting the CNS neuronal
uptake of serotonin. It is likely to cause
sleepiness, so is usually taken at bedtime. In
addition to helping to alleviate depression, it can
also help to reduce anxiety and can be helpful for
patients with mild insomnia.10,11,36
Side effects include:4,10,11
Drowsiness.
Confusion.
Dizziness.
Orthostatic hypotension.
Dry mouth.
Headache.
Nausea.
Weakness.
Blurred vision.
Arrhythmias.
Fatigue.
Constipation.
Diarrhea.
Drug alert! Trazodone has been linked to a
rare condition called priapism. Priapism is a
persistent, painful erection not associated with
sexual arousal. Patients who have an erection
that lasts longer than four hours should seek
emergency medical treatment.10
There are a number of potentially dangerous drug
interactions with trazodone. These include:4
CYP3A4 inducers or inhibitors: May alter
hepatic metabolism of trazodone.
Other antidepressants: May increase the
risk of serotonin syndrome.
Anti-hypertensives: May increase the antihypertensive effect of trazodone.
Digoxin and phenytoin: Trazodone may
increase the levels of these drugs.
MAOIs: Avoid concurrent use.
Warfarin: May increase INR. Warfarin
dosage may need to be adjusted.
Herbs: Ginkgo biloba may increase sedation
effects. St. John’s wort may lead to serotonin
syndrome.
Alcohol: May increase CNS depression.
Drug alert! Trazodone may decrease hemoglobin
levels.4
Counseling points for trazodone36
Patients should be told to take trazodone as
directed by their doctor, and to not miss doses
or discontinue abruptly.
Counsel patients on the symptoms and
severity of serotonin syndrome, and tell them
to notify their pharmacist or doctor if they
start new medications, herbs, or supplements.
Notify patients of potential side effects,
including the risk of priapism in men, and
when they should contact their doctor or seek
emergency care.
Inform patients of black box warnings on
antidepressants and tell them to contact
their doctor if they experience severe mood
changes.
Discuss timing of dosing; trazodone is
generally taken at bedtime because it can
cause drowsiness.
Practice question
Hermione has noticed that in the past few
months, she has lost interest in magic, has been
gaining weight and has been sleeping too much.
Her doctor diagnosed her with depression and
has determined that she should be started on an
antidepressant. She is taking tamoxifen for breast
cancer treatment and has high blood pressure.
She does not have anxiety or any allergies to
medications. Which of the following medications
would be best for her to take?
a. Paroxetine.
b. Venlafaxine.
c. Fluoxetine.
d. Sertraline.
Herbal medicines
A number of herbal medicines have been used
in the treatment of depression. Patients should
be cautioned that if they are consulting with
herbal medicine practitioners, they MUST inform
their other health care providers of any herbal
supplements they are taking. Some patients
believe that herbs are “natural” and therefore
do not have adverse side effects or interactions
with medicines. It is imperative that patients
understand that herbs have the potential to
cause dangerous, even fatal, side effects and
interactions with other drugs as well as affect lab
tests.
Drug alert! Herbs should only be prescribed by
a practitioner who is well-versed and qualified
in herbal medicine. All health care practitioners
should ask their patients whether they are taking
any type of herbal supplement to avoid dangerous
side effects or drug interactions.
A few of the herbal medicines used to treat
depression are described here.
St. John’s wort
St. John’s wort is available in capsule, tablet,
tincture, sublingual capsule and cream
formulations. It should not be used during
pregnancy and lactation, nor should it be given
to children. Side effects include dizziness,
insomnia, restlessness, fatigue, constipation,
abdominal cramps, photosensitivity, rash and
hypersensitivity.18,19
The following drug interactions are associated
with St. John’s wort:18,19
MAOIs: May increase MAOI inhibition.
Avoid concurrent use.
Antidepressants: May increase risk for
serotonin syndrome. Avoid concurrent use.
ACE inhibitors, loop diuretics and thiazide
diuretics: Concurrent use may lead to severe
photosensitivity. Avoid concurrent use.
Alcohol: May increase drug action. Avoid
concurrent use.
Amphetamines: May cause serotonin
syndrome.
NSAIDs: May lead to severe
photosensitivity. Avoid concurrent use.
Birth control: May decrease the
effectiveness of birth control.
Patients taking St. John’s wort should limit
foods high in tyramine. These include aged
cheeses, beer, smoked and pickled meats, and soy
products.9,19
St. John’s wort may cause increased growth
hormone and decreased serum prolactin, serum
iron and digoxin.19
Ginkgo
Ginkgo is a tree native to China and Japan but is
now also found in Europe and the United States.
It is available in capsule, fluid extract, tablets
Answer: D – Sertraline would be best for
and tincture form. It should not be used during
Hermione for the treatment of depression.
Paroxetine and fluoxetine are CYP2D6 inhibitors pregnancy or lactation, nor should it be given to
and can increase the side effects of her tamoxifen. children. It is also contraindicated in patients with
coagulation or platelet disorders, hemophilia or
Venlafaxine should be avoided in patients with
high blood pressure because it has the potential to seizures. Side effects include headache, anxiety,
increase blood pressure.
Elite
Page 59
restlessness, nausea, vomiting, anorexia, diarrhea,
flatulence and rash.9,19
The following drug interactions are associated
with ginkgo:18,19
St. John’s wort: May cause hypomania if
used in conjunction with ginkgo.
MAOIs: MAOI action may be increased if
taken with ginkgo. Avoid concurrent use.
Anticoagulants and platelet inhibitors:
May increase the risk of bleeding. Avoid
concurrent use.
Anticonvulsants: Ginkgo may decrease
the effectiveness of anticonvulsants. Avoid
concurrent use.
Buspirone and fluoxetine: May cause
hypomania if used concurrently.
Trazadone (Oleptro, Desyrel): Concurrent
use may cause increased sedation and
potentially coma.
Ginkgo may increase bleeding time and decrease
platelet activity, thereby leading to increased risk
of bleeding.19
Khat
Khat is a tree found in Africa and on the Arabian
Peninsula, and the raw leaves of the tree are used
to make herbal medicine. It is ingested by eating
the raw leaves followed by fluids.18,19
Khat should not be used during pregnancy and
lactation, nor should it be given to children.
Its use is contraindicated in patients who have
compromised renal, cardiac or hepatic systems.19
Side effects include tachycardia, arrhythmias,
elevated blood pressure, pulmonary edema,
circulatory collapse, restlessness, insomnia,
headache, hallucinations, hyperthermia,
diaphoresis, nausea, vomiting, anorexia,
constipation, abdominal pain and spasms,
cerebral hemorrhage, decreased sperm count and
decreased libido.18,19
Khat may increase the action of the following
drugs:18,19
Amphetamines.
Anti-arrhythmia agents.
Antihistamines.
Anti-hypertensives.
Beta-blockers.
Calcium channel blockers.
Cardiac glycosides.
Decongestants.
MAOIs.
Drug alert! The preceding paragraphs describe
only a few of the many herbal preparations used
in the treatment of depression. The importance of
finding out whether the patient is taking herbal
preparations cannot be overemphasized.
Antianxiety pharmacology
Jeffrey is a nurse practitioner in a family
practice setting. He has a reputation of being
a perfectionist. He describes himself as a
“worrier.” In fact, Jeffrey does more than worry.
He feels anxious almost all of the time, even
when there is no obvious reason for anxiety. He is
starting to have difficulty concentrating at work
and focusing on his wife and children at home.
After a serious discussion with his wife, Jeffrey
decides to seek help from his health care provider
for treatment of anxiety.
Paroxetine (Paxil): SSRI antidepressant.
Sertraline (Zoloft): SSRI antidepressant.
Venlafxine (Effexor): SSNRI antidepressant.
Everyone feels anxious at times. Anxiety is a
normal reaction to threatening, dangerous or
otherwise challenging situations. However,
patients dealing with an anxiety disorder
experience excessive, chronic anxiety that
interferes with normal functioning. These people
feel anxious even when no overt external stress
exists.14
Drug alert! For detailed information on SSRI
and SSNRI antidepressants, see the potion of
this program that deals with antidepressant
pharmacology.
There are two types of anxiety disorders.
Generalized anxiety disorder (GAD) is
characterized by anxiety or excessive worry
on most days over at least six months that the
patient feels he or she cannot control. To make a
diagnosis of GAD, the patient must have at least
three of the following symptoms: restlessness,
irritability, easily fatigued, muscle tension,
difficulty concentrating, or sleep difficulties.36
Panic disorder is another type of anxiety disorder.
It is characterized by panic attacks along with
at least four of the following psychic or somatic
symptoms:36
Depersonalization.
Fear of dying.
Fear of losing control or going crazy.
Sweating.
Trembling.
Shaking.
Choking.
Chest pain.
Nausea.
Abdominal pain.
Palpitations.
Tachycardia.
Shortness of breath.
Dizziness.
Chills.
Hot flashes.
It is believed that anxiety disorders occur as a
result of hyperactivity in certain areas of the
brain. This is thought to be related to low levels
of the neurotransmitter gamma-aminobutyric
acid (GABA), which helps to regulate nerve cell
activity. Family history of anxiety disorders also
increases the risk of development.14
More than 6 million people suffer from GAD in
the United States. The disorder affects women
(60 percent) more often than men (40 percent).
Because descriptions and perceptions of anxiety
vary among cultures, it is difficult to calculate an
exact incidence worldwide.15
Several drug classifications are used in the
treatment of anxiety disorders. These include
antidepressants, benzodiazepines, beta-blockers,
and the drug buspirone (BuSpar), an anxiolytic.
Antidepressants
A number of antidepressants have been used to
treat anxiety disorders. These include:4,16
Fluoxetine (Prozac): SSRI antidepressant.
Fluvoxamine (Luvox): SSRI antidepressant.
Imipramine (Tofranil): Tricyclic
antidepressant.
Benzodiazepines
Benzodiazepines are believed to work
by increasing the effectiveness of the
neurotransmitter GABA. They are thought to
do this by binding to and opening the GABA-A
receptor, which allows an influx of chloride
ions into the cell and decreases the polarity
of the neuron, decreasing the rate of neural
firing. Patients respond by experiencing a
reduction in feelings of anxiety and stress and
an improvement in ability to function and
concentrate. 17,36
Short-acting benzodiazepines are generally
preferred when using as a sedative and for use in
the elderly, because they cause less accumulation.
They are also preferred in patients with liver
disorders because they are metabolized more
easily. These drugs are generally associated
with more rebound anxiety and withdrawal
symptoms when discontinued than longer-acting
benzodiazepines. Longer-acting benzodiazepines
are associated with less rebound anxiety and
are preferred when tapering patients off of this
category of drugs.
Drug alert! Because of the high potential
for abuse and overdose, benzodiazepines are
controlled substances under DEA schedule IV.
Caution is advised when using these medications
in patients with substance-use disorders because
overdose can result in respiratory depression and
death.36
Benzodiazepines can cause additive CNS
depression when taken with other medications
that cause CNS depression, including alcohol.
Combination should be avoided when possible.36
Benzodiazepines are in pregnancy category D.
Use in pregnant women should be avoided.
Side effects associated with benzodiazepines
include:
Anxiety.
Ataxia.
Behavioral disturbances.
Bradycardia.
Confusion.
Constipation.
Depression.
Diarrhea.
Dizziness.
Drowsiness.
Dry mouth.
Fatigue.
Headache.
Impaired coordination.
Insomnia.
Irritability.
Lethargy.
Memory problems.
Page 60
Elite
Nausea.
Respiratory depression.
Risk of suicide.
Sedation.
Somnolence.
Urinary retention.
Benzodiazepines prescribed for anxiety
include:4,16,17,36
Alprazolam (Xanax): Short-acting;
average half-life is 12 hours. Given in
doses of 0.25-3 mg. up to three times daily.
Contraindicated in patients with acute
angle-closure glaucoma. Should be used
with caution in patients with compromised
renal, pulmonary and hepatic systems or
patients with a history of substance abuse.
Avoid concurrent use with kava, St. John’s
wort, and grapefruit juice. Concurrent use
with tricyclic antidepressants may increase
levels of these drugs. Smoking may decrease
the effects of alprazolam. Alprazolam is a
CYP3A4 substrate, and should not be used
with 3A4 inhibitors, such as clarithromycin,
ketoconazole, ritonavir, and nefazodone.
Chlordiazepoxide (Librium): Long-acting;
average half-life is 100 hours. Given in
doses of 5-25 mg. up to four times daily.
Should not be used in conjunction with the
herb kava. Concurrent use of cimetidine
may increase the risk of adverse reactions.
Chlordiazepoxide may increase digoxin
levels and the risk of digoxin toxicity,
so patients should be closely monitored.
Chlordiazepoxide may increase liver function
test results and decrease granulocyte count.
This medication is a partial CYP3A4
substrate, and if used with 3A4 inhibitors
such as clarithromycin, ketoconazole,
ritonavir, and nefazodone, it should be given
in lower doses. The drug may also cause a
false-positive pregnancy test.
Clonazepam (Klonopin): Long-acting;
average half-life is 34 hours. Given in
doses of 0.25-2 mg up to twice daily. This
drug is contraindicated in patients with
acute angle-closure glaucoma or significant
hepatic disease. Clonazepam should be
used with caution in children, patients
with chronic respiratory disease, openangle glaucoma or a history of substance
abuse. It should also be used with caution
in elderly patients. Clonazepam should not
be used with phenytoin. This medication
is a partial CYP3A4 substrate, and if used
with 3A4 inhibitors, such as clarithromycin,
ketoconazole, ritonavir, and nefazodone, it
should be given in lower doses. Concurrent
use with St. John’s wort may cause a
decrease in the drug’s effects. Clonazepam
may increase liver function test results and
eosinophil count. It may decrease platelet and
white blood cell count.
