March 2022

Focus on: Pain Management

Opting for Vitamins

& Minerals in
Pain Management
Anticipating
the First RA
Biosimilar
2 CE Credits
Managing
Chronic,
Noncancer Pain
With Opioids

Health Systems
Edition
Pharmacogenomic Considerations
in Opioid Therapy
Controlling Acute Pain
in Opioid Use Disorder
 TOO YOUNG
TO VACCINATE?
NOT AT
THIS AGE.
0+
ARS
Indication
SHINGRIX is a vaccine indicated for prevention
X Gray (10K)
of herpes zoster (shingles) in adults aged
50 years and older.
SHINGRIX is not indicated for prevention of
primary varicella infection (chickenpox).
Important Safety Information
• SHINGRIX is contraindicated in anyone with
a history of a severe allergic reaction (eg,
anaphylaxis) to any component of the vaccine
or after a previous dose of SHINGRIX
• Review immunization history for possible
vaccine sensitivity and previous vaccination-
related adverse reactions. Appropriate
medical treatment and supervision must be
available to manage possible anaphylactic
reactions following administration of
SHINGRIX
50+
YEARS
• In a postmarketing observational study, an
increased risk of Guillain-Barré syndrome
was observed during the 42 days following
vaccination with SHINGRIX
K.O. (TURN OFF
• Syncope (fainting) can be associated with the
administration of injectable vaccines, including
SHINGRIX. Procedures should be in place to
BACKGROUND
avoid falling injury and to restore cerebral
perfusion following syncope
• Solicited local adverse reactions reported in
LAYER WHEN
individuals aged 50 years and older were pain
(78%), redness (38%), and swelling (26%)
• Solicited general adverse reactions reported in
USING)
individuals aged 50 years and older were myalgia
(45%), fatigue (45%), headache (38%), shivering
(27%), fever (21%), and gastrointestinal
symptoms (17%)
 AS AGE INCREASES, SO DOES THE RISK OF SHINGLES1-3
The age-related decline in immunity is a real threat for your patients aged 50+ years.1-3
No matter how healthy they may look or feel, they’re at risk for shingles.1,4-7

AGE IMMUNITY SHINGLES

Increasing age As immune function declines, Age-related decline in

causes a natural
decline in immunity.1
there is a reduction in the immunity leads to a sharp
number and functionality of increase in the incidence
immune cells that prevent and complications of
reactivation of VZV.1-3,7-9 shingles.1,2 By age 85, the
lifetime risk of shingles
VZV=varicella zoster virus. rises from 1:3 to 1:2.1,10

NEARLY EVERYONE ≥50 YEARS OF AGE IS

AT RISK FOR SHINGLES1,11,12
99.5% of people ≥50 years old are infected with the
varicella zoster virus.11 In 1 out of 3 people, the dormant
virus reactivates and causes shingles—a blistering rash
that can be excruciatingly painful.1,12

WHAT CAN YOU DO ABOUT SHINGLES? VACCINATE.

Talk to your appropriate patients about SHINGRIX, the vaccine proven to help prevent
shingles in patients 50 years of age and older.13

Get resources to help your staff and patients at talkShingles.com

Important Safety Information (cont’d)
• The data are insufficient to establish if there
is vaccine-associated risk with SHINGRIX in
pregnant women
• It is not known whether SHINGRIX is excreted
in human milk. Data are not available to assess
the effects of SHINGRIX on the breastfed infant
or on milk production/excretion
• Vaccination with SHINGRIX may not result
in protection of all vaccine recipients
Please see Brief Summary of
Prescribing Information for SHINGRIX
on the following pages.
References: 1. CDC. MMWR. 2008;57(RR-5):1-30. 2. Kimberlin DW,
Whitley RJ. N Engl J Med. 2007;356(13):1338-1343. 3. Levin MJ. Curr
Opin lmmunol. 2012;24(4):494-500. 4. Mahalingam R, et al. N Engl J
Med. 1990;323(10):627-631. 5. Lungu O, et al. Proc Natl Acad Sci USA.
1995;92(24):10980-10984. 6. Furuta Y, et al. J Infect Dis. 1992;166(5):1157-
1159. 7. Weinberg A, et al. J Infect Dis. 2010;201 (7):1024-1030. 8. Chlibek R,
et al. Vaccine. 2014;32(15):1745-1753. 9. Patterson-Bartlett J, et al. Vaccine.
2007;25(41):7087-7093. 10. Schmader K. Clin Infect Dis. 2001;32:1481-1486.
11. Kilgore PE, et al. J Med Virol. 2003;70(suppl 1):S111-S118. 12. Kawai K,
et al. BMJ Open. 2014;4(6):e004833. doi:10.1136/bmjopen-2014-004833.
13. Prescribing Information for SHINGRIX.

Trademarks owned or licensed by GSK.

©2021 GSK or licensor.

SGXJRNA210080 September 2021
Produced in USA.
 BRIEF SUMMARY documented dose). Across both studies, the percentages of subjects
aged 50 years and older reporting each solicited local and general
SHINGRIX (Zoster Vaccine Recombinant, Adjuvanted) adverse reaction following administration of SHINGRIX (both doses
combined) were pain (78%), redness (38%), and swelling (26%); and
The following is a brief summary only; see full prescribing myalgia (45%), fatigue (45%), headache (38%), shivering (27%), fever
information for complete product information. (21%), and gastrointestinal symptoms (17%).
1 INDICATIONS AND USAGE
The reported frequencies of specific solicited local adverse reactions
SHINGRIX is a vaccine indicated for prevention of herpes zoster (HZ) and general adverse reactions (overall per subject), by age group,
(shingles) in adults aged 50 years and older. from the 2 studies are presented in Table 1.
Limitations of Use: Table 1. Percentage of Subjects with Solicited Local and
• SHINGRIX is not indicated for prevention of primary varicella General Adverse Reactions within 7 Daysa of Vaccination in
infection (chickenpox). Adults Aged 50 to 59 Years, 60 to 69 Years, and 70 Years and
Olderb (Total Vaccinated Cohort with 7-Day Diary Card)
2 DOSAGE AND ADMINISTRATION
2.2 Administration Instructions Aged 50-59 Aged 60-69 Aged ≥70
Adverse Years Years Years
For intramuscular injection only. Reactions
SHINGRIX Placeboc SHINGRIX Placeboc SHINGRIX Placebo c
After reconstitution, administer SHINGRIX immediately or store Local
refrigerated between 2° and 8°C (36° and 46°F) and use within n =1,315 n =1,312 n = 1,311 n =1,305 n = 2,258 n = 2,263
Adverse
6 hours. Discard reconstituted vaccine if not used within 6 hours. Reactions % % % % % %
2.3 Dose and Schedule Pain 88 14 83 11 69 9
Two doses (0.5 mL each) administered intramuscularly according Pain,
to the following schedule: 10 1 7 1 4 0.2
Grade 3 d
• A first dose at Month 0 followed by a second dose administered Redness 39 1 38 2 38 1
2 to 6 months later. Redness, 3 0 3 0 3 0
4 CONTRAINDICATIONS >100 mm
Do not administer SHINGRIX to anyone with a history of a severe Swelling 31 1 27 1 23 1
allergic reaction (e.g., anaphylaxis) to any component of the vaccine Swelling,
or after a previous dose of SHINGRIX [see Description (11) of full 1 0 1 0 1 0
>100 mm
prescribing information]. General n = 1,315 n = 1,312 n =1,309 n = 1,305 n = 2,252 n = 2,264
5 WARNINGS AND PRECAUTIONS Adverse
Reactions % % % % % %
5.1 Preventing and Managing Allergic Vaccine Reactions
Myalgia 57 15 49 11 35 10
Prior to administration, the healthcare provider should review the
immunization history for possible vaccine sensitivity and previous Myalgia,
Grade 3e 9 1 5 1 3 0.4
vaccination-related adverse reactions. Appropriate medical treatment
and supervision must be available to manage possible anaphylactic Fatigue 57 20 46 17 37 14
reactions following administration of SHINGRIX.
Fatigue, 9 2 5 1 4 1
5.2 Guillain-Barré Syndrome (GBS) Grade 3e
In a postmarketing observational study, an increased risk of GBS Headache 51 22 40 16 29 12
was observed during the 42 days following vaccination with
SHINGRIX [see Adverse Reactions (6.2)]. Headache,
Grade 3e 6 2 4 0.2 2 0.4
5.3 Syncope Shivering 36 7 30 6 20 5
Syncope (fainting) can be associated with the administration of Shivering,
injectable vaccines, including SHINGRIX. Syncope can be Grade 3e 7 0.2 5 0.3 2 0.3
accompanied by transient neurological signs such as visual
disturbance, paresthesia, and tonic-clonic limb movements. Fever 28 3 24 3 14 3
Procedures should be in place to avoid falling injury and to restore Fever,
cerebral perfusion following syncope. Grade 3 f 0.4 0.2 1 0.2 0.1 0.1
6 ADVERSE REACTIONS GIg 24 11 17 9 14 8
6.1 Clinical Trials Experience GI, 2 1 1 1 1 0.4
Grade 3e
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a vaccine
cannot be directly compared with rates in the clinical trials of another Total vaccinated cohort for safety included all subjects with at
vaccine and may not reflect the rates observed in practice. There is least 1 documented dose (n).
the possibility that broad use of SHINGRIX could reveal adverse
reactions not observed in clinical trials.
a
7 days included day of vaccination and the subsequent 6 days.
Adults Aged 50 Years and Older
b
Data for subjects aged 50 to 59 years and 60 to 69 years are based
on Study 1. Data for subjects 70 years and older are based on pooled
Overall, 17,041 adults aged 50 years and older received at least 1 data from Study 1: NCT01165177 and Study 2: NCT01165229.
dose of SHINGRIX in 17 clinical studies. c
Placebo was a saline solution.
The safety of SHINGRIX was evaluated by pooling data from 2
placebo-controlled clinical studies (Studies 1 and 2) involving 29,305
d
Grade 3 pain: Defined as significant pain at rest; prevents
subjects aged 50 years and older who received at least 1 dose of normal everyday activities.
SHINGRIX (n = 14,645) or saline placebo (n = 14,660) administered e
Grade 3 myalgia, fatigue, headache, shivering, and GI: Defined
according to a 0- and 2-month schedule. At the time of vaccination, as preventing normal activity.
the mean age of the population was 69 years; 7,286 (25%) subjects
were aged 50 to 59 years, 4,488 (15%) subjects were aged 60 to 69 f Fever defined as ≥37.5°C/99.5°F for oral, axillary, or tympanic
years, and 17,531 (60%) subjects were aged 70 years and older. Both route, or ≥38°C/100.4°F for rectal route; Grade 3 fever defined
studies were conducted in North America, Latin America, Europe, as >39.0°C/102.2°F.
Asia, and Australia. In the overall population, the majority of subjects g
GI = Gastrointestinal symptoms including nausea, vomiting,
were White (74%), followed by Asian (18%), Black (1.4%), and other diarrhea, and/or abdominal pain.
racial/ethnic groups (6%); 58% were female.
The incidence of solicited local and general reactions was lower
Solicited Adverse Reactions: In Studies 1 and 2, data on solicited local in subjects aged 70 years and older compared with those aged
and general adverse reactions were collected using standardized diary 50 to 69 years.
cards for 7 days following each vaccine dose or placebo (i.e., day of
vaccination and the next 6 days) in a subset of subjects (n = 4,886 The local and general adverse reactions seen with SHINGRIX had
receiving SHINGRIX, n = 4,881 receiving placebo with at least 1 a median duration of 2 to 3 days.
(continued on next page)
There were no differences in the proportions of subjects reporting
any or Grade 3 solicited local reactions between Dose 1 and
Dose 2. Headache and shivering were reported more frequently
by subjects after Dose 2 (28% and 21%, respectively) compared
with Dose 1 (24% and 14%, respectively). Grade 3 solicited
general adverse reactions (headache, shivering, myalgia, and
fatigue) were reported more frequently by subjects after Dose 2
(2.3%, 3%, 4%, and 4%, respectively) compared with Dose 1
(1.4%, 1.4%, 2.3%, and 2.4%, respectively).
Unsolicited Adverse Events: Unsolicited adverse events that
occurred within 30 days following each vaccination (Day 0 to 29)
were recorded on a diary card by all subjects. In the 2 studies,
unsolicited adverse events occurring within 30 days of
vaccination were reported in 51% and 32% of subjects who
received SHINGRIX (n = 14,645) or placebo (n = 14,660),
respectively (Total Vaccinated Cohort). Unsolicited adverse events
that occurred in ≥1% of recipients of SHINGRIX and at a rate at
least 1.5-fold higher than placebo included chills (4% versus
0.2%), injection site pruritus (2.2% versus 0.2%), malaise (1.7%
versus 0.3%), arthralgia (1.7% versus 1.2%), nausea (1.4% versus
0.5%), and dizziness (1.2% versus 0.8%).
Gout (including gouty arthritis) was reported by 0.18% (n = 27)
versus 0.05% (n = 8) of subjects who received SHINGRIX or
placebo, respectively, within 30 days of vaccination; available
information is insufficient to determine a causal relationship
with SHINGRIX.
Serious Adverse Events (SAEs): In the 2 studies, SAEs were
reported at similar rates in subjects who received SHINGRIX
(2.3%) or placebo (2.2%) from the first administered dose up to
30 days post-last vaccination. SAEs were reported for 10.1% of
subjects who received SHINGRIX and for 10.4% of subjects who
received placebo from the first administered dose up to 1 year
post-last vaccination. One subject (<0.01%) reported
lymphadenitis and 1 subject (<0.01%) reported fever greater than
39°C; there was a basis for a causal relationship with SHINGRIX.
Optic ischemic neuropathy was reported in 3 subjects (0.02%)
who received SHINGRIX (all within 50 days after vaccination) and
0 subjects who received placebo; available information is
insufficient to determine a causal relationship with SHINGRIX.
Deaths: From the first administered dose up to 30 days post-last
vaccination, deaths were reported for 0.04% of subjects who
received SHINGRIX and 0.05% of subjects who received placebo
in the 2 studies. From the first administered dose up to 1 year
post-last vaccination, deaths were reported for 0.8% of subjects
who received SHINGRIX and for 0.9% of subjects who received
placebo. Causes of death among subjects were consistent with
those generally reported in adult and elderly populations.
Potential Immune-Mediated Diseases: In the 2 studies, new onset
potential immune-mediated diseases (pIMDs) or exacerbation of
existing pIMDs were reported for 0.6% of subjects who received
SHINGRIX and 0.7% of subjects who received placebo from the first
administered dose up to 1 year post-last vaccination. The most
frequently reported pIMDs occurred with comparable frequencies in
the group receiving SHINGRIX and the placebo group.
Dosing Schedule: In an open-label clinical study, 238 subjects 50
years and older received SHINGRIX as a 0- and 2-month or 0- and
6-month schedule. The safety profile of SHINGRIX was similar when
administered according to a 0- and 2-month or 0- and 6-month
schedule and was consistent with that observed in Studies 1 and 2.
6.2 Postmarketing Experience
The following adverse reactions have been identified during
postapproval use of SHINGRIX. Because these reactions are
reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a
causal relationship to the vaccine.
General Disorders and Administration Site Conditions
Decreased mobility of the injected arm which may persist for 1 or
more weeks.
Immune System Disorders
Hypersensitivity reactions, including angioedema, rash, and urticaria.
Nervous System Disorders
Guillain-Barré syndrome.
Postmarketing Observational Study of the Risk of Guillain-Barré
Syndrome following Vaccination with SHINGRIX
The association between vaccination with SHINGRIX and GBS was
evaluated among Medicare beneficiaries aged 65 years or older.
Using Medicare claims data, from October 2017 through February
2020, vaccinations with SHINGRIX among beneficiaries were
identified through National Drug Codes, and potential cases of
hospitalized GBS among recipients of SHINGRIX were identified
through International Classification of Diseases codes.
The risk of GBS following vaccination with SHINGRIX was assessed
in self-controlled case series analyses using a risk window of 1 to 42
days post-vaccination and a control window of 43 to 183 days
post-vaccination. The primary analysis (claims-based, all doses)
found an increased risk of GBS during the 42 days following
vaccination with SHINGRIX, with an estimated 3 excess cases of
GBS per million doses administered to adults aged 65 years or older.
In secondary analyses, an increased risk of GBS was observed
during the 42 days following the first dose of SHINGRIX, with an
estimated 6 excess cases of GBS per million doses administered to
adults aged 65 years or older, and no increased risk of GBS was
observed following the second dose of SHINGRIX. These analyses
of GBS diagnoses in claims data were supported by analyses of
GBS cases confirmed by medical record review. While the results
of this observational study suggest a causal association of GBS
with SHINGRIX, available evidence is insufficient to establish a
causal relationship.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
The data are insufficient to establish if there is vaccine-associated
risk with SHINGRIX in pregnant women [see Use in Specific
Populations (8.1) of full prescribing information].
8.2 Lactation
Risk Summary
It is not known whether SHINGRIX is excreted in human milk. Data
are not available to assess the effects of SHINGRIX on the breastfed
infant or on milk production/excretion [see Use in Specific
Populations (8.2) of full prescribing information].
8.5 Geriatric Use
Adults Aged 60 Years and Older
Of the total number of subjects who received at least 1 dose of
SHINGRIX in Studies 1 and 2 (n = 14,645), 2,243 (15%) were aged
60 to 69 years, 6,837 (47%) were aged 70 to 79 years, and 1,921
(13%) were 80 years and older. There were no clinically meaningful
differences in efficacy across the age groups [see Clinical Studies
(14.1, 14.2, 14.3) of full prescribing information].
The frequencies of solicited local and general adverse reactions in
subjects aged 70 years and older were lower than in younger adults
(aged 50 through 69 years). [See Adverse Reactions (6.1).]
17 PATIENT COUNSELING INFORMATION
• Inform patients of the potential benefits and risks of immunization
with SHINGRIX and of the importance of completing the 2-dose
immunization series according to the schedule.
• Inform patients about the potential for adverse reactions that have
been temporally associated with administration of SHINGRIX.
• Provide the Vaccine Information Statements, which are available
free of charge at the Centers for Disease Control and Prevention
(CDC) website (www.cdc.gov/vaccines).
Trademarks are owned by or licensed to the GSK group
of companies.
Manufactured by GlaxoSmithKline Biologicals
Rixensart, Belgium, U.S. License 1617, and
Distributed by GlaxoSmithKline
Research Triangle Park, NC 27709
©2021 GSK group of companies or its licensor.
July 2021 SHX:6BRS
©2021 GSK or licensor.
SGXJRNA210080 September 2021
Produced in USA.