Diazepam (Valium): Long-acting; average
half-life is 100 hours. Given in doses of 2-10
mg. 2-4 times daily. Fast onset is greater
than one hour. Diazepam is contraindicated
in patients with acute-angle glaucoma and
should be used with caution in patients
with compromised liver or renal systems,
depression, history of substance abuse, or
chronic open-angle glaucoma. It must be
used with caution in elderly or debilitated
patients. Diazepam may increase digoxin
level and the risk of digoxin toxicity. If
used in conjunction with phenobarbital, the
effects of both drugs may be increased. The
herb kava may increase sedative effects
and should not be used in conjunction with
diazepam. Diazepam is a CYP3A4 and
CYP2C19 substrate, and should not be used
with 3A4 inhibitors, such as clarithromycin,
ketoconazole, ritonavir, and nefazodone,
and used with caution with 2C19 inhibitors,
such as fluconazole, fluvoxamine, and
voriconazole. Diazepam may increase liver
function test results and decrease neutrophil
count.
Lorazepam (Ativan): Short-acting; average
half-life is 15 hours. Given in doses of 0.5-2
mg. 2-3 times daily. May increase digoxin
level and digoxin toxicity; smoking may
decrease lorazepam’s effectiveness. The
herb kava may increase sedation if taken
in conjunction with lorazepam. Use with
caution in patients with pulmonary, hepatic
or renal problems or history of substance
abuse. Use with caution in elderly or acutely
ill patients.
Oxazepam (Serax, Oxpam): Short-acting;
average half-life is eight hours. Given in
doses of 10-30 mg. 3-4 times daily. Slow
onset is greater than three hours. Oxazepam
should be used with caution in elderly
patients, those with a history of substance
abuse, and those who may experience cardiac
problems if they experience a decrease in
blood pressure. If taken with digoxin, digoxin
levels may be increased. The herb kava may
increase sedative effects. Oxazepam may
increase liver function test results.
Drug alert! Benzodiazepines should not be
discontinued abruptly.
Counseling points for benzodiazepines36
Patients should be told to take
benzodiazepines as directed by their doctor,
and to not miss doses or discontinue the
medication abruptly.
Notify patients of potential side effects and
when they should contact their doctor or seek
emergency care.
Because benzodiazepines are controlled
substances and have a high potential for
addiction, it is important to emphasize that
these medications should not be shared with
other patients and may not be refilled early.
Discuss timing of dosing and emphasize that
these should not be combined with alcohol or
other CNS depressants, and patients should
not drive while taking these medications.
Remind women of childbearing age that
these medications should not be taken while
pregnant.
Elite
Practice question
Dr. Who is trying to wean his patient Katarina
off of benzodiazepines. She has been taking
alprazolam 0.5 mg. twice daily. He wants to start
her on a longer-acting benzodiazepine to prevent
withdrawal symptoms. Which of the following
medications would be most appropriate?
a. Alprazolam.
b. Lorazepam.
c. Oxazepam.
d. Clonazepam.
Answer: D. Clonazepam would be the most
appropriate benzodiazepine to wean Katarina
off. It is a long-acting benzodiazepine that will
prevent withdrawal symptoms.
Beta-blockers
Beta-blockers, normally used to treat cardiac
conditions, may be used to control physical
symptoms of anxiety, such as trembling and
diaphoresis. Taking beta-blockers for a short
period of time can help keep uncomfortable
symptoms under control.20
The beta-blockers propranolol (Inderal) and
clonidine (Catapres) have been used to treat the
physical symptoms of anxiety.16,20
Clonidine
Clonidine is thought to work by stimulating
alpha-2 receptors and inhibiting central
vasomotor centers. This decreases sympathetic
outflow to the heart, kidneys and peripheral
vasculature. Peripheral vascular resistance is
lowered as is blood pressure and heart rate. It
is used in doses of 0.1-0.3 mg. given 1-2 times
daily.4,36
The most common side effects of clonidine
include drowsiness, dizziness, sedation,
weakness, hypotension, constipation, dry mouth
and pruritis. Its pregnancy category risk is C
(animal studies show adverse effects on the fetus,
but adequate studies have not been conducted on
humans). Clonidine may also cause bradycardia
and severe rebound hypertension.4
Drug alert! Beta-blockers can cause lifethreatening side effects. Patients taking these
types of drugs must be closely monitored.4
Clonidine must be used with caution in patients
with cerebrovascular disease, chronic renal
failure, and compromised liver function and
in patients with severe coronary insufficiency,
recent myocardial infarction and conduction
disturbances.4
Drug interactions with clonidine include:4,36
CNS depressants: May increase risk of CNS
depression.
Anti-hypertensives: May increase
hypotensive effects.
Digoxin and verapamil: May cause AV
block and severe hypotension.
Capsaicum and ma huang: May reduce the
effectiveness of anti-hypertensives.
Clonidine may decrease urinary excretion of
vanillylmandelic acid and catecholamines. It
may also cause Coombs’ test results to be weakly
positive.4
Page 61
Counseling points for clonidine36
Patients should be told to take clonidine as
directed by their doctor, and to not miss doses
or discontinue abruptly.
Notify patients of potential side effects,
especially hypotension and dizziness, and
when they should contact their doctor or seek
emergency care.
Remind patients that clonidine should not be
combined with other CNS depressants.
Propranolol (Inderal)
Propranolol works by reducing cardiac oxygen
demand. It is a nonselective beta-blocker and
blocks both beta-1 and beta-2 receptors to
decrease adrenergic stimulation in the heart and
smooth muscle. The drug’s pregnancy category
risk is C (animal studies show adverse effects
on the fetus, but adequate studies have not been
conducted on humans).4,36
Drug alert! Propranolol is often used as needed
for anxiety-inducing performances, such as
public speaking or singing performances. It is
given in doses of 10-80 mg. one hour before an
anxiogenic event.
The most common side effects of propranolol
include fatigue, lethargy, constipation, nausea,
and hypotension. Possible life-threatening
side effects include bradycardia, heart failure,
agranulocytosis, bronchospasm and an increase in
AV block.4,36
Propranolol is contraindicated with bronchial
asthma, sinus bradycardia, greater than firstdegree heart block, heart failure and cardiogenic
shock. The drug may necessitate dosage
alterations of insulin and other anti-diabetic
drugs.
Drug interactions with propranolol include:4,36
CYP1A2, 2C19 and 2D6 inhibitors or
inducers: May alter hepatic metabolism of
propranolol.
Anti-hypertensives and thioridazine:
May increase hypotensive effects. Use with
thioridazine is contraindicated.
Alcohol: May increase propranolol levels and
should not be used when taking propranolol.
Betel palm: Should not be used in
conjunction with propranolol.
Propranolol can affect some lab test results. It
may decrease granulocyte count and T3 level. It
may increase T4, BUN, transaminase, potassium,
LDH and alkaline phosphatase levels.4
Counseling points for propranolol36
Patients should be told to take propranolol
as directed by their doctor, and to not miss
doses or discontinue the medication abruptly.
Notify patients of potential side effects,
especially hypotension and dizziness, and
when to contact doctor or seek emergency
care.
Patients often use this medication on an asneeded basis, and if so, should be counseled
to only take when needed.
Buspirone (BuSpar)
Buspirone is a non-benzodiazepine anxiolytic that
is used in the treatment of anxiety disorders.16,20 It
is believed to work by acting as a partial agonist
at serotonin receptors as well as having a low
affinity for dopamine receptors. It is thought that
the action at the serotonin receptor is responsible
for the anti-anxiolytic effects.36
Buspirone is used in doses of 15-60 mg. per day,
divided into 1-2 doses per day. It has a pregnancy
risk category of B, meaning that animal studies
have not shown a risk to the fetus, but controlled
studies have not been conducted in pregnant
women, or animal studies have shown an adverse
effect on the fetus, but adequate studies in
pregnant women have not shown a risk to the
fetus.4
Common side effects of buspirone include:4,17
Dizziness.
Drowsiness.
Nervousness.
Nausea.
Fatigue.
Buspirone should be avoided in patients with
severe renal or hepatic impairment.36
Drug alert! Although buspirone is less likely
to have sedative effects than other anxiolytics,
patients should still be monitored for CNS
reactions. Such reactions are unpredictable, and
it should not be assumed that such reactions will
not take place.4
There are a number of potential interactions with
buspirone. These include:4,17,36
Azole antifungals: May cause adverse
effects. Patients must be closely monitored.
CNS depressants, including alcohol: May
increase CNS depressive effects. Avoid
concurrent use or use with great caution.
MAOIs: May cause an elevation in blood
pressure. Avoid concurrent use.
CYP3A4 inhibitors or inducers: May alter
hepatic metabolism of buspirone.
SSRIs: Should be used with caution, and
patients should be monitored for serotonin
syndrome.
Counseling points for buspirone4,17,36
Notify patients of potential side effects,
especially hypotension and dizziness, and
when they should contact their doctor or seek
emergency care.
Do not give with grapefruit juice.
Teach the patient to take the drug in a
consistent manner, meaning at the same times
each day and always with or without food. In
other words, if the patient takes the drug with
food, he or she should always take it with
food.
Warn the patient not to stop taking the
drug abruptly. It must be stopped under the
guidance of the patient’s health care provider.
Counsel patients on symptoms and severity
of serotonin syndrome, and tell them to notify
their pharmacist or doctor if they start new
medications, herbs, or supplements.
Explain to patients that effects of the drug
may not be apparent for several weeks.
Herbal medicines
Some herbalists have identified herbal medicines
as treatment for multiple diseases and health
problems, including anxiety. It is critical that
patients inform their health care providers of any
herbal medications they are taking or thinking of
taking.
Chamomile
Chamomile is found in Europe as a perennial
plant. It is available in capsule, tea, fluid extract,
cream and lotion formats. The dried flowers of
the plant are used to make the various forms of
chamomile. In addition to anxiety, it is commonly
used to treat digestive problems, and in topical
formats, to promote wound healing. Research
is under way to assess the effectiveness of
chamomile as an antioxidant.18,19
There are various types of chamomile. Roman
chamomile has been shown to promote abortion
of the fetus and therefore should not be used
during pregnancy and lactation, but may be used
in children. German chamomile has opposite
effects.19
Adverse effects include nausea, vomiting, and
with topical forms, burning of the face, eyes and
mucous membranes.18,19
The use of chamomile with alcohol and other
CNS depressants may increase sedative effects.
These drugs should not be used concurrently
with chamomile. There is some evidence that
chamomile may interfere with the actions
of anticoagulants. Concurrent use should be
avoided.18,19
Kava
Kava is a shrub that is found on the South Sea
islands. In addition to anxiety, kava is used as an
antidepressant, antipsychotic and anti-epileptic,
as well as to treat insomnia, restlessness and
attention deficit-hyperactivity.18,19 Research is
being conducted to assess kava for its use as an
anti-cancer agent.19
Kava is available in capsule, soft gel, beverage,
extract, tablet and tincture forms. The dried
roots of the shrub are used to make the herbal
preparation. Explain to patients that kava
absorption is increased if taken with food.18,19
Drug alert! Patients should be taught to store
kava products in a cool, dry place. They should
also be instructed not to use kava for more than
three months unless under the direction of an
herbalist and in conjunction with their health care
providers. Kava may be habit forming.19
Kava should not be used during pregnancy or
lactation, nor should children younger than 12
years old use it. It is also contraindicated in
patients with diagnosed major depressive disorder
or Parkinson’s disease.19 Kava may also be
associated with hepatic disease; therefore patients
with hepatic disease should not use kava.18
Page 62
Elite
Side effects associated with kava include:18,19
Headache.
Sedation.
Increased reflexes.
Blurred vision.
Nausea and vomiting.
Anorexia.
Weight loss.
Hematuria.
Decreased platelets and lymphocytes.
Shortness of breath.
Drug interactions associated with kava
include:18,19
CNS depressants, including alcohol: May
cause increased sedation when used with
kava. Concurrent use should be avoided.
Anti-Parkinson’s drugs such as levodopa:
Interactions can increase parkinsonism
symptoms. These drugs should not be taken
concurrently with kava.
Antipsychotics: Can cause neuroleptic
movement disorders.
Benzodiazepines: Increase the possibility of
increasing sedative effects. Avoid concurrent
use.
Kava may increase liver function tests.19
Lavender
Lavender is a flowering shrub. Its flowers are
used to make oils, tinctures, lotions and tea.
Lavender is used orally, topically or by inhalation
for its antidepressant, antianxiety and calming
effects. It should be stored in a cool, dry place,
protected from heat and moisture.18,19
Until more conclusive research is available,
lavender should not be used during pregnancy
and lactation or given to children.19
Side effects associated with lavender include
headache, dizziness, drowsiness, nausea,
vomiting, constipation and increased appetite.18,19
Lavender may interact with CNS depressants,
such as alcohol, sedatives and antihistamines, by
increasing their sedative effects. Concurrent use
should be avoided. The absorption of iron salts
may be decreased by lavender. Separate their use
by at least two hours.18,19
Lavender has been shown to reduce cholesterol
test levels.19
Lemon balm
Lemon balm is a perennial found in Europe,
Asia and North America. It has been used to
treat gastric problems as well as depression
and nervous disorders, such as anxiety. The
dried leaves, fresh leaves and whole plant are
used to make dry and fluid extracts, creams and
powder. Lemon balm should be stored in a sealed
container protected from heat and moisture.18,19
Until more conclusive research findings are
available, lemon balm should not be used during
pregnancy and lactation nor should it be given
to children.19 It should be used with caution in
men with BPH, patients with thyroid disorders,
and patients who are allergic to lemon or citrusscented perfumes.18
Side effects associated with the use of lemon
balm include nausea and anorexia.19
Lemon balm may interact with barbiturates by
increasing sedative effects. It may also increase
the effects of CNS depressants.18,19 Lemon balm
may interfere with the effectiveness of thyroid
replacement therapy; therefore, concurrent use is
contraindicated.18 Lemon balm tea may interfere
with the absorption of iron salts. Use should be
separated by at least two hours.19
Lemon may interact with herbs such as catnip,
chamomile, kava and valerium by increasing
sedative effects. Concurrent use is discouraged.18
Mugwort
Mugwort is a perennial found in North America.
Its leaves and roots are used to make tinctures
and teas. The roots are the parts of the plants
that are used in the treatment of mental health
problems such as depression and anxiety.
Research is being conducted to evaluate whether
mugwort has antibacterial and antifungal
attributes.19
Mugwort stimulates the uterus, so should not be
used by pregnant women. Nor should it be used
by children or by women who are breast-feeding.
Mugwort is also contraindicated in patients who
have bleeding disorders. 19
Patients who are sensitive to members of
the Asteraceae (Compositae) family, such as
ragweed, daisies, sage and marigolds, or who are
allergic to tobacco, honey or royal jelly may have
allergic reactions to mugwort.18
Side effects associated with mugwort include
nausea, vomiting, anorexia and hypersensitivity
reactions, such as contact dermatitis. Severe
allergic reactions, such as anaphylactic shock,
can occur.18,19
Mugwort may increase sedative effects if taken
in conjunction with CNS depressants, including
alcohol. If mugwort is taken in conjunction with
anticoagulants, such as warfarin and heparin,
there is an increased risk of bleeding. Mugwort
should not be used with anticoagulants.18,19
Mugwort may cause an increase in direct
bilirubin levels.19
Passion flower
Passion flower is a perennial found in the tropics
of the Americas. Its flowers and fruit are used to
make liquid and solid extracts, tinctures and dried
herbs.18,19 Research is being conducted to identify
possible use of passion flower as a treatment for
the symptoms of Parkinson’s disease.19
Women who are pregnant or lactating and
children should not use passion flower.19
Excessive amounts of this herb may cause
sedation. It may also cause headache, agitation,
hypotension, tachycardia, nausea, vomiting,
asthma, ventricular arrhythmias and hepatic
toxicity.18,19
Passion flower may interact with CNS
depressants, including alcohol, causing increased
sedation. It may increase MAOI activity,
Elite
and concurrent use with MAOIs should be
avoided. Passion flower may also increase the
action of anticoagulants, and concurrent use is
contraindicated.18,19 Passion flower may alter Pt
and INR results.18
Valerian
Valerian is a perennial cultivated throughout the
world. Its roots are used as the medicinal parts of
the plants. Valerian products should be kept away
from heat and moisture. In addition to treating
anxiety and mood disorders, Valerian is used to
treat insomnia, restlessness and symptoms of
psychological stress. It is available in capsule,
crude herb, extract, tablets, tea and tincture form.
18,19
Women who are pregnant or lactating should not
use Valerian, nor should it be given to children.
It is contraindicated in patients with hepatic
disease.19
Drug alert! Liver function studies should be
monitored, particularly if patients are taking
valerian as part of long-term treatment. If results
of these studies are elevated, valerian should be
discontinued.19
Side effects associated with valerian include
restlessness, decreased mental alertness,
uneasiness, headache, insomnia, nausea,
vomiting, anorexia, vision changes and
palpitations.18,19
Potential drug interactions with valerian include:
CNS depressants, including alcohol: May
increase sedative effects. Patients should be
closely monitored.18,19
MAOIs: Valerian may negate desired
therapeutic effects. They should not be used
concurrently.19
Phenytoin: Valerian may negate the desired
therapeutic effects of phenytoin. They should
not be used concurrently.19
Warfarin: Valerian may negate the
therapeutic effects of warfarin. They should
not be used concurrently.19
Herbs with sedative effects (e.g., catnip,
hops, kava, passion flower): Sedative effects
may be increased. Patients should be closely
monitored.18
Valerian may cause an increase in ALT, AST,
total bilirubin and urine bilirubin.19
Practice question
Don Draper has been feeling anxious for most
days over the last six months. He has also been
feeling irritable, restless, and has had difficulty
concentrating on his latest advertising project.
He went to see his doctor, and was diagnosed
with generalized anxiety. His workplace drinking
habits have led him to alcoholism, which has led
to his current state of liver failure. Which of the
following medications would be appropriate to
treat Don’s anxiety?
a. Kava.
b. Alprazolam.
c. Buspirone.
d. Diazepam.
e. None of the above.
Page 63
Answer: E – None of the above medications
would be appropriate to treat Don’s anxiety. All
of the above medications are not indicated in
patients who are in liver failure, and all cause
additive CNS depression when used with alcohol.
Medications used in the treatment of
alcoholism
Alcohol, a central nervous system depressant,
is swiftly absorbed into the bloodstream.16
Alcohol dependence and alcohol abuse can
severely impact the lives of the patients
affected, their families, employers and society.
Alcohol withdrawal can be life-threatening,
and detoxification needs to be conducted under
medical supervision.16
Alcoholism is a chronic, progressive and possibly
fatal disease. It is characterized by frequent,
excessive drinking, inability to reduce or stop
drinking even in the presence of medical,
psychological or social complications, increased
alcohol tolerance, and occurrence of withdrawal
symptoms (tremors, seating, tachycardia,
hypertension, vomiting, hallucinations).21
Other health problems, including mental health
issues, often exist in conjunction with alcoholism
and other substance-abuse problems. In fact,
research shows that patients dealing with
alcoholism are nearly twice as likely as those
without alcoholism to suffer from depression.22
Alcoholism and other substance-abuse disorders
are a serious national health problem in the
United States. It is estimated that more than 15
million Americans are dependent on alcohol, and
500,000 of them are between the ages of 9 and
12 years of age. There are about 5,000 alcoholrelated deaths every year associated with the
consumption of alcohol by young patients under
the age of 21. These fatalities are the result of
motor-vehicle accidents, homicide, suicide and
other injuries. One person is killed every 30
minutes in an alcohol-related traffic accident in
the United States.16
The financial costs associated with alcoholism
are staggering. It is estimated that alcoholism is
the cause of 500 million lost days of work, 40
percent of industrial fatalities, and 47 percent of
workplace injuries.16
Pharmacologic interventions
Pharmacologic treatment in alcoholism has two
main goals: to permit safe withdrawal from
alcohol and to prevent relapse.16
Vitamin B1 (thiamine)
Vitamin B1 (thiamine) is a water-soluble vitamin
prescribed to prevent or to treat WernickeKorsakoff syndrome. This syndrome is a disorder
of the brain caused by a lack of thiamine,
common in patients with chronic alcoholism.
It is comprised of two distinct syndromes
that generally occur together. Wernicke’s
encephalopathy is characterized by confusion,
ataxia, nystagmus, anisocoria, and slow or
impaired pupil reflexes, and can result in coma
or death if left untreated. It occurs in a state of
acute severe deficiency of thiamine, a cofactor in
the metabolism of glucose. Korsakoff’s psychosis
involves anterograde and retrograde amnesia,
confabulation, and hallucinations. Korsakoff’s
syndrome is a state of psychosis that occurs from
Wernicke’s encephalopathy.23,36
Drug alert! Patients taking disulfiram must be
told to avoid products that contain alcohol, such
as mouthwash, cough syrup, perfume, aftershave,
vinegar, vanilla and other extracts. Teach patients
to read labels very carefully, because any product
that contains alcohol can cause symptoms.16
Alcoholics who are detoxifying in an inpatient
setting should be given 100 mg. thiamine daily
to decrease symptoms of Wernicke-Korsakoff
syndrome.36
Disulfiram should never be administered until the
patient has abstained from alcohol for at least 12
hours. He or she must be clearly informed about
the effects of the drug and give permission for its
use. Effectiveness of this treatment depends on
the cooperation of the patient.4
Drug alert! Folic acid, multivitamins, and
vitamin B12 (cyanocobalamin) are also often
prescribed for deficiencies of nutrition, which are
often seen in patients with alcoholism.16,36
Medications to manage symptoms of
alcohol withdrawal
Alcohol withdrawal is usually managed with a
benzodiazepine anxiolytic drug. The purpose of
administering such a medication is to control or
suppress the symptoms of alcohol abstinence and
to decrease the risk of seizures associated with
alcohol withdrawal.16,36 The most commonly used
benzodiazepines for the treatment of alcohol
withdrawal are:16
Lorazepam (Ativan).
Chlordiazepoxide (Librium).
Diazepam (Valium).
Detailed information about the preceding
benzodiazepines can be found in the previous
section on antianxiety medications. These
medications can be administered around the clock
on a fixed schedule or on an as-needed basis.
Giving them on an as-needed basis has been
found to be just as effective as administering
them on a fixed schedule and seems to promote a
more rapid withdrawal from alcohol as well.16
Medications to prevent relapse of
alcoholism
Several medications are available to help prevent
patients from drinking and to reduce cravings for
alcohol. These medications are prescribed at least
12 hours after the patient’s last alcoholic drink,
and may be used in combination with counseling
and psychiatric treatment if necessary.16,32
Disulfiram (Antabuse)
Disulfiram (Antabuse) is prescribed to help
dissuade patients from drinking. Patients take
125-500 mg. by mouth daily until permanent
self-control is achieved. It works by inhibiting
the enzyme responsible for breaking down
acetaldehyde, which is a toxic byproduct of
alcohol synthesis. By preventing the breakdown
of acetaldehyde, the negative consequences of
drinking become more prominent when a patient
taking disulfiram drinks alcohol.
If someone who is taking disulfiram drinks
alcohol, he or she will experience severe adverse
effects, including flushing, throbbing headache,
sweating, nausea and vomiting. In severe
instances, confusion, extreme hypotension and
even death may occur. Treatment with disulfiram
may continue for months or years, depending on
the individual.4,16
While taking disulfiram, patients may experience
drowsiness, fatigue, depression, neuritis,
psychotic reactions, delirium, optic neuritis,
metallic or garlic aftertaste, impotence and acne.4
There are a number of drugs that can interact with
disulfiram. These include:4,36
CYP2C9 inhibitors: May alter hepatic
metabolism of disulfiram.
CNS depressants and barbiturates: May
prolong effects of these drugs. Use with
caution.
Anticoagulants: May increase anticoagulant
effect, thus dose of anticoagulant may need
adjustment.
Isoniazid: May cause ataxia or significant
behavioral changes. Avoid concurrent use.
Metronidazole: May cause psychotic
reaction. Avoid concurrent use.
Phenytoin: May increase toxic effect of
phenytoin. Phenytoin levels must be carefully
monitored and dose adjusted as needed.
Tricyclic antidepressants: May cause
transient delirium.
Herbal preparations containing alcohol:
Such herbs must not be used while taking
disulfiram.
Caffeine: May increase elimination half-life
of caffeine.
Warfarin: May increase INR and risk of
bleeding.
Drug alert! Ingestion of alcohol can cause
adverse reactions for one to two weeks after the
last dose of disulfiram.16
Disulfiram may increase cholesterol levels.4 It
is contraindicated in patients with psychoses or
cardiac disease, those taking alcohol-containing
products, and in those who are experiencing
alcohol intoxication or who have ingested alcohol
in the previous 12 hours.4
Counseling points for disulfiram36
Disulfiram should not be taken with
alcohol. Patients need to avoid any products
that contain alcohol, including over-thecounter cough syrups, herbal extracts, and
mouthwash.
Disulfiram may continue to cause reactions
with alcohol for up to two weeks after the last
disulfiram dose.
The patient must be clearly informed of how
this medication works. It should never be
given to patients without their consent.
Page 64
Elite
Notify patients of potential side effects,
especially hypotension and dizziness,
and when to contact their doctor or seek
emergency care.
Naltrexone (ReVia, Vivitrol)
Naltrexone is an opioid antagonist frequently
used to treat opioid overdose. Alcohol increases
the release of naturally occurring opioid-like
peptides in the body, so it is thought that giving
an opioid antagonist will decrease the urge
and cravings to drink, because any increase in
opioid-like substances in the body would be
inefficient.16,36 For alcohol dependence, 50 mg. is
given by mouth once daily.
Common side effects of naltrexone include
insomnia, anxiety, nervousness, headache,
nausea, vomiting, abdominal pain, muscle and
joint pain, and injection site reaction. Serious
reactions include depression, suicidal thoughts
and hepatotoxicity.4,36
Naltrexone should be avoided in patients in
hepatic failure or who are suffering acute
hepatitis.
If administered with thioridazine, naltrexone may
increase lethargy. If given with opioid-containing
products, the effectiveness of the opioid may be
decreased. Concurrent use should be avoided.
Naltrexone may increase the following lab test
results:4
Lymphocyte count.
AST.
ALT.
LDH.
Counseling points for naltrexone
36
Inform the patient that any opiate pain
medications will not be as effective if taken
with naltrexone.
Notify patients of potential side effects,
especially hypotension and dizziness,
and when to contact their doctor or seek
emergency care.
Monitoring of liver enzmes may need to be
done while taking this medication.
Acamprosate (Campral)
Acamprosate may be prescribed to help patients
recovering from alcohol abuse or dependence
to help decrease alcohol cravings and relieve
emotional discomfort. Its mechanism of action
is not entirely clear, but it is thought to bind to
GABA receptors and decrease glutamate levels
to restore balance between neuronal inhibition
and excitation. Patients should take 666 mg. by
mouth three times daily.36
Acamprosate is contraindicated in patients with
severe renal impairment (CrCl < 30mL/min), and
those with a CrCl of 30-50 mL/min should reduce
the dose by half to 333 mg three times daily.16,36
It should be used with caution in pregnant or
lactating women, elderly patients and those with
a history of depression and suicidal thoughts or
attempts.4
Side effects associated with acamprosate include
diarrhea, nausea, flatulence, insomnia, anxiety,
depression, dizziness, and pruritis.16,36 There
are no known significant interactions with
acamprosate. The drug may decrease platelet
count, hemoglobin level and hematocrit. It may
increase ALT, AST, bilirubin, blood glucose and
uric acid levels.4
Counseling points for acamprosate
4,36
Notify patients of potential side effects,
especially hypotension and dizziness, and
when they should contact their doctor or
emergency care.