EDITORIAL BOARD OF ADVISORS
Carmen Catizone, RPh
Executive Director,
National Association of
Boards of Pharmacy
Tammie Lee Demler, BS, PharmD,
MBA, BCGP, BCPP
Clinical Associate Professor and
Director of Psychiatric Pharmacy
Residency Programs
University of Buffalo
Mark Litzinger, RPh
Market Director,
Walmart
Mario Sylvestri, PharmD, PhD
Senior Director,
Medical Sciences Liaison
Amylin Pharmaceuticals
Mary Ann E. Zagaria, PharmD, MS, BCGP
Clinical Consultant Pharmacist
and President of MZ Associates, Inc.
CONTRIBUTING EDITORS
Loyd V. Allen, Jr., PhD, RPh
Emily M. Ambizas, PharmD, MPH, BCGP
Jack DeRuiter, PhD
Ed DeSimone, PhD, RPh
Marlon S. Honeywell, PharmD, ALFP
Joshua J. Neumiller, PharmD, CDCES,
FADCES, FASC
Somnath Pal, BS (Pharm), MBA, PhD
Manouchehr Saljoughian, PharmD, PhD
Jesse C. Vivian, RPh, JD
Mea A. Weinberg, DMD, MSD, RPh
Send your comments via email
rdavidson@uspharmacist.com
Mail: U.S. Pharmacist
395 Hudson Street, 3rd Floor
New York, NY 10014
www.uspharmacist.com
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twitter.com/USPharmacist
EDITORIAL
Large Migraine Study Manifests New
Genetic Risk Factors
A n international consortium of leading migraine scientists identified
more than 120 regions of the genome that are connected to risk of
migraine. The groundbreaking study helps researchers better understand
the biological basis of migraine and its subtypes and could speed up the
search for new treatment of the condition, which affects over a billion indi-
viduals worldwide.
In the largest genome study of migraine yet, researchers have more than
tripled the number of known genetic risk factors for migraine. Among the
identified 123 genetic regions are two that contain target genes of recently
developed migraine-specific drugs.
The study involved leading migraine research groups in Europe, Austra-
lia, and the United States working together to pool genetic data from more
than 873,000 study participants, 102,000 of whom had migraine. The new
findings, published in Nature Genetics, also uncovered more of the genetic
architecture of migraine subtypes than previously known.
Migraine is believed to be a neurovascular
disorder with disease mechanisms within both
the brain and the blood vessels of the head.
Previous research has shown that genetic fac-
tors contribute significantly to the migraine
risk. However, it has long been debated
whether the two main migraine types—
migraine with and without aura—share similar
genetic backgrounds.
To gain more insight into the specific risk
genes, researchers from the International Head- Robert Davidson
ache Genetics Consortium assembled a large Editor-in-Chief
rdavidson@uspharmacist.com
genetic dataset to conduct a genome-wide asso-
ciation study, looking for genetic variants that
were more common in those who had migraine in general or one of the
two main migraine types. The results demonstrated that migraine sub-
types have both shared risk factors and risk factors that appear specific to
one subtype. The analyses highlighted three risk variants that appear to
be specific to migraine with aura and two that appear to be specific to
migraine without aura.
Furthermore, the results supported the concept that migraine is brought
about by both neuronal and vascular genetic factors, strengthening the view
that migraine truly is a neurovascular disorder. Migraine is globally the sec-
ond largest contributor to years lived with disability. Therefore, there is
clearly a large need for new treatments.
A particularly interesting finding was the identification of genomic risk
regions containing genes that encode targets for recently developed
migraine-specific therapeutics. One of the newly identified regions contains
genes (CALCA/CALCB) encoding calcitonin gene–related peptide, a mole-
cule involved in migraine attacks and blocked by the recently introduced
calcitonin gene–related peptide inhibitor migraine medications. Another risk
region covers the HTR1F gene encoding serotonin 1F receptor, also a target
for new migraine-specific medications.
4
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 March 2022

PATIENT TEACHING AID

Vol. 47 No. 3
© Scott Bodell / Jobson Healthcare

Psoriatic Arthritis .
See page 15

Features
Anticipating the First Adalimumab Biosimilar . . . . . . . . . . . . . . . . . . . . . . . .18
Appropriate pain management has The drug has long been a vital part of rheumatoid arthritis treatment, but this is the first
been a growing concern since the rise
of the opioid epidemic. Patients seek interchangeable product that mimics the structure and function of the original agent.
alternative therapies when prescription Amanda Ye, RPh, PharmD
pharmacologic agents do not alleviate
their pain or are not easily accessible. Vitamins and Minerals for Pain Management . . . . . . . . . . . . . . . . . . . . . . . .25
Vitamins and minerals are one option
that has gained traction and attracted Although evidence supporting the effectiveness of these nutrients in pain relief is limited,
researchers’ interest. pharmacists are in a position to help patients make educated decisions on the use of
these products.
Tara Smith, PharmD Candidate 2023; Brandon Morel, PharmD Candidate 2023; and
Elina Delgado, PharmD, BCPS
THIS MONTH
Editorial Focus:
Pain Management