Patients should be instructed to swallow
tablets whole, not to crush, break or chew
them.
Practice question
Which of the following medications used to treat
alcoholism should be avoided in patients who
may continue to drink?
a. Disulfram.
b. Chlordiazepoxide.
c. Naltrexone.
d. A and B.
e. A, B, and C.
Answer: D – Disulfram and chlordiazepoxide
should be avoided in patients who may continue
to drink. Disulfram can cause flushing, headache,
nausea, vomiting, confusion or hypotension if the
patient drinks while taking it. Chlordiazepoxide
can cause additive CNS depression when
combined with alcohol. Both products should be
avoided.
Herbs used in the treatment of
alcoholism
Kudzu
Found in China and Japan, kudzu is a vine that
has been used in traditional Chinese medicine to
manage alcoholism. This herb is also believed
to have hypoglycemic effects. The medicinal
parts of the vine are the roots, which are used to
prepare capsules, tablets, powder and extract.18,19
Kudzu is contraindicated in the following
patients:18
Pregnant women.
Lactating women.
Patients with clotting disorders.
Patients with cardiovascular disease.
Patients with diabetes.
Patients who take anticoagulants, aspirin,
anti-diabetic agents, estrogen, hormonal
contraceptives and tamoxifen.
Common side effects associated with the use of
kudzu include nausea, vomiting, anorexia and
hypersensitivity reactions.19
There are a number of potential drug interactions
with kudzu. These include:18
Tamoxifen: May interfere with tamoxifen’s
action. Avoid concurrent use.
Estrogen and hormonal contraceptives:
Kudzu may decrease effectiveness of these
types of contraceptives. Concurrent use
should be avoided or else the patient should
use a non-hormonal form of contraception.
Anti-diabetic drugs: Because kudzu has
hypoglycemic properties, concurrent use may
Elite
enhance those effects. Concurrent use should
be avoided.
Cardiovascular drugs: May interfere with
cardiovascular drug effectiveness. Should not
be used together.
The following herbs may cause additive effects:
alfalfa, black cohosh, licorice, red clover, soy and
flaxseed.18
Kudzu may also affect some lab studies. It may
decrease glucose and cholesterol levels and
increase clotting time, PT and INR.18
Drug alert! Remember to impress upon patients
the necessity of discussing any desire to take
herbal supplements with their health care
providers before starting any herbal therapy.
Alfalfa
Alfalfa grows throughout the world and is
available as capsules, flour, tablets, sprouts,
poultice, infusion and fluid extract forms. The
medicinal parts of the plants are its flowers,
germinating seeds, leaves and whole herbs.18,19 Its
primary benefit for those dealing with alcoholism
seems to be its use as a nutritive tonic. Alfalfa
is a good source of beta-carotene, calcium, iron,
phosphorus, potassium and vitamins A, C, E and
K.18,19
Research is under way to determine whether
alfalfa can protect the gastrointestinal tract
from cancer, reduce cholesterol levels, prevent
symptoms related to menopause, and treat
atherosclerosis.19
Alfalfa acts as a uterine stimulant and should
not be used during pregnancy. It is also
contraindicated in patients who have lupus
erythematosus. It is also thought to be a good
source of vitamin K. 19
Drug alert! The seeds of alfalfa must not be
eaten. They contain a toxic amino acid.19
Side effects associated with the use of alfalfa
include hypotension, photosensitivity, systemic
lupus erythematous, bleeding and blood
dyscrasias, diarrhea, digestive upsets and
photosensitivity.18,19
The following drug interactions are associated
with use of alfafa:18,19
Anticoagulants: Alfalfa may interfere with
coagulation and increase prothrombin time
and prolong bleeding time. Concurrent use is
not recommended.
Anti-diabetics: Alfalfa should be used
cautiously in conjunction with medications
for diabetes. The herb may potentiate
hypoglycemic effects.
Chlorpormazine: Alfalfa may increase druginduced photosensitivity. They should not be
used concurrently.
Hormonal contraceptives: Large amounts
of alfalfa may interfere with contraceptive
action. Concurrent use should be avoided.
Estrogen replacement therapy: Alfalfa may
interfere with hormone replacement therapy.
Herbs with clotting potential, such as
nettle, parsley and plantain: Excessive use
Page 65
of vitamin K-containing herbs may increase
the risk of clotting in patients who are taking
anticoagulants. These herbs should not be
used concurrently.
Vitamin E: Absorption may be inhibited.
Avoid concurrent use.
Alfalfa may reduce cholesterol and glucose
levels.18
Pharmacologic interventions for bipolar
disorder
Mark is the manager of an exclusive restaurant
in a major metropolitan area. His staff complains
that he has “moods.” One employee describes
him as “He’s sad and quiet for a couple months,
and then all of a sudden is excited and happy and
working more than 12 hours a day. He expects us
to work those hours and screams and yells if we
don’t. We never know what to expect. Sometimes
he talks really weird. He says he’s going to take
over all the best restaurants in the city and that
everyone will know who he is. I think I’ll quit just
to get away from him!” Mark is displaying the
major mood swings of someone who may suffer
from bipolar disorder.
Bipolar disorder (formerly known as manicdepressive disorder) is a mood disorder
characterized by alternating episodes of mania
and major depression. During manic phases,
patients are euphoric, excited and have poor
judgment, feelings of grandeur, rapid thoughts,
actions and speech. 24
The depressed phase is characterized by feelings
of sadness, hopelessness, helpless, suicidal
ideation, worthlessness or guilt inappropriate to
the situation, tiredness, decreased enjoyment and
interest in previously enjoyable activities, and
difficulty concentrating.16
Bipolar disorder is one of the most prevalent
mental health disorders, second only to major
depression as a cause of worldwide disability.16
Bipolar disorder, according to the National
Institute of Mental Health, affects more than 5
million to 7 million adults in the United States
annually. That means about 3 percent of the
people in this country are affected.24 Bipolar
disorder occurs about equally among men and
women and is more common in highly educated
people.16
The mood swings of bipolar disorder vary in
length and how often they occur. Some patients
with bipolar disorder suffer primarily from major
depression with occasional manic episodes.
Others, however, experience “rapid cycling”
with “at least four episodes of depression,
mania or hypomania (less severe form of mania)
occurring within one year.” There are also people
who have what is referred to as “mixed” states,
during which mania and depression take place
simultaneously or in quite rapid sequence.25
There are two types of bipolar disorder:25
Bipolar type I: The most severe form of the
disorder, bipolar type 1 can cause significant
problems with activities of daily living and
interpersonal relationships. This form is
characterized by manic or mixed episodes
that last at least seven days. Symptoms
may be so severe that hospitalization may
be required. Manic or mixed episodes are
followed by episodes of major depression.
Depression can last weeks or even years.
Fortunately, patients may experience long
periods of time between episodes when they
are free from symptoms.25
Bipolar type II: This form is characterized
by alternating hypomanic episodes that last
at least four days with periods of depression
but no manic or mixed episodes. Hypomanic
episodes have less severe symptoms than the
manic episodes of type 1, but the depressive
episodes may be quite severe.25
There is no cure for bipolar disorder. Treatment
requires a life-long course of medications.
“This is the only psychiatric disorder in which
medications can prevent acute cycles of bipolar
behavior.” Medications used to treat the disorder
include lithium, an anti-manic agent, or anticonvulsant drugs used as mood stabilizers.16
Lithium
Lithium was the first mood stabilizer
approved (in the 1970s) by the Food and Drug
Administration (FDA) for the treatment of mania.
It has been shown to be effective in not only
controlling manic symptoms but also in helping
to prevent recurrence of manic and depressive
episodes.26
Research shows that lithium is helpful in about
75 percent of patients with bipolar disorder.
The remaining 25 percent either do not respond
therapeutically or have problems with lithium
because of its side effects, drug interactions or
adhering to the prescribed treatment regimen.16
Lithium is believed to act by competing for salt
receptor sites with sodium, calcium, potassium
and magnesium ions. The mechanism of action
of lithium is not well understood, but it is thought
to interfere with the storage, synthesis, release
and reuptake of norephinephrine, dopamine and
serotonin.16,36
Lithium is generally used in doses of 900-1,200
mg. per day, divided into 2-4 doses per day.
Blood levels of lithium should be measured
before the morning dose (in order to measure
the trough level) and should be between 0.61.2 mEq/L to achieve therapeutic results. Toxic
concentrations are above 1.5mEq/L.
Lithium is in pregnancy category D, and not
recommended for use in pregnant women
because it can cause first-trimester developmental
abnormalities. It also crosses the blood-brain
barrier and placenta and is found in sweat and
breast milk, so it should be avoided in lactating
women as well.16, 36
Lithium should be used with caution in the
following patients:4
Patients receiving neuromuscular blockers.
Patients receiving diuretics.
Elderly or debilitated patients.
Patients with cardiovascular, renal or thyroid
disease.
Patients with seizure disorders.
Patients with sodium depletion or
dehydration.
Side effects of lithium include fatigue, lethargy,
arrhythmias, bradycardia, vomiting, anorexia,
diarrhea, thirst, polyuria, renal toxicity
(with long-term use), leukocytosis, tinnitus,
hypothyroid, and muscle weakness.4,36
There are a number of potential drug interactions
associated with lithium. Some of these include:4,36
ACE inhibitors: These may increase lithium
levels.
Aminophylline, sodium bicarbonate, urine
alkalinizers: May increase lithium excretion.
Anti-arrhythmic drugs: Have the potential
to increase the occurrence of life-threatening
arrhythmias. Avoid concurrent use.
Calcium channel blockers: May decrease
lithium levels while increasing the risk of
neurotoxicity. They should be used together
with caution and careful monitoring.
Thiazide diuretics: May increase the
reabsorption of lithium causing toxic effects.
If used concurrently, monitor lithium and
electrolyte levels.
Caffeine: May decrease lithium level.
ACE inhibitors and angiotensin receptor
blockers: Can decrease lithium clearance to
increase lithium levels and toxicity.
Serotonergic medications: Can increase the
risk of serotonin syndrome.
Drug alert! People with bipolar disorder are
often found to have thyroid problems. Lithium
may cause low thyroid levels. Such low levels
(hypothyroidism) have been linked with rapid
cycling in some bipolar disorder patients,
especially women.26
Lithium may increase the following lab test
results:4
Glucose.
Creatinine.
TSH levels.
Iodine uptake.
White blood cell counts.
Neutrophil counts.
Lithium may decrease sodium, T3, T4, and
protein-bound iodine levels.4
Counseling points for lithium4,36
Patients taking lithium should be told to stay
hydrated while taking lithium; dehydration
can increase lithium levels.
Lithium should be taken after meals to reduce
the possibility of gastrointestinal upset.
They should also be informed that they
should expect nausea, to void large amounts
of urine, and to experience thirst during the
first few days of therapy.
Regular blood monitoring is necessary while
taking this medication.
Women of childbearing age should use
contraception to prevent pregnancy while
taking lithium.
Page 66
Elite
Warn patients to watch for signs of toxicity
(see side effects) and to call a health care
provider before taking more medication if
such signs appear, but never to abruptly stop
taking the drug.
Anticonvulsants
Valproic acid may increase ammonia, ALT,
AST and bilirubin levels. It may also increase
eosinophil counts and bleeding time, and
decrease platelet, RBC and WBC counts.
Valproic acid may cause false-positive results for
urine ketone levels.4
A number of anticonvulsants have been found
to help stabilize the moods of bipolar disorder
patients. They are classified as miscellaneous
anticonvulsants. Although it is not definitively
known how these anticonvulsants work to
stabilize moods in bipolar patients, it may be that
they increase the brain’s threshold for dealing
with stimulation, thus stopping the patient from
being overwhelmed with external and internal
stimuli.16
Valproic acid (Depakene, Depakote)
Valproic acid (also known as divalproex sodium
or sodium valproate) was approved by the FDA
in 1995 for treating mania. It is an alternative
to lithium as a bipolar disorder treatment. Its
mechanism of action in bipolar disorder is not
entirely clear, but it is thought to increase the
effects of GABA as well as inhibit the effects
of glutamate at the NMDA receptor to decrease
neural excitation. Doses depend on the form of
valproic acid used; Depakote is given in doses of
250-500 mg. every 8 hours for bipolar patients.
Valproic acid blood levels should be monitored
and kept within the therapeutic range of 50125mcg/mL for mania.26,36
Valproic acid has black box warnings on it due
to its teraotgenic effects on the fetus and risk
of causing serious or fatal hepatotoxicity and
pancreatitis. It is in pregnancy category D and is
contraindicated in pregnant women and in those
who may become pregnant, as well as patients
with hepatic or pancreatic impairment.4,36
Valproic acid may increase testosterone levels in
teenage girls, causing polycystic ovary syndrome
(PCOS) in women who begin taking the drug
before they are 20 years of age. PCOS causes a
woman’s eggs to develop into cysts that collect
in the ovaries instead of being released during
monthly menstruation. In turn, this can lead to
obesity, excess body hair and disruptions in the
normal menstrual cycle.26
Valproic acid may cause the following additional
side effects:4,36
Dizziness.
Headache.
Insomnia.
Nervousness.
Somnolence.
Tremor.
Blurred vision.
Diplopia.
Abdominal pain.
Anorexia.
Diarrhea.
Dyspepsia.
Nausea.
Vomiting.
Liver toxicity.
Bone marrow suppression.
Alopecia.
Appetite and weight changes.
Hallucinations or psychosis.
Anemia.
Electrolyte imbalances.
The following drug interactions with valproic
acid are possible:4,36
Aspirin, cimetidine, erythromycin,
clarithromycin: May cause valproic acid
toxicity.
CNS depressants: May cause excessive CNS
depression. Avoid concurrent use.
Phenobarbital: Phenobarbital levels may
increase, and clearance of valproic acid may
decrease.
Phenytoin: May decrease valproic acid level
and increase or decrease phenytoin level.
Rifampin: May decrease valproic acid level.
Alcohol: May cause excessive CNS
depression. Avoid concurrent use.
Doripenem, meropenem, irtapenem,
ertapenem: Can decrease valproic acid
levels.
Aspirin, warfarin, and other blood
thinners: May increase risk of bleeding.
Counseling points for valproic acid16,36
Valproic acid should be taken with food to
reduce gastrointestinal upset.
Notify patients of potential side effects
and when to contact their doctor or seek
emergency care.
Inform patients of black box warnings for
hepatotoxicity and hepatitis, and tell them
to contact a doctor immediately if any
symptoms of these conditions arise.
Carbamazepine (Tegretol)
This drug was the first anticonvulsant found to
have the ability to stabilize moods. While its
mechanism in bipolar disorder is not completely
understood, it is thought to prevent voltage-gated
sodium channels from opening, leaving neurons
in a less excitable state. It is also thought to affect
the GABA receptors to decrease cell excitability.
For bipolar disorder, it is given in doses of 8001,200 mg. per day divided into 2-4 doses per day.
Therapeutic blood levels of carbamazepine are
between 4-12mcg/mL, and toxicity begins above
12mcg/mL.36
Carbamazepine has a black box warning because
it can cause agranulocytosis, toxic epidermal
necrolysis, and Stevens-Johnson syndrome.16,36
It is pregnancy category D and should not be
used by pregnant women. Carbamazepine is
contraindicated in patients with a hypersensitivity
to tricyclic antidepressants, those who have taken
an MAO inhibitor within the previous 14 days,
and in patients with a history of bone marrow
suppression.4
Elite
Side effects include dizziness, drowsiness,
hypotension, ataxia, sedation, blurred vision,
leucopenia, nausea, vomiting, hepatitis or hepatic
failure, aplastic anemia, SIADH, leukopenia,
agranulocytosis, pancreatitis, arrhythmias and
serious rashes.16,36
There are many drug interactions with
carbamazepine because of its extensive activity
in the cytochrome P450 system. It is an inducer
of the 1A2, 2B6, 2C9 and 3A4 enzymes, and can
decrease drug levels of other medications that
are substrates of these enzymes. When starting
a patient on carbamazepine or adding new
medications to a patient on carbamazepine, it is
very important to check for drug interactions.
Some of the potential drug interactions with
carbamazepine include:4,36
Azole antifungals: Contraindicated for
use with carbamazepine. Can increase
carbamazepine levels and decrease antifungal
levels.
Acetaminophen: Patients should limit
acetaminophen to less than 2g per
day because of the increased risk of
acetaminophen toxicity.
MAOIs: May increase depressant and
anticholinergic effects. Avoid concurrent use.
Phenobarbital, phenytoin, primidone: May
decrease carbamazepine level.
Cimetidine: May increase carbamazepine
level.
Nefazodone: Contraindicated for use with
carbamazepine. May increase carbamazepine
levels and toxicity and decrease nefazodone
levels.
Warfarin: Can decrease efficacy of warfarin.
Herbal preparations, such as plantains
(psyllium seed): May interfere with the
gastrointestinal absorption of the drug. Avoid
concurrent use.
Counseling points for carbamazepine36
Tell patients it is important to consult with a
pharmacist or doctor when starting any new
prescription or over-the-counter medications
when taking carbamazepine because of the
many drug interactions.
Notify patients of potential side effects and
when they should contact their doctor or seek
emergency care.
Inform patients of a black box warning for
aplastic anemia and serious skin rashes, and
tell them to contact a doctor immediately if
any symptoms of these conditions arise.
Lamotrigine (Lamictal)
Lamotrigine is another anticonvulsant that may
be prescribed as a mood stabilizer. It works by
blocking voltage-dependent sodium channels to
decrease neuronal excitation. It has a pregnancy
category risk of C, and is unsafe to use in
lactating patients. For bipolar disorder, the goal
dose is 200 mg. per day, but this dose must be
titrated up very slowly to decrease the risk of
serious and potentially fatal rashes.36
Page 67
There are many adverse reactions to lamotrigine;
they include Stevens-Johnson syndrome, other
rashes, diplopia, dizziness, headache, aplastic
anemia, neutropenia, leukopenia, pancytopenia,
hepatic failure, ataxia, nausea/vomiting,
diarrhea, emotional ability, and visual or speech
disturbances.36
Drug interactions with lamotrigine include:36
Hormonal contraceptives: Hormone level
and contraceptive efficacy can be decreased.
Valproic acid: Can increase lamotrigine
levels and the risk of Stevens-Johnson
syndrome. Lower doses of lamotrigine should
be used.
Carbamazepine, phenobarbital, phenytoin,
primidone: Can decrease lamotrigine levels.
Counseling points for lamotrigine36
The dose of lamotrigine will be titrated up
slowly, so when starting the medication,
expect to take increasing doses every week
or two.
Any signs or symptoms of a rash should be
reported to the prescriber immediately.
Gabapentin (Neurontin)
Gabapentin is another anticonvulsant that may
be prescribed as a mood stabilizer. It works by
blocking voltage-dependent calcium channels
to decrease neuronal excitation, as well as
by decreasing excitatory neurotransmitters.
Gabapentin should be used with caution in
elderly patients and those with severely reduced
kidney function, and have a pregnancy category
risk of C. It is given in a wide range of doses,
100-1,200 mg. three times daily.4,36
Drug alert! Adjust dosage in elderly patients
based on creatinine clearance values because of
the possibility of decreased renal function.4
Adverse reactions include dizziness, ataxia,
hypotension, sedation, fatigue, somnolence,
leucopenia, problems with coordination,
nystagmus, nausea and vomiting.4,16
There are relatively few drug interactions related
to gabapentin. These include:4
Antacids: May cause a decrease in
absorption of gabapentin. Antacids and
gabapentin should not be given within two
hours of each other.
Hydrocodone: May increase gabapentin
level and decrease hydrocodone. Monitor
drug levels and adjust dosage as needed.
Ethanol and CNS depressants: Should be
avoided with gabapentin due to additive CNS
depression.
Be aware that valproic acid may decrease white
blood cell count.4
Counseling points for gabapentin
4,16,36
Notify patients of potential side effects and
when they should contact their doctor or seek
emergency care.
The oral solution form of gabapentin should
be refrigerated.
Give gabapentin with food to reduce
gastrointestinal upset.
Topiramate (Topamax)
This anticonvulsant drug is also prescribed on
occasion as a mood stablilizer.16 While its exact
mechanism in bipolar disorder is not completely
understood, it is thought to block glutamate
receptors and voltage-gated sodium channels and
enhance the activity of GABA to decrease cell
excitability. Topiramate is used in doses of 25200 mg. twice a day.36
was recommended that she start treatment for
bipolar disorder. Her medical conditions include
severe uncontrolled hypothyroidism. Which of
the following medications will have the greatest
effect on her thyroid disorder?
a. Gabapentin.
b. Topirimate.
c. Carbamazepine.
d. Lithium.
Topiramate is pregnancy category D and should
be avoided in pregnant women, those who are
breast-feeding, and in patients with impaired
hepatic function.4
Answer: D – Lithium would have the greatest
effect on Mary’s thyroid. Lithium is known to
affect the thyroid and can cause hypothyroidism
as well as rapid cycling of bipolar disorder.
Topiramate can cause dizziness, anxiety,
ataxia, confusion, memory problems, fatigue,
somnolence, paresthesia, psychomotor slowing,
tremor, abnormal vision, nystagmus, anorexia,
nausea, decrease or increase in weight, slurred
speech, weakness, vomiting, and blurred or
double vision.4,16
Antidepressant use in bipolar disorder
Topiramate is metabolized via the cytochrome
P450 system, and is a weak inhibitor of 2C19 and
a weak inducer of 3A4. Beware of the following
potential drug interactions with topiramate:4,26
CNS depressants, including alcohol: May
cause increased CNS depression. Avoid
alcohol. Use CNS depressants only with
caution.
Hormonal contraceptives: The effectiveness
of such contraceptives may be decreased
when taking over 200 mg. of topiramate
per day. Patients should be advised to use
alternate methods of contraception while
taking these doses.
Phenytoin: Interactions may decrease
topiramate level and increase phenytoin
levels. Levels of both drugs must be carefully
monitored if used concurrently.
Valproic acid: May decrease both valproic
acid and topiramate levels. Monitor levels
closely.
Carbamazepine: May decrease topiramate
level. Careful monitoring is needed.
Carbonic anhydrase inhibitors: May
decrease topiramate level. Avoid concurrent
use.
ACE inhibitors, ARBs, diuretics: Can
increase the risk of hypokalemia; potassium
monitoring may be necessary with
combination therapy.
Topiramate can affect several lab test results.
The drug can increase liver enzyme levels and
decrease bicarbonate and hemoglobin levels and
hematocrit as well as white blood cell count.4
Counseling points for topiramate16,36
With this drug and other drugs that have similar
side effects, patients must be assessed for ability
to ambulate safely and maintain coordination.
Give topiramate with food to reduce
gastrointestinal upset.
Practice question
A friend of Mary Poppins recommended that
she see a psychiatrist after she spent the past
few months flying around the city nonstop with
her umbrella. When she went to her doctor, it
Sarah is a social worker who has recently
relocated from a large metropolitan area to a
rural community. She was diagnosed with bipolar
disorder three years ago and has responded
well to treatment with lithium. Shortly after
relocating, Sarah begins to suffer the symptoms
of a depressive episode. She is “tired of taking
lithium” and decides to visit one of the two
doctors in her new town, a tiny rural town.
Unfortunately, Sarah decides not to tell the
doctor about her bipolar disorder and only
tells him about her depression, attributing it to
her recent divorce. The physician prescribes
an antidepressant. After a few weeks, Sarah’s
depression lifts and she immediately swings into
a serious manic phase, something that has not
happened for over a year.
The use of antidepressants in bipolar disorder
patients remains controversial. There is only
limited evidence to support antidepressant
treatment for bipolar depression.27 If
antidepressants are used, it is generally
recommended that a mood stabilizer be taken as
well to prevent or reduce the risk for switching to
manic or hypomanic phases or developing rapid
cycling symptoms. In fact, research results from a
large National Institute of Mental Health (NIMH)
study showed that adding an antidepressant
to a mood stabilizer “is no more effective in
treating the depression than using only a mood
stabilizer.”26
Herbal preparations for use in bipolar
disorder
Herbal preparations should never be used unless
under the direction of a qualified herbalist and
with the knowledge and approval of patients’
primary health care providers. As mentioned
throughout this education program, it is
absolutely imperative that patients divulge that
they are taking any herbal preparations. These
preparations can produce significant adverse
side effects as well as interacting adversely with
prescription, non-prescription and other herbal
medicines.
Fish oils
Fish oils contain omega-3 fatty acids, and are
used to prevent cardiovascular disease and to
treat depressive disorder, bipolar disorder and
dysmenorrheal disorders. Fish oils are available
as capsules and in liquid form.19
Page 68
Elite
There are no reported side effects or interactions
with other herbs or foods. There is some evidence
that fish oils may increase the risk of bleeding,
so concurrent use with anticoagulants should be
avoided. Fish oils should not be used in women
who are pregnant or lactating, in children, or
in patients with breast or prostate cancer or in
known heart disease, unless under the supervision
of a doctor.19
Lecithin
Lecithin is found in common foods such as
eggs, peanuts and beef liver and can be found
in capsule and tablet forms. It is used to lower
cholesterol levels, treat hepatic disease and treat
Alzheimer’s disease and bipolar disorder.19
The most common side effects include nausea,
vomiting, anorexia and hepatitis. There are no
known drug, food or other herb interactions with
lecithin. Lecithin may decrease cholesterol test
results. 19
Perseveration: Persistent verbalization on a
single idea or topic. There may be continuous
repetition of a word, sentence or phrase, and
attempts to change the topic or redirect the
patient are met with resistance.
Ideas of reference: Patients’ false beliefs that
external events have particular meaning for
them.
Echopraxia: Imitation or mimicking of
the behaviors, movements and gestures of
another person who is being observed by the
patient.
Associated looseness: Poorly related
thoughts and ideas.
Ambivalence: Expression of contradictory
beliefs about the same person or situation.
Soft or negative signs and symptoms include:16,28
Flat affect: Lack of facial expression that
would normally indicate feelings, moods or
emotions.
Blunted affect: Limited range of emotional
expression.
Lecithin should not be used during pregnancy and
lactation, nor should it be given therapeutically to Lack of volition: Lack of will or ambition to
take action.
children.19
Apathy: Display of indifference toward
Pharmacologic interventions for
people, situations or activities.
schizophrenia
Alogia: Little verbalization or expression of
Schizophrenia is the most debilitating of mental
the substance or meaning of a situation.
health disorders. It interferes with the ability
Anhedonia: Inability to feel joy or to
to function in work, society and interpersonal
take pleasure from life’s activities or from
relationships.28 Usually diagnosed in late
interpersonal relationships.
adolescence or early adulthood, schizophrenia
Catatonia: “Psychologically induced
seldom becomes apparent in childhood. The
immobility occasionally marked by periods
incidence of onset peaks between 15 to 25 years
of agitation or excitement.”16 The patient is
of age for men and 25 to 35 years of age for
sometimes described as being in a trance-like
women.16
state and seems motionless.