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earn additional CE credits online at: When pre-exposure prophylaxis is used consistently, it is effective at preventing
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Jennifer LaPreze, PharmD, BCACP, CDCES, CPP, and Brooke Nowicki, PharmD, AAHIVP
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EDITORIAL STAFF March 2022
Editor-in-Chief Vol. 47 No. 3
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Managing Acute Pain in Opioid Use Disorder . . . . . . . . . . . . . . . . . . . . . .HS-2
Too often, patients with this condition experience abrupt drug cessation or inappropriate
pain management when admitted to the hospital or in the postoperative period.
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 PAIN NEWS DIGEST
Rising Opioid-Overdose Death Rates
Among Older Adults
A common stereotype for an “older adult” might
include early-bird specials, dentures, and tickets to
the matinee show.
A new Northwestern Medicine study that analyzed
20 years of fatal opioid-overdose data in adults aged
55 years and older paints a much different picture.
Between 1999 and 2019, opioid-related overdose
deaths increased exponentially in U.S. adults aged 55
years and older, from 518 deaths in 1999 to 10,292
deaths in 2019: a 1,886% increase.
“Many of us think drug misuse is a problem of the
young. However, older adults are experiencing an
explosion in fatal opioid overdoses,” said Maryann
Mason, an associate professor of emergency medi-
cine at Northwestern University Feinberg School of
Medicine. The findings were published in JAMA Net-
work Open.
In the 20-year span, 79,893 people in the U.S. aged
55 to 80 years died by opioid overdose, with about
half being between age 55 and 64 years, Dr. Mason
said. The annual overall death rate per 100,000 people
aged 55 years and older ranged from a low of 0.9 in
1999 to a high of 10.7 in 2019 and increased annually
from 2000 on, the study found.
Lori Post, Buchler Professor of Geriatric Medicine,
said ageism is one of the contributing factors for the
increase in fatal opioid overdoses among older adults,
explaining that doctors often do not screen for drug
misuse during appointments with older people because
“it doesn’t fit the stereotype of what it means to be
old.”
Black men experienced the largest increases in opi-
oid-overdose deaths among older adults since 2013,
the study found. By 2019, the opioid-overdose fatality
rate among non-Hispanic black or black males aged
55 years and older was 40.03 per 100,000 popula-
tion—four times greater than the overall opioid fatality
rate of others of the same age.
Dr. Mason added that black men are also more
likely to have experienced trauma, lack access to health
insurance and healthcare, not trust healthcare provid-
ers, and be undertreated for pain compared with other
subpopulations of older adults.
The study suggested other contributing factors in
the exponential increase among older adults. They
could include social isolation and depression; exposure
to medically prescribed opioids for chronic conditions
such as arthritis and cancer, which increase with age;
8
U.S. Pharmacist • March 2022 • www.uspharmacist.com
and declining cognitive function that may interfere
with taking opioids as prescribed. In addition, the
body’s ability to metabolize opioids decreases with age,
meaning that people are more vulnerable to overdose.
Promoting Safer Pain Relief With
New Compounds
Scientists at Scripps Research in Florida have cre-
ated a collection of new pain-relieving compounds
that, like morphine and other drugs, provide relief
via activation of opioid receptors but without
inducing many dangerous and unwanted side
effects that have driven opioid-related overdose and
deaths.
Writing in the journal Proceedings of the National
Academy of Sciences, biochemist Laura Bohn, PhD,
and colleagues describe a compound called SR-17018,
which activates the same pain-relieving receptor as opi-
oid drugs, including morphine, oxycodone, and fen-
tanyl; however, it binds to opioid receptors in a differ-
ent way from those drugs, leaving the opioid receptor
open and available to the body’s own natural pain-
relieving substances, apparently augmenting pain
relief. In a study by Pantouli et al published in 2021 in
Neuropharmacology, the group showed that the com-
pound performed particularly well in mouse studies of
chemotherapy-induced neuropathic pain, the scientists
write.
In the current report, the authors have made strides
in understanding why these drugs seem so different.
“We demonstrate that these compounds bind to a dif-
ferent site on the receptor than a typical opioid.
Because of that, they seem to leave the receptor on and
yet still receptive to endogenous opioids,” says Dr.
Bohn, who chairs the Scripps Research Department of
Molecular Medicine in Jupiter, Florida. “In neuropa-
thy pain, we show they are far superior to morphine
and oxycodone; moreover, SR-17018 does not
decrease breathing.”
The authors also described a related compound
that, being more potent, induces respiratory suppres-
sion but at higher doses than are needed to relieve pain.
Importantly for safety, this compound, SR-14968,
proved responsive to the overdose-rescue medication
naloxone when given at doses high enough to suppress
breathing.
Perhaps most importantly for people with severe
chronic pain, SR-17018 showed an ability to provide
sustained pain relief over time without development of
tolerance, the problem of reduced efficacy over time
 Pain News Digest
that requires increased dosages, increasing the danger
of overdose.
Going forward, the team is continuing to refine and
test the compounds so that they could eventually be
tested in a clinical setting.
“Severe and chronic pain associated with surgery,
nerve damage, and trauma require strong pain
relief,” Dr. Bohn says. “Safer solutions are needed.
We believe these new compounds are a big step in the
right direction.”
New Treatment Reduces Long-Term Pain
Following Knee Surgery
With one in five people experiencing ongoing pain
long after knee-replacement surgery, new research,
led by the University of Bristol and North Bristol
NHS Trust in the U.K. and published in The Lancet
Rheumatology, has shown a way to help reduce
continuing pain that could also save the NHS time
and money.
Each year, 100,000 knee-replacement surgeries are
carried out in the U.K. Most of these operations take
place to treat pain related to osteoarthritis. Unfortu-
nately, every year around 20,000 people who have
knee-replacement surgery to relieve their pain find that
they have moderate to severe pain 3 months or longer
after their operation, which impacts their everyday
lives.
The study found the STAR (support and treatment
after joint replacement) care pathway reduces pain
severity, the amount pain interferes with people’s lives,
and is cost effective. The new treatment could poten-
tially save the NHS up to £14 million ($19 million) per
year through reduced inpatient admissions.
The study found that patients who received the
STAR care pathway had less pain severity and impact
on daily life at both 6 and 12 months after treatment (9
and 15 months after surgery); half the number of hos-
pital readmissions; reduced length of hospital stay for
any inpatient admissions 3 months after surgery; and
less unpaid time off work.
The program looked at how likely patients are to
experience ongoing knee pain after their operation and
discovered why they avoid seeking help. The research
team developed a new treatment—a care pathway—
and compared how patients did on the STAR care
pathway when compared with a control group who
had the usual care.
As part of the STAR care pathway, 3 months after
surgery patients attended an hour-long clinic run by
specially trained healthcare professionals, and detailed
9
U.S. Pharmacist • March 2022 • www.uspharmacist.com
pain questionnaires were filled out and x-rays were
taken as well as a blood test for infection. If needed,
patients were referred for ongoing treatment. In addi-
tion, patients received up to six phone calls over the
next 12 months, making sure they had their referral
and to check on how they were doing.
Might a Dangerous Microbe Offer a
New Way to Suppress Pain?
Anthrax has a scary reputation. Widely known to
cause serious lung infections in humans and
unsightly, albeit painless, skin lesions in livestock
and people, the anthrax bacterium has even been
used as a weapon of terror.
Now the findings of a new study suggest that the
dreaded microbe also has unexpected beneficial poten-
tial—one of its toxins can suppress multiple types of
pain in animals.
The research reveals that this specific anthrax toxin
The findings of a new study suggest
that the dreaded microbe [anthrax]
also has unexpected beneficial
potential—one of its toxins can
silence multiple types of pain
in animals.
works to alter signaling in pain-sensing neurons and,
when delivered in a targeted manner into neurons of
the central and peripheral nervous system, can offer
relief to animals in distress.
The work, led by investigators at Harvard Medical
School (HMS) in collaboration with industry scientists
and researchers from other institutions, was published
in Nature Neuroscience.
Furthermore, the team combined parts of the
anthrax toxin with different types of molecular cargo
and delivered it into pain-sensing neurons. The tech-
nique can be used to design novel precision-targeted
pain treatments that act on pain receptors but without
the widespread systemic effects of current pain-relief
drugs, such as opioids.
“This molecular platform of using a bacterial toxin
to deliver substances into neurons and modulate their
function represents a new way to target pain-mediating
neurons,” said study senior investigator Isaac Chiu,
associate professor of immunology in the Blavatnik
Institute at HMS.
 Pain News Digest
“There’s still a great clinical need for developing
non-opioid pain therapies that are not addictive but
that are effective in silencing pain,” said study first
author Nicole Yang, HMS research fellow in immunol-
ogy in the Chiu Laboratory. “Our experiments show
that one strategy, at least experimentally, could be to
specifically target pain neurons using this bacterial
toxin.”
The researchers caution, however, that for now, this
approach remains purely experimental and still needs
to be tested and further fine-tuned in more animal
studies and, eventually, in humans.
For the current study, they started out by trying to
determine how pain-sensing neurons may be different
from other neurons in the human body. To do so, they
first turned to gene-expression data. One of the things
that caught their attention: Pain fibers had receptors
for anthrax toxins, whereas other types of neurons did
not. In other words, the pain fibers were structurally
primed to interact with the anthrax bacterium. They
wondered why.
The newly published research sheds light on that
question while also pointing to novel avenues for
drug development beyond the traditional small-mole-
cule therapies that are currently being designed across
laboratories.
“Bringing a bacterial therapeutic to treat pain raises
the question ‘Can we mine the natural world and the
microbial world for analgesics?’” Dr. Chiu said.
“Doing so can increase the range and diversity of the
types of substances we look to in search for solutions.”
Fat Could Inject Relief Into Patients With
Plantar Fasciitis Pain
A novel technique that transplants a patient’s own fat
into the sole of the foot could offer relief to those suf-
fering from a common and painful condition called
plantar fasciitis (PF), according to University of Pitts-
burgh (Pitt) School of Medicine researchers.
In a pilot study in Plastic and Reconstructive Sur-
gery and led by a wife-and-husband team, the fat-injec-
tion procedure improved symptoms of PF in patients,
laying the groundwork for a larger clinical trial.
“We developed this procedure to harness the regen-
erative properties of fat,” said Jeffrey Gusenoff, MD,
professor of plastic surgery at Pitt. “In this proof-of-
concept study, we showed that fat injections into the
foot reduced heel pain, helped patients get back to
doing sports and activities, and boosted quality of life.”
“Plantar fasciitis is exceptionally painful,” said Beth
Gusenoff, DPM, clinical assistant professor of plastic
10
U.S. Pharmacist • March 2022 • www.uspharmacist.com
surgery at Pitt. “When you get up from a sitting posi-
tion or from sleeping, it’s a sharp, searing pain that
some people describe as being like a nail going right
through their heel.”
The acute form of PF can be treated with stretching,
shoe orthotics, or cortisone injections. But about 10%
of patients progress to the chronic form in which the
foot’s collagen degenerates and the plantar fascia thick-
ens. For these patients, surgical release of the plantar
fascia with a small cut can help, but this surgery comes
with risks, according to Dr. Beth Gusenoff.
“Recently, there has been a plea among podiatrists
to stop cutting the plantar fascia because some peo-
ple get a lot of scar tissue, which causes pain,” she
explained. “And if too much is cut, the foot can
become destabilized, so people end up with almost
like a floppy foot.” Inspired by the regenerative
properties of fat stem cells, the Gusenoffs developed
a technique that uses fat from a patient’s belly or
other body area.
To test this method, the team recruited 14 patients
with chronic PF and split them into two groups. Group
In a pilot study led by a wife-and-
husband team, the fat-injection
procedure improved symptoms of
plantar fasciitis in patients, laying
the groundwork for a larger
clinical trial.
1 participants received the procedure at the beginning
of the study and were followed for 12 months, and
their Group 2 counterparts received the procedure
after a 6-month observation period and were followed
for an additional 6 months.
“We found that Group 1 had improvements in
quality of life and sports activity, decreased plantar fas-
cia thickness, and reduced pain levels,” said Dr. Jeffrey
Gusenoff. “And a lot of the measures that were
improving 6 months after the procedure got even bet-
ter by 12 months.”
Pain and Anxiety Affect Breathing on
a Cellular Level
Why people’s breathing rate increases dramati-
cally when they are hurting or anxious was not
previously understood. Now, a team of Salk Insti-
tute scientists has uncovered a neural network in
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 Pain News Digest
the brain that coordinates breathing rhythm with
feelings of pain and fear. Along with contributions
to the fields of pain management, psychological
theories of anxiety, and philosophical investiga-
tions into the nature of pain, these findings could
lead to development of an analgesic that would
prevent opioid-induced respiratory depression
(OIRD), the disrupted breathing that causes over-
dose deaths.
In the study published in Neuron, the Salk group
focused on a group of neurons in the brainstem
called the lateral parabrachial nucleus, which is
arranged in a core-shell configuration. They found
that neurons in the core project to the amygdala, an
area of the brain that processes fear and the emo-
tional experience of pain. Neurons in the shell proj-
ect to the pre–Bötzinger complex, a region that gen-
erates breathing rhythm. The core and shell neurons
influence each other according to inputs from these
areas, making people breathe faster when they
experience pain or anxiety.
“We are the first group to demonstrate how the lat-
eral parabrachial nucleus coordinates breathing and
pain,” says the paper’s senior author, Sung Han, assis-
tant professor in Salk’s Clayton Foundation Laborato-
ries for Peptide Biology. “By understanding the circuits
in this brain region, we may be able to tease apart
breathing regulation and pain regulation to develop a
medication that inhibits feelings of pain without
repressing breathing, like OIRD.”
In OIRD, opioids repress breathing as well as pain;
it is the major cause of death from opioids. In previous
work, Dr. Han’s laboratory showed that opiates like
morphine repress breathing by triggering specific
receptors, called mu-opioid receptors (MORs), leading
to the inhibition of neurons that express them. It also
showed that reactivating the cells that express MORs
can reverse OIRD. The current work suggests addi-
tional approaches for preventing OIRD, possibly by
inhibiting neurons in the region’s core (blunting fear/
anxiety) while exciting similar neurons in the shell
(supporting breathing).
Dr. Han is eager to see the team’s discovery applied
translationally. “The biggest problem these days is that
opioids reduce pain but also reduce breathing, so peo-
ple die,” says Dr. Han, holder of the Pioneer Fund
Development Chair. “By understanding those two
mechanisms in our research, maybe we can manipulate
certain populations of neurons by pharmacological
intervention so that we can control pain without
changing the breathing.”
12
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Soft Tissue Destruction and
Lower Back Pain
Back pain affects many people at some point in
their lives, and a common cause is damage to the
squishy discs or flexible, rubbery tissues of the
spine. However, observing this damage at an early
stage is difficult with current imaging methods.
Now, researchers reporting in ACS Nano can see
microscopic soft tissue destruction in animal spines
by targeting denatured collagen with fluorescent
molecules.
Any area along the spine, from the neck to tail
bone, can become uncomfortable when its soft and
protective tissues, including the cartilage and jelly-
like intervertebral discs, become damaged and lose
their structure. Daily wear and tear, as well as some
disorders, such as facet joint osteoarthritis or anky-
losing spondylitis, can degrade and unfurl the colla-
gen proteins that give these tissues their bounce and
flexibility. Detecting compromised collagen early
could help patients get relief before the pain becomes
severe, but this is very difficult to do with existing
medical technologies, such as x-rays and MRI.
Previously, Yang Li and colleagues developed a col-
lagen hybridizing peptide (CHP) probe that specifically
binds unfurled collagen molecules, which happens
when they deteriorate and lose their ability to cushion
vertebrae. So, Li, Kuibo Zhang, Hong Shan, and col-
leagues wanted to test if CHP labeled with fluorescent
tags could be used as an imaging method to identify
collagen destruction in the body.
To make the peptide probe more stable in the body,
the researchers modified CHP by substituting a
hydroxyl group with fluorine and then attaching a flu-
orescent dye to it. When healthy mice and rats were
injected with the fluorescent dye–labeled CHP and
imaged with near-infrared fluorescence, the team con-
firmed that the fluorescing molecules accumulated on
the soft tissues between the vertebrae.
The researchers then removed a portion of the ani-
mals’ spines and imaged them with light sheet fluores-
cence microscopy. This technique produced precise 3D
maps, which revealed denatured collagen. Because
CHP is known to target damaged collagen, the team
says their imaging experiments show that even healthy
animals can have a modest degree of deteriorated col-
lagen around load-bearing joints, especially in the
lower back.
The content contained in this article is for informational purposes
only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is
solely at your own risk.
March 2022

Managing Acute Pain in Opioid Use Disorder . . . . . . . . . . . . . . . . HS-2

Pharmacogenomic Considerations in Opioid Therapy . . . . . . . . . . .HS-7

 Health Systems Edition

Managing Acute Pain

in Opioid Use Disorder
opioids (especially fentanyl that
was illicitly manufactured). 2-4
Globally, the burden of disease
from opioids approaches 11 mil-
lion life-years lost to health prob-
lems, disabilities, and early death.5