It is estimated that schizophrenia affects about
There are several types of schizophrenia
1 percent of the worldwide population. In the
described by the DSM-IV-TR. Classification is
United States, approximately 2.5 million people
dependent on presenting symptoms. The various
have schizophrenia.28
types are:16
The financial impact of schizophrenia is
incredible. Patients with schizophrenia occupy
about 10 percent of the hospital beds in the
United States and cost an estimated 2 percent
of the gross national product in missed work,
public assistance and costs of treatment.28
However, thanks to proper diagnosis, advances in
community-based treatment and the effectiveness
of newer atypical antipsychotic drugs, many
people with schizophrenia are able to live in the
community with family and societal support.16
Signs and symptoms of schizophrenia
Schizophrenia is not a single illness, but is
a syndrome with many different types and
symptoms. Symptoms are primarily psychotic in
nature and are divided into two major categories:
positive or hard signs and symptoms, and soft or
negative signs and symptoms.16
Hard or positive signs and symptoms include:
Hallucinations: These include false visual,
auditory or tactile perceptions that do not
exist in reality.
Delusions: Fixed false beliefs that include
distorted thoughts and perceptions.
Flight of ideas: Constant verbalizations that
rapidly move from one topic to another.
16,28
Schizophrenia, paranoid type:
Characterized by feelings of persecution or
grandiose delusions, hallucinations, delusions
with a religious focus or hostile behavior.
Schizophrenia, disorganized type:
Characterized by significantly inappropriate
or flat affect, incoherence and extremely
disorganized behavior.
Schizophrenia, catatonic type:
Characterized by significant psychomotor
disturbance, which can include either
motionlessness or excessive motor activity.
Schizophrenia, undifferentiated type:
Characterized by mixed schizophrenic
symptoms of other types accompanied by
disturbances of thought, affect and behavior.
Schizophrenia, residual type: Characterized
by at least one prior but not current episode
as well as social withdrawal, flat affect and
looseness of association.
There is no known cure for schizophrenia.
Treatment focuses on psychopharmacology in the
form of antipsychotic medications, also known as
neuroleptics. They are administered to decrease
dopamine, and sometimes serotonin levels, to
reduce or control signs and symptoms.16,28,36
Elite
The older or “conventional” antipsychotic
medications are dopamine antagonists, and the
newer antipsychotics are both dopamine and
serotonin antagonists.16
Because of the enormity of the effects of the
antipsychotic medications, this section of the
program is divided as follows:
Listing of conventional and atypical
antipsychotics.
Side effects of antipsychotic medications.
Some specific information for each
antipsychotic, such as contraindications, drug
interactions and impact on lab studies.
Conventional antipsychotics4,16
These antipsychotics work by blocking the
postsynaptic dopamine receptors in the brain.36
Chlorpromazine (Thorazine).
Perphenazine (Trilafon).
Fluphenazine (Prolixin).
Thioridazine (Mellaril).
Thiothixene (Navane).
Haloperidol (Haldol).
Trifluoperazine (Stelazine).
Atypical antipsychotics4,16,29
These antipsychotics work by blocking the
postsynaptic dopamine and serotonin (5HT2A)
receptors in the brain, except for Abilify, which
is a partial agonist of postsynaptic dopamine and
serotonin (5HT2A) receptors.36
Clozapine (Clozaril).
Risperidone (Risperdal).
Olanzapine (Zyprexa).
Quetiapine (Seroquel).
Ziprasidone (Geodon).
Paliperidone (Invega).
Aripiprazole (Abilify).
Side effects of antipsychotic medications
The FDA has mandated that all antipsychotic
medications receive a black box warning stating
that antipsychotic agents may increase the risk
of cardiovascular or infectious deaths in elderly
patients with dementia. It is unclear at this time
whether this is due to the medication or the
patient’s history.36
The side effects of antipsychotic medications
range from slight discomfort to serious, even
incapacitating effects and permanent movement
disorders.16
Drug alert! The side effects can be so devastating
to patients that they may discontinue taking them
or reduce the amount of the drug that they take
without medical approval. In fact, side effects are
often cited as the main reason for discontinuing
drugs.16
Extrapyramidal side effects
More common with conventional antipsychotics,
extrapyramidal side effects (EPS) are reversible
movement and posture disturbances.30 They
include dystonic reactions, pseudo-parkinsonism,
and akathsia. Extrapyramidal side effects
are more common with the conventional
antipsychotics than the atypical antipsychotics.16
Dystonic reactions are noted early in the
course of medication treatment and are
Page 69
characterized by intermittent spasmodic or
sustained involuntary contractions of discrete
muscle groups in the face, neck, trunk, pelvis
and extremities.31 Spasms of the neck muscles
are referred to as torticollis, and spasms of
the eye muscles are referred to as oculogyric
crisis. Spasms may be accompanied by
tongue protrusion, dysphagia and laryngeal
or pharyngeal spasms that can obstruct the
airway and require emergency medical
intervention. Dystonic reactions are treated
with diphenhydramine (Benadryl) either I.M.
or intravenously or with I.M. benztropine
(Cogentin).16
Pseudo-parkinsonism is neuroleptic
medication-induced parkinsonism. The
patient exhibits a shuffling gait, drooling,
muscle stiffness and akinesia (slowness and
trouble initiating movement). This side effect
is generally noticed within the first few days
after beginning an antipsychotic medication
or after increasing the dose. Pseudoparkinsonism is treated with a variety of
medications such as benzropine (Cogentin),
diazepam (Valium), propranolol (Inderal) and
amantadine (Symmetrel).16
Akathisia is characterized by a feeling of
motor restlessness, including inability to
remain seated and quivering muscles.32
Akathisia usually appears when an
antipsychotic medication is initiated or when
the dose is increased. The most effective
treatment for akathisia is administration of
beta-blockers, although benzodiazepines have
also been found to be helpful.16
Tardive dyskinesia
More common with conventional antipsychotics,
tardive dyskinesia is a late-appearing side effect.16
It is characterized by involuntary movements
of the tongue, lips, face, trunk and extremities.
These movements include lip smacking,
protrusion of the tongue, chewing, blinking and
grimacing. These effects are embarrassing for the
patient and for persons observing them.16,33
blood pressure, stupor, muscular rigidity,
increased muscle enzymes and leukocytosis.16,34
This syndrome usually develops within the first
two weeks of treatment, but can develop at any
time during treatment.34 An estimated 0.1 percent
to 1 percent of all patients taking antipsychotics
develop NMS.16
severe cardiovascular disease, arrhythmias,
hepatic impairment, leukopenia, respiratory
disorders, hypoglycemia or glaucoma.4,35,36
Agranulocytosis
Chlorpromazine is extensively metabolized
through the liver, and is both an inhibitor and
substrate of CYP 2D6. There are many drug
interactions between chlorpromazine and other
medications, and they include:4,35,36
Amiodarone, anti-arrhythmics,
medications that alter electrolyte
levels, and those that may cause QT
prolongation: Chlorpromazine should be
avoided in patients on these medications due
to risk of QT prolongation.
CYP2D6 inhibitors or inducers: May alter
hepatic metabolism of chlorpromazine.
Lithium: Concurrent use may increase
neurologic side effects and requires close
monitoring.
Antacids: May interfere with absorption.
Administration should be separated by at
least two hours.
Anticonvulsants: May lower seizure
threshold. Monitor closely.
CNS depressants, including alcohol: May
increase CNS depression. Concurrent use
should be discouraged.
Oral anticoagulants: May decrease
anticoagulant effect. Monitor closely.
Centrally acting anti-hypertensives: May
interfere with anti-hypertensive effects.
Monitor closely.
St. John’s wort: May cause photosensitivity.
Avoid excessive sunlight exposure.
Agranulocytosis, failure of the bone marrow
to produce adequate white blood cells, is
a hematologic disorder characterized by
spontaneous gum bleeding and other systemic
hemorrhages.16,30 Agranulocytosis develops
abruptly and causes progressive fatigue
and weakness, followed by fever, chills and
leukopenia. The patient develops an ulcerative
sore throat that upon inspection reveals oral
lesions that are usually rough edged with a gray
or black membrane.30
Clozapine (Clozaril) is the antipsychotic that
has the potential to cause agranulocytosis, a
potentially fatal side effect. Agranulocytosis does
not usually appear immediately, but can develop
as long as 18 to 24 weeks after the initiation
of drug therapy. Patients must have their white
blood cell counts monitored every week for the
first six months of clozapine therapy and every
two weeks thereafter.16
Atypical antipsychotics are less likely to
cause extrapyramidal side effects and tardive
dyskinesia, but they are more likely to cause
metabolic issues, such as weight gain, increased
blood sugar levels, and increased lipid levels.
Blood sugar, weight and lipid levels should be
monitored carefully in patients taking atypical
antipsychotics.36
Drug alert! Many antipsychotic medications
can cause false-positive results for many urinary
results, such as amylase and urobilinogen.4
Drug alert! Many antipsychotic medications
should be used with caution in persons exposed
to extremes in temperature.4
Drug alert! Unfortunately, tardive dyskinesia
is irreversible once it begins, but decreasing the
dose or discontinuing the medication can stop the
progression. However, clozapine (Clozaril) an
atypical antipsychotic, has not produced this side
effect and may be a good alternative for patients
who experience tardive dyskinesia while taking
conventional antipsychotic drugs.16
Practice question
Seizures
Answer: D – Akathisia is the extrapyramidal
side effect characterized by feelings of motor
restlessness.
Seizures, although they occur, are not a
frequently seen side effect of antipsychotics.
They occur in only 1 percent of patients who
take antipsychotic medications. However, it is
important to note that clozapine (Clozaril) has an
incidence of 5 percent for seizure occurrence. If
seizures do occur, dosage should be lowered or
the medication causing this side effect changed.16
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome (NMS) is
a life-threatening neurological disorder. It is
characterized by high fever, sweating, unstable
Which of the following terms describes the
extrapyramidal side effect characterized by
feelings of motor restlessness?
a. Torticollis.
b. Dysphagia.
c. Akinesia.
d. Akathisia.
Specific additional points of interest for
antipsychotics
Chlorpromazine (Thorazine)
Chlorpromazine is used in doses of 200-800 mg.
per day divided into 3-4 doses per day depending
on severity of psychosis. It is contraindicated
in patients with CNS depression, bone marrow
suppression, Parkinson’s disease or subcortical
damage. The drug must be administered
cautiously in patients who are elderly or have
Drug alert! Patients taking chlorpromazine are
particularly vulnerable to extrapyramidal side
effects, a sudden drop in blood pressure, and to
orthostatic hypotension.4,36
Drug alert! Chlorpromazine use may cause
photosensitivity. Advise patients to avoid
excessive sunlight exposure and to wear
sunblock.4
Chlorpromazine may decrease hemoglobin and
hematocrit. The drug may increase liver function
test values and eosinophil count and decrease
granulocyte, platelet, and white blood cell
counts.4
Perphenazine (Trilafon)
Perphenazine is used in doses of 8-16 mg. given
2-4 times daily. It is contraindicated in patients
with CNS depression, blood dyscrasias, bone
marrow depression, hepatic damage, subcortical
damage, dementia patients, and in patients
receiving large doses of CNS depressants.4,35
It should be used cautiously in patients who
are elderly, debilitated, taking other types of
CNS depressants or anti-cholinergics, or are
going through alcohol withdrawal, psychotic
depression or suicidal ideation. Perphenazine
should also be used with caution in patients who
have cardiovascular disease, renal disease or
respiratory disorders.4,35,36
Drug interactions include:4,35,36
Amiodarone, anti-arrhythmics,
medications that alter electrolyte
Page 70
Elite
levels, and those that may cause QT
prolongation: Perphenazine should be
avoided in patients on these medications
because of the risk of QT prolongation.
CNS depressants, including alcohol: CNS
depression may increase. Use concurrently
only with caution.
Antacids: May interfere with perphenazine
absorption. Separate administration by at
least two hours.
Barbiturates: May decrease perphenazine
effectiveness. Monitor patient closely.
Fluoxetine, sertraline, tricyclic
antidepressants: May increase phenothiazine
level. Monitor closely.
Lithium: May increase adverse neurologic
side effects. Patients must be monitored
carefully.
St. John’s wort: May cause photosensitivity.
Avoid excessive sunlight exposure.
Drug alert! Advise patients to avoid excessive
sun exposure and to wear sunblock.4
Perphenazine may decrease hemoglobin and
hematocrit and increase liver function test
values and eosinophil count. White blood cell
counts, granulocyte and platelet counts may be
reduced.4,35
Fluphenazine (Prolixin)
Fluphenazine is used in doses of 2.5-10 mg.
per day divided into 3-4 doses per day. It is
contraindicated in patients with CNS depression,
bone marrow suppression or other types of blood
dyscrasias, subcortical damage, dementia or
hepatic damage. As with other antipsychotics,
fluphenazine should be used with caution in
elderly or debilitated patients. It should also
be used with caution in patients with severe
cardiovascular disease because the drug
may cause an abrupt drop in blood pressure,
and in those with peptic ulcer, respiratory
disorders, hypocalcemia, seizure disorder,
mitral insufficiency, glaucoma or prostatic
hyperplasia.4,35,36
Drug interactions are similar to other
conventional antipsychotics and include:4,35
Amiodarone, anti-arrhythmics,
medications that alter electrolyte
levels, and those that may cause QT
prolongation: Fluphenazine should be
avoided in patients on these medications
because of the risk of QT prolongation.
Antacids: May interfere with drug
absorption. Separate administration of
antacids and fluphenazine by at least two
hours.
Anti-cholinergics: May increase anticholinergic effects and should be used
together with caution.
Barbiturates and lithium: May decrease
drug’s effectiveness and increase the potential
for anti-cholinergic effects. These drugs
should be used with fluphenazine with
caution.
Centrally acting hypertensives: Antihypertensive effects may be decreased. Blood
pressure must be carefully monitored.
CNS depressants, including alcohol: CNS
depression may increase, especially affecting
psychomotor skills. Alcohol use should be
discouraged. If other drugs that are CNS
depressants must be prescribed, the patient
must be carefully monitored.
CYP2D6 inhibitors or inducers: May alter
hepatic metabolism of fluphenazine.
St. John’s wort: Increases the potential for
photosensitivity. The patient should avoid
excessive exposure to the sun and wear sun
block.
As with some other antipsychotics, the risk for
photosensitivity is increased with use of this
drug. Encourage patients to avoid excessive
exposure to sunlight and to wear sun block.4
Fluphenazine may increase liver function
test results and eosinophil count. It may
decrease hemoglobin and hematocrit as well
as granulocyte, platelet, and white blood cell
counts.4
Thioridazine (Mellaril)
Thioridazine (Mellaril) is indicated in patients
who fail to respond to at least two other
antipsychotic drugs.4 It is used in doses of 200800 mg. per day divided into 2-3 doses per day. It
is contraindicated in patients with:4,35
CNS depression or coma.
Severe hypertension or hypotension.
Cardiac disease.
Reduced levels of CYP2D6 enzyme.
Long QT interval or history of arrhythmias.
Thioridazine is also contraindicated in patients
who are taking fluvoxamine, propranolol,
pindolol, fluoxetine, and drugs that inhibit
CYP2D6 enzyme or that prolong the QT interval.
It should be used with caution in elderly or
debilitated patients.4
Drug interactions are similar to other
conventional antipsychotics and include:4,35
Amiodarone, anti-arrhythmics,
medications that alter electrolyte
levels, and those that may cause QT
prolongation: Thioridazine should be
avoided in patients on these medications
because of the risk of QT prolongation.
Antacids: May interfere with drug
absorption. Separate administration of
antacids and thioridazine by at least two
hours.
Anticholinergics: May increase anticholinergic effects and should be used
together with caution.
Barbiturates and lithium: May decrease
drug’s effectiveness and increase the
potential for anti-cholinergic effects. These
drugs should be used with thiroidazine with
caution.
CNS depressants, including alcohol: CNS
depression can increase. Monitor carefully or
avoid use.
St. John’s wort: Increases the potential for
photosensitivity. The patient should avoid
excessive exposure to the sun and wear sun
block.
Elite
CYP2D6 substrates, inhibitors or inducers
and 3A4 inhibitors or inducers: May alter
hepatic metabolism of haloperidol.
Thiothixene (Navane)
Thiothixene is used in doses of 2-5 mg. 2-3
times daily. It is contraindicated in patients who
are experiencing CNS depression, circulatory
collapse, coma or blood dyscrasias. Thiothixene
should be used with caution in patients who are
elderly or debilitated, have a history of seizure
disorders, cardiovascular disease, hepatic disease,
glaucoma, prostatic hyperplasia, heat exposure,
and in those who are dealing with withdrawal
from alcohol.4,35
Drug alert! Thiothixene is not recommended for
use in children less than 12 years of age.4
There are relatively few drug or environmental
interactions compared to some other
antipsychotics. These include:4,36
CNS depressants, including alcohol:
Danger of increased CNS depression.
Discourage concurrent use.
Anti-hypertensives: Can increase the risk of
hypotension.
Sun exposure: May increase photosensitivity
reactions. Advise patients to avoid excessive
exposure to sunlight and to wear sun block.
Thiothixene may increase or decrease white
blood cell counts and decrease granulocyte
counts.4
Haloperidol (Haldol)
Haloperidol is used in doses of 0.5-5 mg. 2-3
times daily. It is contraindicated in patients with
CNS depression, coma and those who have
parkinsonism. It should be used with caution
in patients who are elderly, have a history
of seizures or EEG abnormalities, dementia,
allergies, significant cardiovascular disorders,
glaucoma or history of urine retention. The drug
should also be used with caution in patients who
are taking anticonvulsants, anticoagulants, antiparkinsonians or lithium.4
Drug interactions associated with haloperidol
include:4,35
CYP2D6 substrates, inhibitors or inducers
and 3A4 inhibitors or inducers: May alter
hepatic metabolism of haloperidol.
Amiodarone, anti-arrhythmics,
medications that alter electrolyte levels,
and those that may cause QT prolongation:
Haloperidol should be avoided in patients on
these medications because of the risk of QT
prolongation.
Anti-cholinergics: May increase anticholinergic effects and glaucoma. Concurrent
use should be avoided.
Antifungals, buspirone: May increase the
haloperidol levels.
Carbamazepine: May decrease haloperidol
level.
CNS depressants, including alcohol: May
increase CNS depression, and concurrent use
should be avoided.
Lithium: May lead to lethargy and
confusion.
Page 71
Methyldopa: May lead to dementia.
Rifampin: May decrease haloperidol level.
There are relatively few effects on lab tests.
Haloperidol may increase liver function test
results and increase or decrease white blood cell
counts.4
Trifluoperazine (Stelazine)
Trifluoperazine is used in doses of 1-5 mg. twice
daily. It is contraindicated in patients with CNS
depression, coma, bone marrow suppression
or hepatic damage. It should be used with
caution in persons who are elderly or those who
have dementia, cardiovascular disease, seizure
disorder, glaucoma or prostatic hyperplasia.4,35
Drug alert! Trifluoperazine should be used in
children only if they are hospitalized or under
extremely close supervision.4
Drug interactions include:4,35
Amiodarone, anti-arrhythmics,
medications that alter electrolyte
levels, and those that may cause QT
prolongation: Trifluoperazine should be
avoided in patients on these medications
because of the risk of QT prolongation.
Antacids: May interfere with trifluoperazine
absorption. Doses of these medications
should be separated by at least two hours.
Barbiturates and lithium: May decrease
trifluoperazine’s effectiveness.
CNS depressants, including alcohol: May
increase sedative effects. Avoid concurrent
use.
Centrally acting anti-hypertensives:
May interfere with the effectiveness of
anti-hypertensives. Blood pressure must be
monitored closely.
Propranolol: May increase both propranolol
and trifluoperazine levels.
Warfarin: May decrease the effectiveness
of oral anticoagulants. PT and INR must be
carefully monitored.
St. John’s wort: May increase the risk of
photosensitivity. Avoid excessive sunlight
exposure.
Drug alert! Trifluoperazine may cause
photosensitivity even without the concurrent
use of St. John’s wort. Advise patients to avoid
excessive sunlight exposure and to wear sun
block.4
Trifluoperzine may increase liver enzyme levels
and decrease white blood cell and granulocyte
counts.4
white blood cell count below 3,500/mm3, severe
CNS depression, coma, paralytic ileus and
myelosuppressive disorders.4,35
have cardiovascular disease, cerebrovascular
disease, dehydration, hypovolemia, breastfeeding, pregnancy, or history of seizures.4,35
Drug alert! Clozapine carries a black box
warning stating that use of this drug with other
psychotropic drugs and benzodiazepines may
increase the risk of sedation and cardiac and
respiratory arrest.4
Drug interactions include:4,35
CYP2D6 inhibitors: May increase
risperidone levels and risk of toxic effects.
Anti-hypertensives: May increase
hypotensive effects. Blood pressure must be
carefully monitored.
Azole antifungals: May increase the drug’s
plasma level.
Carbamazepine: May decrease the
effectiveness of risperidone.
Clozapine: May decrease the clearance of
risperidone and increase the potential for
toxicity.
CNS depressants, including alcohol: May
increase the potential for additive CNS
depression. Discourage concurrent use.
Fluoxetine and paroxetine: May increase
the risk of adverse side effects of risperidone.
Clozapine also has the additional following
potential drug interactions:4,35
CYP1A2, 2D6 and 3A4 inhibitors or
inducers: May alter hepatic metabolism of
clozapine.
Amiodarone, anti-arrhythmics,
medications that alter electrolyte
levels, and those that may cause QT
prolongation: Clozapine should be avoided
in patients on these medications because of
the risk of QT prolongation.
Bone marrow suppressants: Has the
potential to increase bone marrow toxicity.
Concurrent use should be avoided.
Digoxin, warfarin, and other highly
protein-bound drugs: May increase these
drug levels. Patients must be monitored
closely for adverse side effects.
Ritonavir: May increase clozapine levels and
the risk of toxicity. Avoid concurrent use.
Alcohol: May increase CNS depression.
Alcohol use should be discouraged.
Phenytoin: May decrease clozapine level and
lead to “breakthrough” psychosis.
Drug alert! Smoking may decrease clozapine
level. Encourage patients to stop smoking.4
Here are additional black box warnings for
clozapine:4,35
Increases the risk of fatal myocarditis.
Orthostatic hypotension can occur, and rarely,
can be accompanied by respiratory or cardiac
arrest.
Seizures may occur, particularly in patients
receiving large doses of the drug.
The drug is not indicated for use in elderly
patients with dementia-related psychoses.
Despite the dangers of using clozapine, it is the
only antipsychotic medication listed as pregnancy
category B. The other antipsychotics, both typical
and atypical, are pregnancy category C.36
Clozapine may increase glucose, cholesterol and
triglyceride levels as well as eosinophil counts.
The drug may decrease granulocyte and white
blood cell counts.4
Clozapine (Clozaril)
Drug alert! Clozapine is dispensed every seven
to 14 days only, and is only available through
restricted pharmacies registered with the
clozapine registry. In order to obtain a refill, the
patient’s white blood cell count must be above
3,500 cells/mm.3,16
(For detailed information about agranulocytosis,
see the section of this program that describes the
side effects of antipsychotics).
Risperidone (Risperdal)
Clozapine is given to patients who are quite ill
and who do not respond to other antipsychotics.
It causes significant risk of agranulocytosis.
When it is deemed appropriate to use, it is given
in doses of 150-300 mg. twice daily.4,35,36
The drug is contraindicated in patients with
uncontrolled epilepsy, history of agranulocytosis,
Risperidone is given in doses of 1-4 mg. divided
into 1-2 doses per day. Use of risperidone is
contraindicated in elderly patients with dementia.
It should be used with caution in patients who
As with other antipsychotics, sun exposure may
increase the risk of photosensitivity. Tell patients
to avoid excessive sun exposure and to wear sun
block.4
Risperidone may increase prolactin level and
blood glucose and decrease hemoglobin and
hematocrit.4,36
Olanzapine (Zyprexa)
Olanzapine is given to patients in doses of 2.5-20
mg. daily. It contains a black box warning stating
that sedation and delirium have been noted
following injections of this drug. Another black
box warning states that olanzapine may increase
the risk of cardiovascular or infectious deaths in
elderly patients with dementia.4,35
Drug interactions include:4,35
CYP1A2, 2D6 and 2C19 inhibitors or
inducers: May alter hepatic metabolism of
olanzapine.
Potassium salts: Using solid dosage forms of
potassium with risperidone is contraindicated.
This is because of the risk of slowing
potassium passage through the GI, increasing
ulcer risk.
Anti-hypertensives: May increase antihypertensive effects. Monitor blood pressure
closely.
Carbamazepine, omeprazole, rifampin:
May increase olanzapine clearance. Monitor
drug levels closely.
Ciprofloxacin: May increase olanzapine
level and increase the risk of adverse side
effects.
Diazepam: May increase CNS effects.
Levodopa: May cause antagonistic effects.
Monitor patient closely.
Fluoxetine: May increase olanzapine level.
Fluvoxamine: May increase olanzapine
level.
Alcohol: May increase sedative effects.
Avoid concurrent use.
St. John’s wort: May decrease olanzapine
level.
Page 72
Elite
Drug alert! Smoking may increase olanzapine
clearance. Discourage smoking.4
Olanzapine may increase the following lab test
results:4,35
AST.
ALT.
GGT.
CK.
White blood cell count.
Triglyceride levels.
Eosinophil count.
Blood glucose.
Quetiapine (Seroquel)
Quetiapine is given in doses of 150-750 mg. per
day divided into 2-3 doses per day. Its immediate
release form is not approved for use in children
less than 10 years of age. The extended release
form is not approved for use in children younger
than 18 years of age.4,36
The drug contains a black box warning that
it may increase suicidal ideation in children,
adolescents and young adults ages 18 to24.4
Drug interactions include:4,35
CYP3A4 inhibitors or inducers: May alter
hepatic metabolism of quetiapine.
Anti-hypertensives: May increase antihypertensive effects.
Conventional antipsychotics: Caution
advised because of the risk of QT
prolongation.
Amiodarone, anti-arrhythmics,
medications that alter electrolyte
levels, and those that may cause QT
prolongation: Quetiapine should be avoided
in patients on these medications because of
the risk of QT prolongation.
CNS depressants, including alcohol: CNS
effects may be increased. Avoid concurrent
use.
Lorazepam: May decrease lorazepam
clearance and lead to increased CNS effects.
Quetiapine may increase liver enzymes,
cholesterol and glucose levels. It may decrease
white blood cell count, thyroid-stimulating
hormone levels and T4.4,35
Ziprasidone (Geodon)
Ziprasidone is given in doses of 20-80 mg. twice
daily. It is contraindicated in elderly patients with
dementia-related psychosis, persons with a recent
myocardial infarction or uncompensated heart
failure, hypokalemia or hypomagnesemia, history
of arrhythmia, prolonged QT interval or taking
other drugs that prolong the QT interval.4,35,36
Drug interactions include:4,35
CYP3A4 inhibitors or inducers: May alter
hepatic metabolism of ziprasidone.
Anti-arrhythmics or drugs that increase
the QT interval: May increase the risk of
life-threatening arrhythmias. Concurrent use
is contraindicated.