Overview
Data suggest that opioid use disor-
der (OUD) is a chronic disease that
should be managed medically. Sev-
eral medications have been
approved by the FDA for OUD.
With medication management,
patients are more likely to enter
© gettyimages.com / JobsonHealthcare
full recovery, contribute to their
family and community, and reach
ABSTRACT: Opioid use disorder (OUD) may be medically their full potential. 6 Medication
managed with opioid agonist therapy (OAT), including management should involve shared
buprenorphine and methadone. Shared decision making decision making between the patient
between provider and patient is imperative. Clinicians and the medical provider. Addition-
should discourage unplanned cessation or tapering of ally, patient preference, adverse
medication without a compelling cause. Frequently, patients effects, availability, cost, access, and
receiving OAT experience episodes of acute pain during tolerability should also play a role.
inpatient hospitalization or in the postoperative setting. Long-term pharmacotherapy for
This situation frequently leads to encounters with providers OUD doubles the likelihood of opi-
who may not be well-versed in OAT pharmacology or in the oid abstinence compared with
use of these agents. Additionally, concerns for possible behavior therapy alone.7 Addition-
manipulative behavior by patients may deter clinicians from ally, a meta-analysis found that
treating acute pain appropriately. Pharmacists can play a key patients receiving opioid agonist
role in the management of OAT in acute pain and ensuring therapy (OAT) had significantly
appropriate home OAT administration routes, doses, and lower rates of mortality compared
frequencies. with patients not receiving OAT. 8
However, access to OAT and insur-

F rom 1999 to 2019, an estimated 500,000 peo-

ple died from overdoses of prescription or illicit
opioids in the United States.1 The literature classi-
ance coverage for OAT remain low, presenting
challenges for patients.

fies the increase in deaths from opioid overdose
into three different waves. An increase in the pre-
scribing of opioids in the 1990s constituted the first University of Kentucky Medical Center
wave; the second wave, which began in 2010, was
defined by rapid increases in overdose deaths
involving heroin; and 2013 saw the beginning of
the third wave, characterized by substantial
increases in overdose deaths related to synthetic
Breanne M. Mefford, PharmD, BCCCP
Critical Care Pharmacist, Medical Intensive Care Unit
Department of Pharmacy
Lexington, Kentucky
J. Chris Donaldson, PharmD, BCCCP
Critical Care Pharmacist, Medical Intensive Care Unit
Department of Pharmacy
University of Kentucky Medical Center
Lexington, Kentucky

HS-2
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 At the
request of
the
advertiser,
this page
intentionally
left blank.
 Health Systems Edition
Managing Acute Pain in Opioid Use Disorder
The abrupt cessation or tapering of OAT with-
out a compelling cause should be discouraged. Too
often, however, patients with OUD experience
abrupt cessation or inappropriate management of
acute pain when admitted to the hospital or in the
postoperative period. Many clinicians are unfamil-
iar with OAT and the treatment of acute pain in
patients with OUD. Additionally, many providers
are concerned with manipulative or drug-seeking
behavior, and this may deter the use of opioid
agents to treat acute pain. This review aims to
describe the pharmacology of OAT agents and dis-
cuss current considerations for the treatment of
acute pain in patients receiving OAT.
Treatment of OUD
Buprenorphine and methadone are commonly used
for the treatment of OUD. The pharmacologic
properties of these agents differ substantially, as
highlighted below.
Buprenorphine: This agent is a semisynthetic partial
opioid analgesic that binds to mu-, kappa-, and
delta-opioid receptors. Its analgesic effect is via
high-affinity binding to the opiate receptors in the
central nervous system. Buprenorphine displays
partial mu-agonist and weak kappa-antagonist
activity, but its agonist activity at the delta receptor
is not well understood. The half-life of buprenor-
phine is variable, ranging from 3 hours for IV
administration to 24 to 60 hours for sublingual
administration. 9 The dissociation from binding
sites is slow, leading to a longer duration of action
than that of other opioids. This slow dissociation
allows for prolonged therapeutic effects in treating
opioid dependence and chronic pain.10 Buprenor-
phine’s high binding affinity and slow mu-opioid
receptor dissociation make the use of mu-opioid
receptor antagonists, such as naloxone, difficult.
Multiple buprenorphine formulations are FDA
approved for the treatment of OUD, including sub-
lingual tablet, sublingual film, buccal film,
implant, and extended-release injection. The
buprenorphine concentration of these formula-
tions has euphoric effects when administered IV;
accordingly, naloxone is added because its effect
is significantly increased when injected IV, antago-
nizing buprenorphine’s euphoric effects and pre-
cipitating immediate withdrawal, thus discourag-
ing misuse.9 Patients should show signs of opioid
withdrawal prior to starting buprenorphine, as
HS-4
U.S. Pharmacist • March 2022 • www.uspharmacist.com
buprenorphine’s high affinity causes it to rapidly
displace opioid agonist–bound mu receptors,
thereby hastening withdrawal.9
Buprenorphine provides analgesia at low-to-
moderate doses and is approximately 25 to 100
times more potent than morphine.10 Furthermore,
buprenorphine exhibits a ceiling effect, so doses
exceeding 32 mg do not produce a greater analgesic
effect.11 Providers typically are more inclined to use
buprenorphine for OUD because of its decreased
potential for abuse and because, in contrast to
methadone, it enables the provision of office-based
treatment. Additionally, buprenorphine has a lower
risk of respiratory depression than methadone, and
it has the ability to treat opioid-induced hyperal-
gesia through kappa-receptor antagonism. 11
Because buprenorphine antagonizes the action of
mu agonists, the practice of withholding buprenor-
phine before surgery has become widespread. Pre-
clinical and clinical studies have shown that the
administration of buprenorphine and mu agonists
produces an additive analgesic response at analge-
sic doses of buprenorphine. However, little is
known about the interaction between buprenor-
phine and opioid agonists when buprenorphine is
used to treat OUD.9 The difficulties of managing
pain in patients taking buprenorphine, combined
with the pharmacologic properties noted above,
have led to conflicting views on how to optimally
treat acute pain in these patients.
The difficulties of managing pain in
patients taking buprenorphine,
combined with the pharmacologic
properties noted above, have led to
conflicting views on how to optimally
treat acute pain in these patients.
Methadone: Methadone, a synthetic full mu-recep-
tor agonist, is structurally unrelated to other opi-
oids; it exhibits N-methyl-d-aspartate (NMDA)
receptor antagonist activity. Available formula-
tions are racemic mixtures of two isomers. The
R-isomer is an NMDA receptor antagonist that
inhibits the uptake of norepinephrine and sero-
tonin, and the S-isomer is a mu- and delta-opioid
receptor agonist.12 Historically, an influx of heroin
into U.S. metropolitan areas following World War
 Health Systems Edition
Managing Acute Pain in Opioid Use Disorder
II resulted in increased rates of illicit drug use,
leading to the establishment of narcotic-mainte-
nance programs that used methadone as the pri-
mary opioid-replacement agent based on its slow
onset of action (3-5 days) and long elimination
half-life (8-59 hours). 11 In higher doses, metha-
done may have serious side effects including respi-
ratory depression, arrhythmias due to prolonged
QT interval, and drug-drug interactions from
CYP450 metabolism. A study of maintenance
methadone found that patients were cross-tolerant
to the analgesic effects of morphine and that pain
relief, when achieved, did not last as long as
expected.13 Cross-tolerance between opioids may
explain why patients receiving OAT require higher
and more frequent doses of opioid analgesics for
adequate pain control. These are all important
considerations in the management of acute pain in
the setting of methadone OAT.
Managing Acute Pain in OUD
The approach to managing acute pain—including
perioperative pain—in patients receiving OAT is a
common clinical conundrum. As aforementioned,
clinicians may be less familiar with OAT, poten-
tially leading to the undertreatment of acute pain.
Undertreatment is often perpetuated by some pro-
viders’ fear of adverse effects, including respiratory
and cognitive suppression, and by the misinterpre-
tation of patient-reported pain as drug-seeking
behavior. Furthermore, the misconception that
patients derive sustained analgesia from OAT may
play a role in the undermanagement of acute pain.
Chronic opioid exposure results in opioid- and
NMDA-receptor trafficking, which contributes to
tolerance and hyperalgesia and minimizes the anal-
gesic properties of chronic OAT.14 Therefore, it is
important for clinicians to familiarize themselves
with the management of acute pain in patients
receiving OAT.
Methadone Management: Adequate analgesia may
be more challenging to achieve in patients on meth-
adone maintenance therapy (MMT), as there is
often a degree of opioid cross-tolerance.13,15,16 Ret-
rospective studies have demonstrated that patients
on MMT frequently have higher opioid require-
ments in the setting of acute perioperative pain. 17,18
Furthermore, methadone has an analgesic duration
of action of 4 to 8 hours, which is substantially
shorter than the suppression of opioid withdrawal.
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U.S. Pharmacist • March 2022 • www.uspharmacist.com
It is recommended to continue the patient’s home
MMT and employ short-acting opioids to manage
acute breakthrough pain.14 Given methadone’s
unique pharmacologic profile, dose conversion to
an alternative opioid often is inaccurate, limiting
the practicality of alternative regimens. In addition,
nonopioid analgesics—including nonsteroidal anti-
inflammatory agents and acetaminophen—should
be used when appropriate. If a patient is unable to
take oral medications, the methadone dose may be
administered IV or subcutaneously as one-half to
two-thirds of the maintenance dose divided into
two to four equal doses.14 Importantly, the patient’s
methadone clinic should always be contacted in
order to confirm the patient’s MMT regimen as
well as to inform the staff of the patient’s hospital-
ization, as these clinics routinely perform urine
drug screens.
Chronic opioid exposure results in
opioid- and NMDA-receptor
trafficking, which contributes to
tolerance and hyperalgesia and
minimizes the analgesic properties
of chronic OAT.
Buprenorphine Management: Guidelines published
in 2004 by the Department of Health and Human
Services’ Center for Substance Abuse Treatment
recommended the discontinuation of home
buprenorphine OAT.19 In conjunction with limited
evidence, this recommendation was largely based
on the considerations that buprenorphine is a par-
tial opioid receptor agonist and that it impairs the
effectiveness of other opioids. However, clinical
studies in the perioperative setting have since
shown that the use of additional opioids for acute
pain plus maintenance of the patient’s home
buprenorphine OAT is an effective strategy. 20,21
Furthermore, clinical studies have demonstrated
that patients whose home buprenorphine OAT was
held perioperatively had increased opioid require-
ments as well as increased pain scores relative to
patients whose home buprenorphine OAT was
continued.22,23
As with methadone, patients who are on
buprenorphine prior to admission may still have
 Health Systems Edition
Managing Acute Pain in Opioid Use Disorder
higher opioid requirements relative to patients not
on chronic opioids. This has led some institutions to
implement perioperative protocols that either hold
or wean buprenorphine products; however, this
likely adds unnecessary complexity including rein-
troduction and may increase the risk of with-
drawal.11,18,19 Discontinuation of buprenorphine has
also been associated with higher rates of illicit opioid
use.24 Accordingly, many experts now recommend
continuing home buprenorphine OAT periopera-
tively and in other acute-pain settings.14,19,25,26
Short-acting opioid agonists are recommended
for management of acute pain, keeping in mind that
these patients will have some degree of cross-toler-
ance. The total daily buprenorphine dose may be
divided into three or four doses, with each dose
taken every 6 to 8 hours.19 Most patients likely can
tolerate transmucosal or sublingual administration,
but for those who cannot, buprenorphine may be
administered IV. Dose equivalence between trans-
mucosal or sublingual and IV administration is not
well established; however, the oral bioavailability
REFERENCES
1. CDC. Mortality data. WONDER [online database]. http://wonder.
cdc.gov. Accessed January 31, 2022.
2. CDC. Vital signs: overdoses of prescription opioid pain relievers—
United States, 1999-2008. MMWR Morb Mortal Wkly Rep.
2011;60(43):1487-1492.
3. Rudd RA, Paulozzi LJ, Bauer MJ, et al. Increases in heroin overdose
deaths—28 states, 2010 to 2012. MMWR Morb Mortal Wkly Rep.
2014;63(39):849-854.
4. Gladden RM, Martinez P, Seth P. Fentanyl law enforcement submissions
and increases in synthetic opioid-involved overdose deaths—27 states,
2013-2014. MMWR Morb Mortal Wkly Rep. 2016;65(33):837-843.
5. Degenhardt L, Whiteford H, Hall WD. The Global Burden of Disease
projects: what have we learned about illicit drug use and dependence
and their contribution to the global burden of disease? Drug Alcohol
Rev. 2014;33(1):4-12.
6. Kaskutas LA, Borkman TJ, Laudet A, et al. Elements that define
recovery: the experiential perspective. J Stud Alcohol Drugs. 2014;75(6):999-
1010.
7. Connery HS. Medication-assisted treatment of opioid use disorder:
review of the evidence and future directions. Harv Rev Psychiatry.
2015;23(2):63-75.
8. Santo T Jr, Clark B, Hickman M, et al. Association of opioid agonist
treatment with all-cause mortality and specific causes of death among
people with opioid dependence: a systematic review and meta-analysis.
JAMA Psychiatry. 2021;78(9):979-993.
9. Quaye ANA, Zhang Y. Perioperative management of buprenorphine:
solving the conundrum. Pain Med. 2019;20(7):1395-1408.
10. Khanna IK, Pillarisetti S. Buprenorphine—an attractive opioid with
underutilized potential in treatment of chronic pain. J Pain Res. 2015;8:859-
870.
11. Anderson TA, Quaye ANA, Ward EN, et al. To stop or not, that is
the question: acute pain management for the patient on chronic buprenor-
phine. Anesthesiology. 2017;126(6):1180-1186.
12. Fredheim OMS, Moksnes K, Borchgrevink PC, et al. Clinical phar-
macology of methadone for pain. Acta Anaesthesiol Scand. 2008;52(7):879-
889.
13. Doverty M, Somogyi AA, White JM, et al. Methadone maintenance
patients are cross-tolerant to the antinociceptive effects of morphine.
Pain. 2001;93(2):155-163.
14. Alford DP, Compton P, Samet JH. Acute pain management for
patients receiving maintenance methadone or buprenorphine therapy.
HS-6
U.S. Pharmacist • March 2022 • www.uspharmacist.com
of the buccal film is 46% to 65% and that of the
sublingual tablet is 29%, so this may be taken into
consideration in establishing an IV dose.27
Conclusion
Many patients with OUD are receiving OAT with
methadone or buprenorphine. Therefore, clinicians
may encounter patients receiving OAT who have
acute pain during hospitalization or in the postop-
erative setting. Providers should familiarize them-
selves with OAT pharmacology and determine the
appropriate regimen for acute pain by continuing
OAT with short-acting agents as needed. As the
opioid epidemic continues, it is of paramount
importance to ensure appropriate acute pain treat-
ment while managing OUD. Pharmacists can play
a key role in managing OAT in the setting of acute
pain and in determining the appropriate administra-
tion route, dose, and frequency of home OAT.
The content contained in this article is for informational purposes
only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is solely
at your own risk.
Ann Intern Med. 2006;144(2):127-134.
15. Athanasos P, Smith CS, White JM, et al. Methadone maintenance
patients are cross-tolerant to the antinociceptive effects of very high
plasma morphine concentrations. Pain. 2006;120(3):267-275.
16. Hay JL, White JM, Bochner F, Somogyi AA. Antinociceptive effects
of high-dose remifentanil in male methadone-maintained patients. Eur
J Pain. 2008;12(7):926-933.
17. Chan FJ, Schwartz AM, Wong J, et al. Use of chronic methadone
before total knee arthroplasty. J Arthroplasty. 2017;32(7):2105-2107.
18. Hansen LE, Stone GL, Matson CA, et al. Total joint arthroplasty in
patients taking methadone or buprenorphine/naloxone preoperatively
for prior heroin addiction: a prospective matched cohort study. J Arthro-
plasty. 2016;31(8):1698-1701.
19. Haber LA, DeFries T, Martin M. Things We Do for No ReasonTM:
discontinuing buprenorphine when treating acute pain. J Hosp Med.
2019;14(10):633-635.
20. Kornfeld H, Manfredi L. Effectiveness of full agonist opioids in
patients stabilized on buprenorphine undergoing major surgery: a case
series. Am J Ther. 2010;17(5):523-528.
21. Harrison TK, Kornfeld H, Aggarwal AK, Lembke A. Perioperative
considerations for the patient with opioid use disorder on buprenorphine,
methadone, or naltrexone maintenance therapy. Anesthesiol Clin.
2018;36(3):345-359.
22. Macintyre PE, Russell RA, Usher KAN, et al. Pain relief and opioid
requirements in the first 24 hours after surgery in patients taking
buprenorphine and methadone opioid substitution therapy. Anaesth
Intensive Care. 2013;41(2):222-230.
23. Quaye A, Potter K, Roth S, et al. Perioperative continuation of
buprenorphine at low-moderate doses was associated with lower post-
operative pain scores and decreased outpatient opioid dispensing compared
with buprenorphine discontinuation. Pain Med. 2020;21(9):1955-1960.
24. Ling W, Hillhouse M, Domier C, et al. Buprenorphine tapering
schedule and illicit opioid use. Addiction. 2009;104(2):256-265.
25. Lembke A, Ottestad E, Schmiesing C. Patients maintained on
buprenorphine for opioid use disorder should continue buprenorphine
through the perioperative period. Pain Med. 2019;20(3):425-428.
26. Goel A, Azargive S, Weissman JS, et al. Perioperative Pain and
Addiction Interdisciplinary Network (PAIN) clinical practice advisory
for perioperative management of buprenorphine: results of a modified
Delphi process. Br J Anaesth. 2019;123(2):e333-e342.
27. Buprenorphine. In: Lexi-Drugs. Hudson, OH: Lexi-Comp, Inc; 2022.
https://online.lexi.com. Accessed January 31, 2022.
 Health Systems Edition