Carbamazepine: May decrease ziprasidone
level.
Drugs that decrease potassium or
magnesium: May increase the risk of
arrhythmias. If used concurrently, it is
important to monitor the levels of these
electrolytes.
Anti-hypertensives: May increase risk
of hypotension. Monitor blood pressure
carefully if used concurrently.
CNS depressants, including alcohol: CNS
effects may be increased.
Ziprasidone can increase blood glucose levels.
Monitor blood sugar carefully.36
Paliperidone (Invega)
Paliperidone is used in doses of 6-12 mg.
once daily. It is contraindicated in those with
dementia-related psychosis, history of cardiac
arrhythmias, congenital long QT syndrome, and
in those with gastrointestinal narrowing. It should
be used with caution in persons with a history of
diabetes or seizures, cardiovascular disease and
cerebrovascular disease.4,35,36
Drug interactions include:4,35
Anti-cholinergics: May increase adverse
side effects.
Anti-hypertensives: May exacerbate
orthostatic hypotension. Avoid concurrent
use.
Drugs that prolong QT interval: May
increase this prolongation. Avoid concurrent
use.
Levodopa: May have antagonistic effects on
each other. Use concurrently with caution.
Alcohol and CNS depressants: May
increase CNS sedation.
Paliperidone may increase insulin, blood glucose
and prolactin levels.4,36
Aripiprazole (Abilify)
Aripiprazole (Abilify) has black box warnings
noting that it is not approved for use in children
with depression or in elderly persons with
dementia-related psychosis. It should be used
with caution in pregnant and lactating women
and in patients with cardiovascular disease,
cerebrovascular disease, a history of seizures,
and in persons who exercise strenuously, take
anti-cholinergics, or who are likely to suffer from
dehydration.4,35,36
Aripiprazole is associated with the following
drug interactions:4,35,36
Anti-hypertensives: May increase antihypertensive effects.
Carbamazepine: May decrease effectiveness
of aripiprazole. Dose may need to be doubled
and patient monitored carefully.
CYP2D6 or 3A4 inhibitors: Increases the
risk of significant toxic effects. The dose of
aripiprazole is often decreased by half when
used with these agents.
Alcohol and CNS depressants: Increases
CNS side effects.
Drug alert! Grapefruit juice may increase the
drug level. Instruct patients not to take the drug
with grapefruit juice.4
Aripiprazole may increase glucose and CK
levels.4
Elite
Counseling points for antipsychotics36
Discuss the common side effects, such as
extrapyramidal side effects, weight gain and
glucose dysregulation.
Highlight more rare side effects and drug
interactions, such as arrhythmias and
interactions with anti-hypertensives and CNS
depressants.
Remind patients that it is important to have a
conversation with their doctor or pharmacist
when adding or stopping medications while
on antipsychotics because of potential
adverse reactions.
Blood monitoring of glucose levels may
be necessary when taking antipsychotic
medications.
Practice question
Elvis Presley has schizophrenia, and was recently
diagnosed with an arrhythmia. His doctor
prescribed him amiodarone, which has worked
well for him. Now that his arrhythmia is stable
on amiodarone, his doctor wants to start him
back on an antipsychotic medication to control
his schizophrenia. Which of the following
medications does not interact with amiodarone?
a. Risperidone.
b. Ziprasidone.
c. Clozapine.
d. Chlorpromazine.
Answer: A – Risperidone is the only medication
listed that does not have a known drug interaction
with amiodarone. When starting a patient with
an arrhythmia on new medication, it is always
important to monitor their condition.
Herbal supplement: Betal palm
Betal palm is a palm found in the tropics of
Africa, in China, India and the Philippines.
The leaves and nuts of the palm are used
for medicinal purposes. Its reported uses by
herbalists include the treatment of depression,
schizophrenia and respiratory conditions. It
should not be used during pregnancy or breastfeeding and should not be given to children.
Patients with oral or esophageal cancers, ulcers,
esophagitis or renal disease should not use betal
palm.19
Betal palm may cause palpitations, dizziness,
seizures, anxiety, insomnia, restlessness and acute
psychosis as adverse side effects.18,19
Betal palm should not be used with the following
drugs:19
Anti-glaucoma drugs.
Beta-blockers.
Calcium channel blockers.
Cardiac glycosides.
Cholinergic drugs.
Neuroleptics.
MAOIs and foods that contain tyramine used in
conjunction with betal palm may increase the risk
of hypertensive crisis.19
To date, there are no known interactions with
other herbs or impact on lab tests.19
Page 73
References
1.Centers Diseases Control and Prevention (CDC). (2011). CDC report: Mental illness
surveillance among adults in the United States. Retrieved December 30, 2011 from
www.cdc.gov/mental1healthsurveillance/fact_sheet.html.
2.Health Communities. (2011). Depression incidence and prevalence. Retrieved
December 31, 2011 from www.healthcommunities.com/depression/incidenceprevalence.shtml.
3.Health Communities. (2011). Depression medications. Retrieved December 15, 2011
from www.healthcommunities.com/depression/antidepressant.shtml.
4.Comerford, K. C. (2012). Nursing 2012 drug handbook. Philadelphia: Wolters Kluwer/
Lippincott Williams & Wilkins.
5.Mayo Clinic. (2010). Selective serotonin reuptake inhibitors (SSRIs). Retrieved
December 31, 2011 from www.mayoclinic.com/health/ssris/MH00066/
METHOD=print.
6.Tonkonogy, J., et. al. 2011). Neuroleptic malignant syndrome. Retrieved January 3,
2011 from http://emedicine.medscape.com/article/288482-overview.
7.Mayo Clinic. (2010). Tricyclic antidepressants and tetracyclic antidepressants.
Retrieved December 31, 2011 from www.mayoclinic.com/health/antidepressants/
MH00071/METHOD=print.
8.Mayo Clinic. (2010). Monoamine oxidase inhibitors (MAOIs). Retrieved December 31,
2011 from www.mayoclinic.com/health/maois/MH00072/METHOD=print.
9.Drugs.com. (2011). Low tyramine diet. Retrieved January 4, 2012 from http://www.
drugs.com/cg/low-tyramine-diet.html.
10. Mayo Clinic. (2010). Atypical antidepressants. Retrieved December 31, 2011 from
www.mayoclinic.com/health/Atypical-antidepressants/MY01561/METHOD=print.
11. National Institute of Mental Health. (2011). Nefazodone. Retrieved January 5, 2012
from www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000956/?report=printable.
12. Harvard Medical School. (2011). Antidepressants and tamoxifen. Retrieved
December 31, 2011 from http://www.health.harvard.edu/newsletters/Harvard_Mental_
Health_Letter/2010/June/antidepressants-and-tamoxifen.
13. Mayo Clinic. (2010). Serotonin and norepinephrine reuptake inhibitors (SNRIs).
Retrieved January 7, 2012 from www.mayoclinic.com/health/antidepressants/
MH00067/METHOD=print.
14. Health Communities. (2011). Anxiety disorders: overview and symptoms. Retrieved
December 30, 2011 from www.healthcommunities.com/anxiety/anxiety-disorderssymptoms.
15. Health Communities. (2011). General anxiety disorder (GAD) overview. Retrieved
December 30, 2011 from http://www.healthcommunities.com/anxiety/overview-ofgeneral-anxiety-disorder-gad.shtml
16. Videbeck, S. L. (2011). Psychiatric-mental health nursing (5th ed.). Philadelphia:
Wolters Kluwer Health/Lippincott Williams & Wilkins.
17. Health Communities. (2011). Treatment for generalized anxiety disorder (GAD).
Retrieved December 30, 2011 from www.healthcommunities.com/anxiety/treatment.
shtml.
18. Webb, S. (Ed.). (2006). Nursing herbal medicine handbook (3rd ed.). Philadelphia:
Lippincott Williams & Wilkins.
19. Skidmoer-Roth, L. (2006). Mosby’s handbook of herbs & natural supplements (3rd
ed.). St. Louis: Elsevier Mosby.
20. National Institute of Mental Health. (2012). What medications are used to treat
anxiety disorders? Retrieved January 8, 2012 from http://www.nimh.nih.gov/health/
publications/mental-health-medications/what-medications-are-used-to-treat-anxiety
http://www.nimh.nih.gov/health/publications/mental-health-medications/whatmedications-are-used-to-treat-anxiety-disorders.shtml.
21. Health Communities. (2011). Alcohol abuse overview. Retrieved January 7, 2012
from www.healthcommunities.com/alcohol-abuse/index.shtml.
22. National Institute of Mental Health. (2009). Co-occurrence of depression with
other illnesses. Retrieved January 10, 2012 from http://www.nimh.nih.gov/health/
publications/men-and-depression/co-occurrence-of-depression-with-other-illnesses.
shtml
23. National Center for Biotechnology. (2010). Wernicke-Korsakoff syndrome. Retrieved
January 10, 2012 from www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001776/
24. Health Communities. (2011). Overview of bipolar disorder. Retrieved January 6,
2012 from www.healthcommunities.com/bipolar-disorder/index.shtml.
25. Health Communities. (2011). Bipolar disorder types and treatments. Retrieved
January 6, 2012 from http://www.healthcommunities.com/bipolar-disorder/bipolartypes-and-treatments_jhmwp.shtml.
26. National Institute of Mental Health. (2011). How is bipolar disorder treated?
Retrieved January 6, 2012 from http://www.nimh.nih.gov/health/publications/bipolardisorder/how-is-bipolar-disorder-treated.shtml.
27. Cipriani, A., & Geddes, J. R. (2008). Antidepressants for bipolar disorder.
Psychiatric Times, 25 (7), retrieved online on January 14, 2012 from www.
psychiatrictimes.com/bipolar-disorder/content/article/10168/1162960.
28. Health Communities. (2011). Schizophrenia overview. Retrieved January 6, 2011
from www.healthcommunities.com/schizophrenia/schizophrenia-overview.shtml.
29. National Institute of Mental Health. (2012). How is schizophrenia treated? Retrieved
January 6, 2012 from www.nimh.nih.gov/health/publications/schizophrenia/how-isschizophrenia-treated.shtml.
30. Robinson, J. M. (Clinical Director). Professional guide to signs & symptoms (6th ed.).
Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.
31. Medscape. (2010). Toxicity, medication-induced dystonic reactions. Retrieved
January 14, 2012 from http://emedicine.medscape.com/article/814632-overview.
32. Web MD. (2006). Akathisia. Retrieved January 15, 2012 from http://dictionary.
webmd.com/terms/akathisia.
33. Brasic, J. R. (2010). Tardive dyskinesia. Retrieved January 15, 2012 from http://
emedicine.medscape.com/article/1151826-overview.
34. National Institute of Neurological Disorders and Stroke. (2007). NINDS neuroleptic
malignant syndrome information page. Retrieved January 15, 2012 from http://www.
ninds.nih.gov/disorders/neuroleptic_syndrome/neuroleptic_syndrome.htm.
35. Skidmore-Roth, L. (2012). Mosby’s 2012 nursing drug reference. St. Louis: Mosby.
36. Brunton LB, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological
Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2010.
PHARMACOLOGY: mENTAL hEALTH
mEDICATIONS
Final Examination Questions
Choose the best answer for questions
36 through 45, mark your answer on the final
examination answer sheet found on page 75
or complete your final examination online at
pharmacy.elitecme.com.
36. Jackie Robinson has been diagnosed with
depression, and he has been suicidal for
the past few weeks after losing several
baseball games in a row. Which of the
following antidepressants would be the
most dangerous to dispense to Jackie in a
one-month supply?
a. Sertraline.
b. Nortriptyline.
c. Duloxetine.
d. St. John’s Wort.
37. Which of the following medications is
considered a short-acting benzodiazepine?
a. Alprazolam.
b. Diazepam.
c. Chlordiazepoxide.
d. Clonazepam.
38. Martha Washington is pregnant and has
anxiety. Which of the following antianxiety
medications would be safest for her to take
while pregnant?
a. Alprazolam.
b. Buspirone.
c. Clonazepam.
d. Sertraline.
39. Mr. Rogers is taking many medications
for his heart failure, heart arrhythmia
and diabetes. He is seeking treatment for
alcoholism, and wants to take something
to prevent relapse. Which of the following
medications would be safest for Mr. Rogers
to take with his other medications?
a. Disulfiram.
b. Acamprosate.
c. Naltrexone.
d. Lorazepam.
41.Which of the following medications is an
inducer of the 1A2, 2B6, 2C9 and 3A4
enzyme systems?
a. Valproic acid.
b. Lamotrigine.
c. Lithium.
d. Carbamazepine.
42.Which of the following atypical
antipsychotic medications is considered
a partial agonist of the postsynaptic
dopamine and serotonin receptors? a. Quetiapine.
b. Ziprasidone.
c. Aripiprazole.
d. Olanzapine.
43.Which of the following antipsychotic
medications is likely to cause
extrapyramidal side effects?
a. Quetiapine
b. Chlorpromazine
c. Olanzapine
d. Paliperidone
44.Why must patients taking clozapine be
registered with the clozapine registry?
a. Because of the risk of QT prolongation
and arrhythmia when taking clozapine.
b. Because of the risk of serious drug
interactions when taking clozapine.
c. Because of the risk of agranulocytosis
when taking clozapine.
d. Because of the risk of potential abuse
of clozapine.
45.Which of the following medications should
be avoided in patients with a prolonged QT
interval?
a. Ziprasidone.
b. Clozapine.
c. Quetiapine.
d. All of the above.
40. Genevive has bipolar disorder and
has recently been diagnosed with
hypothyroidism. Which of the following
medications has the most negative effects
on thyroid hormone levels?
a. Lamotrigine.
b. Carbamazepine.
c. Lithium.
d. Valproic acid.
RPCO07UPE13
Page 74
Elite