Pharmacogenomic Considerations
in Opioid Therapy
ABSTRACT: Opioids are among
the most common medications
used in the treatment of pain,
and they carry many serious
risks if used inappropriately.
Pharmacogenomic considerations
can impact a patient’s treatment
plan for chronic pain, as CYP
polymorphisms may interfere with
nonsteroidal anti-inflammatory
drugs, tricyclic antidepressants,
and opioids. In particular, CYP2D6
polymorphisms may play a
considerable part in the safety and
efficacy of codeine, hydrocodone,
© gettyimages.com / JobsonHealthcare and tramadol, as outlined in the
Clinical Pharmacogenetic
Implementation Consortium (CPIC) guideline on opioids. Based on current research, the CPIC
recently updated its guidance on opioid use and interactions with CYP2D6, OPRM1, and COMT
polymorphisms. Greater pharmacist understanding of CYP polymorphisms can lead to safer
opioid prescribing and better outcomes for patients receiving pain management.

P harmacogenomics is an emerging field of person-

alized medicine that tailors the use of drugs based
on a patient’s genomic variations in order to maxi-
increased risk of side effects. In comparison, an allele
that causes increased metabolic activity of the same
enzyme will result in a rapid or ultrarapid (overactive)
mize efficacy and minimize side effects.1 Currently, metabolizer phenotype, a lower concentration of the
the most common pharmacogenomic testing is for drug, and the risk of therapeutic failure due to sub-
detection of nucleotide variations in the genes encod- therapeutic plasma concentrations. The polymor-
ing for CYP450 or phase II drug-metabolizing phism has the opposite effect if the enzyme is respon-
enzymes. Allelic variations in these enzymes lead to Alexa Zeiger, PharmD
altered drug-metabolizing capacity in patients carry- Clinical Pharmacist
ing the alleles. In pharmacogenomics, these variations Cedars Sinai Medical Network
Beverly Hills, California
in drug-metabolizing capacity are categorized as
metabolic phenotypes. John Andraos, PharmD
Clinical Pharmacist
Depending on whether a given enzyme metabolizes Cedars Sinai Medical Network
a drug to active or inactive metabolites, polymor- Beverly Hills, California
phisms of that enzyme may lead to an increased risk Ajay Sharma, BPharm, PhD
of treatment failure or side effects.1 For example, if a Assistant Professor of Pharmacology
drug is metabolized by an enzyme to inactive metab- Chapman University School of Pharmacy
Irvine, California
olites (e.g., celecoxib and CYP2C9), loss of function
Moom R. Roosan, PharmD, PhD
in the alleles of that enzyme will result in a poor (i.e.,
Assistant Professor
underactive) metabolizer phenotype, a higher concen- Chapman University School of Pharmacy
tration of the parent drug, and accordingly an Irvine, California

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U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Health Systems Edition
Pharmacogenomic Considerations in Opioid Therapy
sible for activating a prodrug to its active metabolite
for the therapeutic effect (e.g., codeine and CYP2D6).
Given the rapid decline in the cost of pharmacoge-
nomic testing and growing clinical evidence on the
impact of pharmacogenomics on pharmacotherapy,
pharmacists are ideally positioned to identify how
pharmacogenomics affects a given pharmacotherapy
and to recommend and interpret pharmacogenomic
test results in order to optimize therapy.
The Clinical Pharmacogenetics Implementation
Consortium (CPIC) publishes guidelines on the
impact of pharmacogenomics on a drug’s efficacy or
risk of side effects based on prospective clinical evi-
dence.2 Recommendations may include close moni-
toring, altering the dose, or avoiding a drug alto-
gether. This article is a critical review of recently
published CPIC guidelines on opioid use based on
pharmacogenomic variations.3
Opioid Use in Pain Management
Opioids are among the most common medications
used in the treatment of pain, and they carry many
serious risks if used inappropriately. In the manage-
ment of both acute and chronic noncancer pain, pal-
liative care, or end-of-life pain, opioids are intended
to be used after nonpharmacologic interventions and
nonopioid pharmacologic treatment options have
failed or proved insufficient.4 Nonpharmacologic
treatment options that may be attempted prior to
opioid therapy include cognitive-behavioral therapy,
exercise therapy, physical therapy, and weight loss.4
For the treatment of active cancer pain, clinicians may
initiate opioid therapy in addition to nonopioid anal-
gesics when the pain is severe enough to warrant it.5
The use of opioids in oncology patients should be
closely monitored for efficacy (in order to avoid lack
of pain control) and safety.5 The many risks of opioid
use, including sedation, constipation, dependence,
overdose, and death, should be discussed with the
patient.4 Opioid treatment should be continued only
after the patient’s improvements in pain and function
have been observed to outweigh these significant
risks.4 In addition, the CDC recommends that clini-
cians consider developing an exit strategy if treatment
with opioids does not prove beneficial for the patient.4
Meperidine is not recommended for the treatment
of cancer pain because of the risk of toxicity, and
given variations in metabolism, codeine is not pre-
ferred unless pharmacogenomic results are available.5
Pharmacologic nonopioid options include acetamin-
ophen, nonsteroidal anti-inflammatory drugs
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U.S. Pharmacist • March 2022 • www.uspharmacist.com
(NSAIDs), antidepressants such as serotonin-norepi-
nephrine reuptake inhibitors (SNRIs) and tricyclic
antidepressants (TCAs), antiepileptic medications
such as gabapentinoids, and topical analgesics such
as lidocaine and capsaicin.
CYP2D6 Polymorphism
CYP2D6, which is one of the major CYP450 enzymes
in human hepatocytes, is responsible for the metabo-
lism of a variety of central nervous system (CNS)–
active drugs, including many centrally acting analgesics
such as opioids. The CYP2D6 gene is highly polymor-
phic, with single nucleotide allelic variations resulting
in reduced or no enzyme activity. Additionally,
CYP2D6 is unique in that it can have multiple copies
of these alleles. The CPIC recommends a scoring sys-
tem based on clinical studies to help translate CYP2D6
genotypes into phenotypes. In this scoring system,
CYP2D6 alleles are given an activity score from 0 (no
activity) to 1 (normal activity). The sum of the alleles’
activity scores constitutes the activity score, which
corresponds to the patient’s ability to metabolize
CYP2D6 substrates. In the presence of multiple copies,
the allele activity score is multiplied by the number of
CYP2D6 copies the patient has, and the sum of these
scores is the patient’s activity score. Multiplication in
genes with normal activity can result in higher activity
scores and increased metabolism. Ultimately, CYP2D6
polymorphisms are categorized into “ultrarapid,”
“normal,” “intermediate,” “poor,” and “indetermi-
nate” metabolizer phenotypes.3,6
Impact of CYP2D6 Polymorphism
on Opioid Metabolism
Several common opioids—specifically, codeine, hydro-
codone, methadone, oxycodone, and tramadol—are
metabolized by the CYP2D6 enzyme (FIGURE 1).7
CYP2D6 converts codeine and tramadol to their more
active metabolites, morphine and O-desmethyltrama-
dol, respectively.8 Therefore, alterations in the metab-
olism of these drugs can have a profound impact on
their analgesic effect or risk of side effects. Oxycodone
and hydrocodone are also converted by CYP2D6 into
oxymorphone and hydromorphone, respectively.9
Although oxymorphone and hydromorphone have
higher morphine equivalents than their parent drugs,
both oxycodone and hydrocodone are active drugs, so
alterations in their metabolism have a less profound
clinical effect than codeine and tramadol. Methadone,
although partially metabolized by CYP2D6, is pre-
dominantly metabolized by other enzymes.10
 Health Systems Edition
Pharmacogenomic Considerations in Opioid Therapy

Role of CYP2D6 in the Metabolism of Codeine, Tramadol,

Figure 1
and Hydrocodonea

Codeine CYP2D6 Morphine (active UGT2B7

UGT1A3 Inactive metabolite
metabolite)

CYP2D6 ultrarapid metabolizerhigher concentration of morphineincreased risk of side effects

CYP2D6 poor metabolizerlower concentration of morphineinadequate pain control
O-desmethyltramadol
CYP2D6
Tramadol (more active metabolite)
CYP3A4
Inactive metabolite

CYP2D6 ultrarapid metabolizerhigher concentration of O-desmethyltramadol increased risk of side effects

CYP2D6 poor metabolizerlower concentration of O-desmethyltramadol inadequate pain control

Hydrocodone CYP2D6 Hydromorphone UGT2B7 Inactive metabolite

(more active metabolite)

CYP2D6 ultrarapid metabolizerhigher concentration of hydromorphoneincreased risk of side effects

CYP2D6 poor metabolizerlower concentration of hydromorphone inadequate pain control
a
The CYP2D6 enzyme converts codeine, tramadol, and hydrocodone to their active metabolites (morphine,
O-desmethyltramadol, and hydromorphone, respectively). CYP2D6 ultrarapid metabolizers are at risk for side effects
from these drugs, whereas CYP2D6 poor metabolizers are at risk for inadequate pain control. Source: Reference 7.

Evidence of CYP2D6 Polymorphisms’
Effect on Opioids and Clinical
Recommendations
Among the opioids, the impact of CYP2D6 polymor-
phisms on codeine has been the best established. Poor
metabolizers have shown both pharmacokinetic and
clinical differences compared with normal metaboliz-
ers. One study showed that patients with poor-metab-
olizer genotypes who took codeine had 96% lower
mean serum morphine AUC and 95% lower mor-
phine serum peak concentrations compared with
normal and intermediate metabolizers.11 This study
also showed no analgesia in poor metabolizers com-
pared with normal and intermediate metabolizers,
who demonstrated analgesic response.12 Another
study found that patients with sickle cell disease who
did not respond to codeine therapy for pain manage-
ment were more likely to have an activity score less
than 1.5.13 The CPIC determined that the evidence
was sufficient to conclude that CYP2D6 poor metab-
olizers who take codeine have greatly reduced mor-
phine formation, thus resulting in decreased analge-
sia. Based on these clinical studies, the CPIC strongly
recommended that codeine be avoided in CPY2D6
poor metabolizers.3
Alternatively, in pharmacokinetic studies,
CYP2D6 ultrarapid metabolizers have been shown
to have higher morphine levels.12 Ultrarapid metab-
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U.S. Pharmacist • March 2022 • www.uspharmacist.com
olizers showed a 45% higher median plasma mor-
phine AUC and 50% higher plasma concentrations
of morphine compared with normal metabolizers.12
Clinical outcomes such as severe adverse effects
(AEs) in ultrarapid metabolizers are limited to case
reports.14 Based on these studies, the CPIC concluded
definitively that when they take codeine, CYP2D6
ultrarapid metabolizers have increased morphine
formation leading to increased AEs, and that they
should avoid the use of codeine.3
Similarly, patients who were CYP2D6 poor metab-
olizers and took tramadol showed lower median
plasma concentrations of O-desmethyltramadol com-
pared with normal metabolizers.10 In several studies,
CYP2D6 poor metabolizers had less analgesia after
taking tramadol compared with normal metaboliz-
ers.10,15,16 These studies led the CPIC to definitively
conclude that CYP2D6 poor metabolizers have
decreased O-desmethyltramadol and less analgesia,
and that they should avoid the use of tramadol.3
Ultrarapid metabolizers have demonstrated both
higher O-desmethyltramadol AUC and greater anal-
gesia compared with normal metabolizers.17 Addi-
tionally, case studies have reported the occurrence of
severe AEs in ultrarapid metabolizers, leading the
CPIC to definitively conclude that CYP2D6 metabo-
lizers should avoid the use of tramadol because of
the potential for toxicity caused by an increase in
 Health Systems Edition
Pharmacogenomic Considerations in Opioid Therapy

CPIC Recommendations for Codeine, Tramadol, and Hydrocodone

Table 1

Based on CYP2D6 Polymorphisms

CYP2D6 Activity Codeine Tramadol Hydrocodone
Phenotype Score Recommendation Recommendation Recommendation

Ultrarapid >2.25 Avoid codeine due to Avoid tramadol due to No recommendation. Effect
metabolizer increased risk of AEs; increased risk of AEs; use on hydrocodone: Evidence on
use alternative alternative analgesics. pharmacokinetic effects,
analgesics. Effect on Effect on tramadol: increase in hydromorphone
codeine: Increased Increased metabolism of and clinical effects, and
metabolism of codeine tramadol to its more increased risk of adverse
to its more active active metabolite, reactions is limited
metabolite, morphine, O-desmethyltramadol,
increases risk of AEs increases risk of AEs

Normal 1.25-2.25 Use codeine according Use tramadol according to Use hydrocodone according
metabolizer to patient’s age/weight. patient’s age/weight. Effect to patient’s age/weight.
Effect on codeine: on tramadol: Tramadol is Effect on hydrocodone:
Codeine is converted converted to its more Hydrocodone is converted to
to its more active active metabolite, its more active metabolite,
metabolite, morphine, O-desmethyltramadol, at hydromorphone, at an
at an expected rate an expected rate expected rate

Intermediate 0.25-1 Use codeine according Use tramadol according to Use hydrocodone according
metabolizer to patient’s age/weight; patient’s age/weight; if no to patient’s age/weight; if no
if no response, switch response, switch to an response, switch to an
to an alternative alternative analgesic. Effect alternative analgesic. Effect
analgesic. Effect on on tramadol: Decreased on hydrocodone: Evidence on
codeine: Decreased metabolism of tramadol to pharmacokinetic effects,
metabolism of codeine its more active metabolite, decreases in hydromorphone
to its more active O-desmethyltramadol, can and clinical effects, and
metabolite, morphine, lead to potentially reduced analgesia is limited
can lead to potentially decreased analgesia
decreased analgesia

Poor 0 Avoid codeine due to Avoid tramadol due to Use hydrocodone according to
metabolizer diminished analgesia; diminished analgesia; use patient’s age/weight; if no
use alternative alternative analgesic. Effect response, switch to an
analgesic. Effect on on tramadol: Greatly alternative analgesic.
codeine: Greatly decreased metabolism of Effect on hydrocodone:
decreased metabolism tramadol to its more Hydrocodone’s conversion to
of codeine to its more active metabolite, its more active metabolite,
active metabolite, O-desmethyltramadol, leads hydromorphone, is decreased;
morphine, leads to to decreased analgesia however, evidence showing
decreased analgesia clinical impact is limited

Indeterminate Contains No recommendation. No recommendation. Effect No recommendation. Effect

metabolizer ≥1 allele Effect on codeine: on tramadol: unknown on hydrocodone: unknown
with unknown
unknown
function

AE: adverse effect; CPIC: Clinical Pharmacogenetics Implementation Consortium. Source: Reference 3.

O-desmethyltramadol.3,18,19 ference between poor metabolizers and normal metab-

Although hydromorphone plasma levels are similar olizers. Normal metabolizers administered
between ultrarapid metabolizers and normal metabo- hydrocodone had hydromorphone levels five times
lizers who use hydrocodone, there is a discernible dif- higher compared with poor metabolizers given the
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U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Health Systems Edition
Pharmacogenomic Considerations in Opioid Therapy

Other Clinical Factors to Consider in Specialty Patient Populations

Table 2

Population General and Pharmacogenomic Considerations

Geriatrics Older patients may be at higher risk for falls and fractures secondary to oversedation. Fall-risk
assessment and continuous monitoring of patient’s bowel regimen, sedation, and cognitive function are
recommended. Consider starting acetaminophen and lower-dose opioids. In the presence of CYP2D6
ultrarapid or poor metabolism, morphine may be an effective opioid alternative

Pediatrics Use of codeine and tramadol is contraindicated in patients aged less than 12 years and for the
management of pain in patients aged 12-18 years following tonsillectomy and/or adenoidectomy
regardless of pharmacogenomic results. In the presence of CYP2D6 interactions, consider starting
NSAIDs, acetaminophen, and lower-dose opioids other than codeine or tramadol

Pregnant Consider tapering opioids because of the risk of withdrawal for both mother and fetus, especially in
women patients with ultrarapid or poor CYP2D6 metabolism. In the presence of CYP2D6 interactions, consider
NSAIDs, acetaminophen, and lower-dose opioids (i.e., low-dose morphine)

Breastfeeding Use of codeine and tramadol should be avoided when possible because of the increased risk of infant
women death, especially in mothers who are CYP2D6 ultrarapid metabolizers. In the presence of CYP2D6
interactions, consider initiating nonopioids (i.e., ibuprofen, acetaminophen), morphine, or
hydromorphone

Renal Avoid hydromorphone ER, meperidine, tramadol ER, codeine, and tapentadol. Use methadone,
insufficiency hydromorphone IR, oxycodone, oxymorphone, morphine, and tramadol IR with caution. In the presence
of CYP2D6 interactions, consider starting fentanyl, buprenorphine, and morphine with caution
Hepatic Avoid methadone, meperidine, codeine, oxymorphone, tramadol ER, and tapentadol. Use
insufficiency hydromorphone, oxycodone, morphine, tramadol IR, and buprenorphine (buccal) with caution. In the
presence of CYP2D6 interactions, consider starting fentanyl. Use hydromorphone, morphine, and
buprenorphine (buccal) with caution

ER: extended-release; IR: immediate-release; NSAID: nonsteroidal anti-inflammatory drug. Source: References 2-4, 27-34.

same dose.20 However, clinical studies highlighting the
effects of CYP2D6 polymorphisms on hydrocodone
safety and efficacy are limited. For this reason, the
CPIC added an optional recommendation to switch
analgesics only if a CYP2D6 poor metabolizer does
not respond to label-based doses of hydrocodone.3
Recommendations for oxycodone and methadone
in CYP2D6 gene polymorphisms are uncertain.
Although in one study poor metabolizers taking oxy-
codone had oxymorphone levels that were 67%
lower than in normal metabolizers, this did not
necessitate an increase in oxycodone dose in poor
metabolizers.21 Additionally, ultrarapid metaboliz-
ers showed no pharmacokinetic differences for oxy-
morphone levels compared with normal metaboliz-
ers.21,22 Prospective studies of clinical effectiveness
are variable; some studies show analgesic and AE
differences between poor, normal, and ultrarapid
metabolizers with oxycodone use, whereas other
studies demonstrate no difference, making evidence
inconclusive.21-25 CYP2D6 metabolizes methadone
to an inactive metabolite to a minor extent, but AEs
and analgesia do not seem to be affected by CYP2D6
HS-11
U.S. Pharmacist • March 2022 • www.uspharmacist.com
polymorphisms. For these reasons, the CPIC con-
cluded that data are insufficient to make recommen-
dations for oxycodone and methadone.
Current CPIC recommendations for opioid use
based on CYP2D6 gene polymorphisms are summa-
rized in TABLE 1.
Safer Alternatives and Other
Considerations
For patients who are not candidates for codeine, tra-
madol, or hydrocodone based on their CYP2D6 poly-
morphisms, the CPIC recommends using opioids that
are not metabolized by CYP2D6—namely, morphine,
fentanyl, tapentadol, buprenorphine, and meperidine.
When indicated, pharmacologic nonopioid options
may include acetaminophen, NSAIDs, SNRIs, TCAs,
gabapentinoids, and topical analgesics. When decid-
ing on alternatives, clinicians should also consider
other CYP interactions. For example, if genetic testing
results are available for a patient, providers should
be aware of alterations in the metabolism of CYP2C9
for NSAIDs and both CYP2D6 and CYP2C19 for
TCAs.26
 Health Systems Edition
Pharmacogenomic Considerations in Opioid Therapy
Pharmacogenomics-guided opioid therapy
enables clinicians to determine the best options for
avoiding treatment failure and serious side effects.
However, clinicians should continue to personalize
pain management by considering other factors as
well (TABLE 2).2-4,26-34 For example, elderly patients
are at higher risk for falls and fractures secondary
to oversedation.4 Therefore, opioid therapy in
elderly patients should be initiated and titrated with
caution, and patients should be monitored more
frequently for constipation, cognitive function, seda-
tion, and fall risk.
It should be noted that the risks of oversedation
and respiratory depression are considerable if opioid
therapy is used in conjunction with additional CNS
depressants, such as muscle relaxants and benzodi-
azepines.4 Particular caution should be taken when
CYP2D6 substrates are used in the presence of sig-
nificant drug-drug interactions, especially CYP2D6
inhibitors (e.g., bupropion, cinacalcet, fluoxetine,
paroxetine, quinidine) and inducers (e.g., dexameth-
asone, oritavancin, rifampin); this is because inter-
acting medications can potentially change the
CYP2D6 phenotype (i.e., phenoconversion).35 An
alternative opioid independent of CYP2D6 may be
safer in patients with interacting medications.
Impact of COMT and OPRM1
Polymorphism on Opioid Use
The recent CPIC opioid guideline introduces other
genes that potentially may be associated with altered
opioid efficacy and AEs—namely, OPRM1 (mu
receptor) and catechol-O-methyltransferase
(COMT).3 Because OPRM1 is a gene that codes for
mu receptors, alterations in OPRM1 can cause
reduced mu-receptor expression.36 COMT conjugates
methyl to catecholamines, such as dopamine, and can
affect synaptic levels of catecholamines and, in turn,
pain perception. COMT polymorphism can lessen
the enzyme’s ability to methylate dopamine, resulting
in higher pain levels and decreased opioid effective-
ness.37 Although polymorphisms in OPRM1 and
COMT have been reported, study results on clinical
differences in patients with OPRM1 and COMT
polymorphism are inconsistent. Some studies show a
slightly increased opioid requirement in patients with
at least one copy of the rs1799971 G allele of
OPRM1.3 No data demonstrate increased opioid AEs
in patients with rs4680, a COMT variant. Therefore,
insufficient evidence is currently available on the pres-
ence of OPRM1 and COMT allelic polymorphisms
HS-12
U.S. Pharmacist • March 2022 • www.uspharmacist.com
and opioid-dose requirements.3 Owing to the lack of
strong evidence, the CPIC did not make any recom-
mendations regarding opioid dosing based on
OPRM1 or COMT genetic polymorphism. However,
this likely will change as knowledge in this area
expands.
The Pharmacist’s Role
Pharmacists play a critical role in the optimization
of pain medications and risk mitigation in patients
receiving chronic opioid therapy. Titrating nonopi-
oid analgesics to their optimal tolerated doses can
reduce the need to escalate opioid regimens or even
to introduce them altogether. On a broader scale,
pharmacists can play a vital part in curbing the
national opioid crisis by providing patient and fam-
ily education and either requesting a prescription
for or furnishing naloxone to patients at higher risk.
By better understanding the pathways of opioid
metabolism, pharmacists can identify patients who
would be appropriate candidates for CYP pharma-
cogenomic testing and can help select the optimal
pharmacogenomic test that takes patients’ ethnicity
and other clinical factors into consideration.38 For
patients who undergo pharmacogenomic testing,
pharmacists can take the lead in accurately inter-
preting the results and making recommendations
for appropriate therapy. Using the test results, phar-
macists may be able to identify patients with drug-
seeking behavior related to uncontrolled pain and
offer them alternatives. In patients without genetic
testing who are responding unconventionally to
opioid treatment, genetic alterations may help
explain treatment failure and point to alternative
options.
Conclusion
As medicine continues to become more personalized,
prescribers must adjust to its advances. Opioids
must be used safely and monitored closely. Pharma-
cogenomics helps practitioners predict clinical
responses to therapies. Understanding the principles
of genetic testing for opioids leads to therapy that
yields improved responses and fewer AEs. Pharma-
cogenomic tests can help pharmacists identify
patients at higher risk for opioid-related side effects
or treatment failure.
References available online at www.uspharmacist.com.
The content contained in this article is for informational purposes
only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is solely
at your own risk.
 INDUSTRYNEWS
FDA Fully Approves Spikevax,
Moderna’s mRNA COVID-19 Vaccine
Moderna, Inc. announced that the FDA approved
the Biologics License Application for Spikevax to
prevent COVID-19 in individuals aged 18 years
and older. The FDA based its decision on the
totality of scientific evidence shared by the com-
pany in its submission package, which included
follow-up data from the phase III COVE study
showing high efficacy and favorable safety
approximately 6 months after the second dose.
Moderna’s COVID-19 vaccine was available
under Emergency Use Authorization in the
United States since December 18, 2020. A
booster dose of the Moderna COVID-19 vaccine
at the 50-µg dose level is authorized for emer-
gency use in the U.S. for adults aged 18 years
and older. A third dose of the Moderna COVID-
19 vaccine at the 100-µg dose level is authorized
for emergency use in immunocompromised indi-
viduals aged 18 years or older in the U.S. who
have undergone solid organ transplantation, or
who are diagnosed with conditions that are con-
sidered to have an equivalent level of immuno-
compromise.
Camber Launches Generic Colcrys,
Fosaprepitant for Injection
Camber Pharmaceuticals announced the addi-
tion of Colchicine Tab-
lets (Colcrys; Takeda
Pharmaceuticals) to its
current portfolio.
Colchicine Tablets
are an alkaloid indi-
cated for prophylaxis
and treatment of gout flares in adults and
familial Mediterranean fever in adults and chil-
dren aged 4 years or older. Camber Colchicine
0.6-mg Tablets are available in 30- and 100-
count bottles.
Camber Pharmaceuticals also announced the
addition of fosaprepitant for injection to its cur-
rent portfolio. Fosaprepitant for injection is
indicated in adults for the prevention of acute
and delayed nausea and vomiting associated
with initial and repeat courses of highly emeto-
13
U.S. Pharmacist • March 2022 • www.uspharmacist.com
genic cancer chemotherapy, including high-dose
cisplatin, and delayed nausea and vomiting asso-
ciated with initial and repeat courses of moder-
ately emetogenic cancer chemotherapy. Fosapre-
pitant for injection is available in 150-mg,
single-dose vials.
FDA Approves Azurity
Pharmaceuticals’ Fleqsuvy
Azurity Pharmaceuticals, Inc., announced the
FDA approval of Fleqsuvy (baclofen oral sus-
pension), 25 mg per 5 mL (5 mg/mL), concen-
trated formulation for the treatment of spastic-
ity from multiple sclerosis (MS) or in patients
with spinal cord injuries and other spinal cord
diseases.
Nearly 1 million people are living with MS in
the U.S. Spasticity is a commonly reported
symptom in MS, with an estimated prevalence
of spasticity of 67%. Due to the severity of
spasticity resulting from MS or from spinal cord
injuries and other spinal cord diseases, dosing
becomes paramount to providing appropriate
relief. Dysphagia is commonly experienced,
affecting approximately 43% of MS patients
and 16% to 30% of patients with spinal cord
injuries.
Fleqsuvy provides an option as a baclofen
oral liquid medication at an effective dose for
patients who have trouble swallowing pills or
prefer a liquid formulation. As the most concen-
trated FDA-approved oral liquid baclofen for-
mulation, Fleqsuvy allows for the lowest volume
to be prescribed for patients, which can be an
important consideration for those suffering from
dysphagia.
Agios Announces Approval of Pyrukynd
Agios Pharmaceuticals, Inc., Cambridge, Massa-
chusetts, announced that the FDA approved
Pyrukynd (mitapivat) in the U.S. for the treat-
ment of hemolytic anemia in adults with pyru-
vate kinase (PK) deficiency, a rare, debilitating,
lifelong hemolytic anemia. Pyrukynd is a first-
in-class, oral PK activator and the first
approved disease-modifying therapy for this
condition.
 TRENDWATCH

Research on Pain Mechanisms

and Nondrug Treatment Approaches

T he National Institutes of Health

notes that pain is the most com-
mon reason for seeking medical
Federally Funded Research on Pain
Mechanisms and Treatments
care. In addition to pharmaceuticals
Pharmaceutical
and nutraceuticals, people turn to mechanisms &
complementary and integrative Transitions in treatments
pain phases Pain &
health approaches for relief from Nonpharmaceutical trauma
mechanisms &
pain. In 2017, according to the treatments
National Health Interview Survey, 18% Biobehavioral
17% of adults experienced severe 15% & psychosocial
9% mechanisms
pain and 11% of adults had daily 13%
Other
2%

pain. In 2011, the Institute of Med-
icine (now the National Academy
Neurobiologic/glial
of Sciences [NAS]) reported that mechanisms
more than 100 million adults expe-
rienced chronic pain, and other
studies have shown that 25 million
adults had daily pain, 10 million
had high levels of pain, and 8 million suffered
from pain severe enough to interfere with their
lives. The annual cost of health care—including
lost productivity due to pain—approximated $600
billion, with missed workdays costing $13 billion
and lost work hours costing $97 billion, according
to the NAS.
Nonpharmaceutical Research: This type of research
focuses on psychological and/or physical
approaches to pain management. To obtain pain
relief, 3 million adults used acupuncture, 4.2 mil-
lion used yoga, 15.4 million used massage therapy,
and 29.7 million used meditation. Nontraditional
methods were also used for pain management in
children and adolescents aged 4 to 17 years, includ-
ing massage (385,000 individuals), meditation (4
million), and yoga (4.5 million).
Characteristics and Type of Research: A systematic
review by the Agency for Healthcare Research and
Quality found increased evidence that nondrug
approaches such as acupuncture, hypnosis, mas-
sage, mindfulness meditation, spinal manipulation,
tai chi, and yoga may help manage some painful
conditions. In some instances, such approaches pro-
Somnath Pal, BS (Pharm), MBA, PhD
Professor of Pharmacy Administration
College of Pharmacy & Health Sciences, St. John’s University
Jamaica, New York
© gettyimages.com / JobsonHealthcare
43%
vided temporary relief rather than a cure. The
National Center for Complementary and Integra-
tive Health supports, conducts, and funds pain
research, as do the Department of Defense and the
Department of Veterans Affairs, which have funded
4% and 5%, respectively, of research. In federally
funded research on pain mechanisms and treat-
ment, 20.4% of studies chiefly focused on neuro-
logic/glial aspects, 7.3% examined nondrug
approaches, and 5.9% investigated biobehavioral
and psychosocial aspects. Although training for
pain management was included in only 7% of stud-
ies, all study protocols addressed basic (40%), clini-
cal (42%), and translational (18%) aspects of
research.
Research Themes: Overarching pain-research
themes in 2011 included pain mechanisms (42%),
basic-to-clinical (11%), disparities (10%), training
and education (10%), tools and instruments (8%),
and surveillance and human trials (5%). Among
the topics of studies related to disparities were
health and access to care (10%); sex and gender
(12%); women’s and minority health (14%); sub-
stance use and abuse/addiction (19%); and specific
patient populations, such as elderly, end-of-life, dis-
abled, and military (45%).
The content in this article is for informational purposes only.
The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is
solely at your own risk.

14
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Psoriatic Arthritis
CUT ALONG PERFORATION

Chronic Inflammatory Disease

Psoriatic arthritis (PsA) is a chronic, progressive inflammatory disease that affects indi-
viduals diagnosed with the skin condition psoriasis. Studies show that up to 30% of patients
with psoriasis will develop PsA as a complication. Still, the actual number might be higher
given that PsA is often mistaken for other types of arthritis. It affects men and women
almost equally, with an average age at onset of 30 to 40 years. In most people, the skin
lesions of psoriasis appear before PsA develops. In some individuals, the arthritic symptoms
appear simultaneously with the skin disease. In others, arthritis occurs before the skin lesions
of psoriasis.

Copyright Jobson Medical Information LLC, 2022 continued

Affects People With Psoriasis

© Jobson Medical Information LLC, 2022

The joint pain, stiffness, and swelling associated with PsA can
resemble other arthritic conditions. Still, the underlying cause of
PsA is the presence of psoriasis. Psoriasis is a skin disease that
manifests as itchy, scaly, red patches on the body—most commonly
the scalp, trunk, knees, and elbows. Scientists believe both genetics
and environmental factors, such as infections and physical injury,
contribute to the development of psoriasis and PsA. Recent studies
have pointed to specific psoriatic risk factors that increase the risk

CUT ALONG PERFORATION

of developing PsA, including having more than three body sites
affected by psoriasis. Lesions located on the scalp or between the People with more than three
body sites affected by psoria-
buttocks seem to increase the risk of PsA. sis have an increased risk of
developing PsA.
Diagnosis Is Challenging But Important
Physicians will look for several characteristic symptoms of PsA when making a diagnosis. Pain,
swelling, and stiffness commonly occur in the knees, fingers, hips, ankles, and wrists. Painful,
sausage-like swelling of a single toe or finger indicates PsA. Lower back pain caused by swelling
of the joints between the vertebrae of the spine and foot pain, especially near the back of the heel
or on the sole of the foot, can be present in PsA. In addition to the joint pain, changes in the nails,
and inflammation of the eye, called uveitis, also indicate PsA. The symptoms of PsA can alternate
between flares and remission and can also change in location over time.
PsA looks very similar to other arthritic conditions, making it challenging to diagnose immedi-
ately. It is crucial that PsA is diagnosed relatively quickly, as permanent damage to the joints can
occur, leading to loss of function, disability, and a significant impact on a person’s quality of life.
Additionally, those with PsA are at a higher risk of developing inflammatory bowel disease, car-
diovascular diseases (including obesity, hypertension, and type 2 diabetes mellitus), depression,
anxiety, and fatty liver disease.

Drug Treatment Can Slow Progression

The past 20 years have provided many new options for managing the symptoms and slowing the
progression of PsA. The therapy goals are to reduce symptoms, minimize joint damage, and pre-
serve physical functioning. In addition to medical management, nonpharmacologic therapies,
including physical therapy, occupational therapy, exercise programs, and smoking cessation, are
often part of the treatment plan. Unfortunately, there is no cure for PsA or psoriasis.
OTC nonsteroidal anti-inflammatory drugs, such ibuprofen and naproxen sodium, can relieve
pain and reduce inflammation for people with mild PsA. Side effects can include stomach irrita-
tion, heart problems, and liver and kidney damage. A large group of medications known as
disease-modifying antirheumatic drugs (DMARDs) is commonly used to treat PsA. These drugs
can slow the progression of PsA and save joints and other tissues from permanent damage.
Depending on the type of PsA symptoms, location, and severity, physicians may choose one or
a combination of synthetic, biologic, or targeted DMARDs. More recently, an oral medication,
apremilast (Otezla), was approved for people with mild or moderate PsA. who cannot take
DMARDs or biologic agents. All medications used for the treatment of PsA have serious side
effects. Those considering them should discuss them thoroughly with a physician or pharmacist.
Complete symptomatic relief is achievable, but a significant majority of patients continue to
have persistent inflammatory disease.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for profes-
sional advice. Reliance on any information provided in this article is solely at your own risk.
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 Anticipating the
First Adalimumab
Biosimilar
ABSTRACT: Rheumatoid arthritis is
among the most common arthritic
diseases, with 71 cases diagnosed per
100,000 people. To alleviate symptoms
and reduce long-term damage,
treatment options available to patients
include biologics, particularly
© gettyimages.com / JobsonHealthcare adalimumab (Humira)—a tumor
necrosis factor inhibitor. The drug has
played a vital role in the treatment of rheumatoid arthritis over the years, but recently
adalimumab-adbm (Cyltezo) was developed as the first interchangeable biosimilar that
mimics the structure and function of the original product.

A ccording to the National Institutes of Health,

autoimmune and inflammatory diseases have
affected more than 24 million people in the United
breakthrough in the realm of autoimmune disease
treatments.

States since 2005.1 These conditions are caused by the
immune system’s inability to differentiate true foreign
invaders. Therefore, the immune system mistakes parts
of the body as threats and releases autoantibodies to
destroy the healthy cells. Although the cause for these
disease states remains a mystery, medications and new
therapeutic guidelines have emerged over time to com-
bat these conditions.
Rheumatoid arthritis (RA), for instance, is one of
the most prevalent autoimmune disorders in the U.S.
Although there is currently no cure for this disease, the
goal is to achieve a state of remission in which symp-
toms are less likely to occur. Adalimumab (Humira),
introduced in 2002, was one of the many common
therapies used to reduce signs and symptoms of RA.2
Despite providing relief to a large number of patients
over the years, there were consistent barriers that pre-
vented individuals from accessing appropriate care.
The FDA recently approved the first interchange-
able biosimilar to adalimumab, creating a major
Rheumatoid Arthritis
Although the cause of autoimmune and inflammatory
diseases remains unknown, there are more than 80
clinical diseases that originate from an autoimmune
response.3 The variety of diseases stems from the fact
that autoimmune disorders can affect any tissue or
organ in the body. Hence, the range of symptoms
between each disease state can differ, with some being
mild and manageable while others are debilitating and
life-threatening. An example of this is the common
condition RA, an autoimmune and inflammatory dis-
ease in which the immune system attacks healthy cells,
causing inflammation mainly in the joints of the body.4
The synovium, the tissue around the joint that pro-
duces fluid allowing for smooth movement, is espe-
cially damaged, and the inflamed area makes the joint
sore and painful, causing difficult movement.5,6 The
Amanda Ye, RPh, PharmD
Medical Director–Health Professional Digital Education
Staten Island, New York

18
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Anticipating the First Adalimumab Biosimilar
most common joints affected by this condition are the
hands, knees, and wrists, but in more severe cases, this
form of arthritis can also affect other parts of the body,
such as the lungs, eyes, and heart.5,6 Internal organs
that are affected become subject to persistent tissue
damage, and RA can cause chronic pain or severe
deformities.
In the U.S., approximately 1.3 million patients
suffer from RA.7 While the number of cases continues
to surge, the total healthcare costs increase as well.7
The objective of ensuring that all patients have afford-
able access to treatment that can relieve their symp-
toms and improve their quality of life remains unmet.
In most cases, the treatment goal, at a minimum, is to
reduce inflammation and swelling while improving
joint function. However, the end result that clinicians
hope for is to slow the progression of the disease and
reduce further damage to the affected areas.6
Management of RA
Currently, there are three main classes of therapeu-
tic options available to treat RA: nonsteroidal
anti-inflammatory agents (NSAIDs), corticosteroids,
and disease-modifying antirheumatic drugs
(DMARDs).5,6 NSAIDs and corticosteroids are used
to relieve pain and help mitigate inflammation at
the site of injury. Side effects most commonly seen
with the use of NSAIDs are stomach and kidney
damage. For patients who have localized gastric
side-effect concerns, cyclooxygenase 2 (COX-2)
anti-inflammatory agents are seen as an alternative.
These agents restrain COX-2 enzyme and decrease
the number of prostaglandins.5 In doing so, pros-
taglandins that are protective of the stomach and
kidney remain, and inflammation is reduced. Mean-
while, low-dose corticosteroids can be utilized to
decrease the amount of inflammation and suppress
flares by regulating the autoimmune system.4
DMARDs are a major class of drugs that halt the
progression of disease by altering the immune system.
There are two categories in this class: traditional
DMARDs and biologics. The severity of the ailment,
side effects, and patient preferences all play a role in
medicine selection. While traditional DMARDs have
been used extensively throughout treatment, biolog-
ics are becoming increasingly popular. Biologics are
produced using recombinant DNA and prevent or
reduce inflammation in the damaged sites.8 They
attack more specific inflammation-causing cells and,
therefore, are considered more effective.8 One exam-
ple of a biologic drug used for RA is adalimumab
19
U.S. Pharmacist • March 2022 • www.uspharmacist.com
(Humira). TABLE 1 shows all of the available FDA-
approved DMARDs for the treatment of RA.6,8
Adalimumab
Adalimumab is a registered trademark of AbbVie Bio-
technology Ltd.9 Adalimumab is a tumor necrosis fac-
tor (TNF) blocker indicated for an array of conditions,
such as moderate-to-severe RA, juvenile idiopathic
arthritis, psoriatic arthritis, ankylosing spondylitis,
Crohn’s disease, ulcerative colitis, plaque psoriasis,
hidradenitis supprativa, and uveitis.2 Its mechanism of
action revolves around TNF, a naturally occurring
cytokine involved in normal inflammatory and
immune responses.2 Elevated levels of TNF are seen in
many autoimmune and inflammatory diseases and play
a role in pathological inflammation and joint destruc-
tion.2 Adalimumab binds to TNF-alpha and blocks its
interaction with TNF receptors on the surface of p55
and p75 cells.2 Specifically, for RA, adalimumab works
by inhibiting the progression of structural damage and
improving physical function in adult patients. It can be
used alone or in combination with a nonbiologic
DMARD.2 Adalimumab is administered as an SC
injection, and the dose varies depending on the patient’s
condition, weight, and age. The most common adverse
effects associated with adalimumab are injection-site
reactions, infections, headache, and rash.2
Adalimumab-adbm
On October 15, 2021, the FDA approved the first
interchangeable biosimilar to adalimumab, called
adalimumab-adbm (Cyltezo). A biosimilar is a bio-
logical product that carries no clinical difference from
the already-approved medication but includes similar
components.10 The idea behind creating interchange-
able biosimilars is to offer products that can be substi-
tuted for the reference product without the worry of a
change in clinical efficacy. Adalimumab-adbm was
originally approved in August 2017 for the treatment
of multiple chronic inflammatory diseases.11 However,
in October 2021, the FDA granted its approval through
the supplemental Biologics License Application to
Boehringer Ingelheim.9 The new biosimilar falls within
its mission’s intention by providing an alternative ther-
apeutic option to help with many chronic inflammatory
conditions. Both products share the same clinical
results, including expected boxed warnings. The
approval of these interchangeable biosimilars creates
increased access to treatment options for patients with
serious medical conditions.4
Adalimumab-adbm is also a TNF inhibitor and is
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to ibrexafungerp
• BREXAFEMME administration during pregnancy may cause fetal harm based on animal studies. Prior
to initiating treatment, verify pregnancy status in females of reproductive potential and advise
them to use effective contraception during treatment
• When administering BREXAFEMME with strong CYP3A inhibitors, the dose of BREXAFEMME should
be reduced to 150 mg twice a day for one day. Administration of BREXAFEMME with strong CYP3A
inducers should be avoided
 A difference that’s affordable
Help patients pay as little as $30†
Use the following information to help them save:

BIN # PCN # GROUP # ID #

004682 CN WCBRX2003 15225835224

Commercial insurance patients may pay as little as $30

Cash-paying patients may pay as little as $120
Patients can also access the Savings Card at BREXAFEMME.com/SAVINGS
or by texting “SAVE” to “BREXA”‡ (27392)

For Terms and Conditions, visit BREXAFEMMEHCP.com/SAVINGS.

†

Message and data rates may apply. 1 message per request. Reply “HELP” for help and “STOP” to stop.
‡

For questions with processing, call 1-800-433-4893.

Important Safety Information (continued)
• Most common adverse reactions observed in clinical trials (incidence ≥2%) were diarrhea, nausea,
abdominal pain, dizziness, and vomiting
To report SUSPECTED ADVERSE REACTIONS, contact SCYNEXIS, Inc. at 1-888-982-SCYX
(1-888-982-7299) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Learn more at BREXAFEMMEHCP.com

Please see accompanying Brief Summary of full Prescribing Information

on the following page.
Reference: BREXAFEMME. Prescribing information. SCYNEXIS, Inc; 2021.

© 2021 SCYNEXIS, Inc. All rights reserved.

BREXAFEMME is a registered trademark of SCYNEXIS, Inc.
Printed in the USA. US-BREX-2100083 September 2021.
BREXAFEMME® (ibrexafungerp tablets), for oral use
BRIEF SUMMARY OF PRESCRIBING INFORMATION
This Brief Summary does not include all information needed to use BREXAFEMME
safely and effectively. Please visit www.BREXAFEMMEHCP.com for full prescribing
information (PI).
INDICATIONS AND USAGE
BREXAFEMME® is indicated for the treatment of adult and post-menarchal
pediatric females with vulvovaginal candidiasis (VVC).
Usage
If specimens for fungal culture are obtained prior to therapy, antifungal therapy
may be instituted before the results of the cultures are known. However, once
these results become available, antifungal therapy should be adjusted accordingly.
DOSAGE AND ADMINISTRATION
Recommended Dosage
The recommended dosage of BREXAFEMME is 300 mg (two 150 mg tablets)
administered approximately 12 hours apart (e.g., in the morning and in the
evening) for one day, for a total daily dosage of 600 mg (four 150 mg tablets).
BREXAFEMME may be taken with or without food.
Dosage Modifications in Patients due to Concomitant Use of a Strong
Inhibitor of Cytochrome P450 Isoenzymes (CYP) 3A
With concomitant use of a strong CYP3A inhibitor, administer BREXAFEMME
150 mg approximately 12 hours apart (i.e., in the morning and in the evening) for
one day. No dosage adjustment is warranted in patients with concomitant use of
a weak or moderate CYP3A inhibitor.
Pregnancy Evaluation Prior to Initiating Treatment
Verify the pregnancy status in females of reproductive potential prior to initiating
treatment with BREXAFEMME.
CONTRAINDICATIONS
BREXAFEMME is contraindicated in pregnancy and in patients with hypersensitivity
to ibrexafungerp.
WARNINGS AND PRECAUTIONS
Based on findings from animal studies, BREXAFEMME use is contraindicated
in pregnancy because it may cause fetal harm. In animal reproduction studies,
ibrexafungerp administered orally to pregnant rabbits during organogenesis was
associated with fetal malformations including absent forelimb(s), absent hindpaw,
absent ear pinna, and thoracogastroschisis at dose exposures greater or equal
to approximately 5 times the human exposure at the recommended human
dose (RHD).
Prior to initiating treatment with BREXAFEMME, verify the pregnancy status in
females of reproductive potential. Advise females of reproductive potential to use
effective contraception during treatment with BREXAFEMME and for 4 days after
the last dose.
ADVERSE REACTIONS
The most frequent adverse reactions (≥ 2%) reported with BREXAFEMME in
clinical trials of vulvovaginal candidiasis treatment were diarrhea (16.7%), nausea
(11.9%), abdominal pain (11.4%), dizziness (3.3%), and vomiting (2.0%).
There were no serious adverse reactions and 2 out of 545 (0.4%) patients
discontinued treatment with BREXAFEMME due to vomiting (1) and dizziness (1).
The following adverse reactions occurred in < 2% of patients receiving
BREXAFEMME: dysmenorrhea, flatulence, back pain, elevated transaminases,
vaginal bleeding, rash/hypersensitivity reaction.
DRUG INTERACTIONS
Ibrexafungerp is a substrate of CYP3A4. Drugs that inhibit or induce CYP3A may
alter the plasma concentrations of ibrexafungerp and affect the safety and efficacy
of BREXAFEMME. Avoid concomitant administration of BREXAFEMME with strong
and moderate CYP3A inducers and reduce the BREXAFEMME dosage with strong
CYP3A inhibitors (see Dosage and Administration above).
USE IN SPECIFIC POPULATIONS
Pregnancy
Based on findings from animal studies, BREXAFEMME use is contraindicated
in pregnancy because it may cause fetal harm. In pregnant rabbits, oral
ibrexafungerp administered during organogenesis was associated with rare
malformations including absent forelimb(s), absent hindpaw, absent ear pinna,
and thoracogastroschisis at dose exposures greater or equal to approximately
5 times the human exposure at the RHD. Oral ibrexafungerp administered to
pregnant rats during organogenesis was not associated with fetal toxicity or
increased fetal malformations at a dose exposure approximately 5 times the
human exposure at the RHD. Available data on BREXAFEMME use in pregnant
women are insufficient to draw conclusions about any drug-associated risks of
major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
There is a pregnancy safety study for BREXAFEMME. If BREXAFEMME is
inadvertently administered during pregnancy or if pregnancy is detected within
4 days after a patient receives BREXAFEMME, pregnant women exposed
to BREXAFEMME and healthcare providers should report pregnancies to
SCYNEXIS, Inc. at 1-888-982-SCYX (7299).
Lactation
There are no data on the presence of ibrexafungerp in either human or animal
milk, the effects on the breast-fed infant, or the effects on milk production.
Females and Males of Reproductive Potential
Based on animal data, BREXAFEMME may cause fetal harm when administered to
a pregnant female. Verify the pregnancy status in females of reproductive potential
prior to initiating treatment with BREXAFEMME. Advise females of reproductive
potential to use effective contraception during treatment with BREXAFEMME and
for 4 days after the last dose.
Pediatric Use
The safety and effectiveness of BREXAFEMME for treatment of VVC have been
established in post-menarchal pediatric females. Use of BREXAFEMME in
post-menarchal pediatric patients is supported by evidence from adequate and
well-controlled studies of BREXAFEMME in adult non-pregnant women with
additional safety data from post-menarchal pediatric females.
The safety and effectiveness of BREXAFEMME have not been established in
pre-menarchal pediatric females.
Geriatric Use
Clinical studies with ibrexafungerp did not include sufficient numbers of
subjects aged 65 and older to determine whether they respond differently from
younger subjects. No clinically meaningful differences in the pharmacokinetics
of ibrexafungerp were observed in geriatric patients compared to younger adults.
Manufactured for:
SCYNEXIS, Inc.
Jersey City, NJ 07302
BREXAFEMME® is a registered trademark of SCYNEXIS, Inc.
Copyright © 2021
 Anticipating the First Adalimumab Biosimilar
Table 1
Available FDA-Approved DMARDs for the Treatment of RA (2021)
DMARD Classification
csDMARD Conventional synthetic
tsDMARD Targeted synthetic
bDMARD Biologic
bDMARD: biologic disease-modifying antirheumatic drug; csDMARD: conventional synthetic disease-modifying antirheu-
matic drug; DMARD: disease-modifying antirheumatic drug; tsDMARD: targeted synthetic disease-modifying antirheumatic
drug; TNF: tumor necrosis factor. Source: References 6, 8.
approved to treat the following conditions: moderate-
to-severe active RA, psoriatic arthritis, ankylosing
spondylitis, moderate-to-severe active Crohn’s disease,
moderate-to-severe active ulcerative colitis, moderate-
to-severe chronic plaque psoriasis, moderate-to-severe
active polyarticular juvenile idiopathic arthritis in
patients aged 2 years and older, and pediatric patients
aged 6 years and older with Crohn’s disease.10,12 The
formulation is a single-dose, prefilled glass syringe with
two available strengths: 40 mg/0.8 mL and 20 mg/0.4
mL.12 Adalimumab-adbm works in the same way as
adalimumab; both bind specifically to TNF-alpha and
block interactions with TNF receptors on the p55 and
p75 cell surfaces and lyse in vitro–expressed surface
TNFs.12 Likewise, treatment can reduce the thickness
of the epidermis and cause infiltration of inflammatory
cells.12 Infections, injection-site reactions, headache,
and rash are all common side effects.11,12
Adalimumab-adbm represents the first interchange-
able monoclonal antibody. With its approval, the
FDA’s Purple Book, the official directory of all
approved biosimilars and interchangeables, is
updated.13 Adalimumab-adbm will not be available
until July 2023, but the therapeutic impact could be
staggering.9 Replacing benchmark products with bio-
similars could further ease the financial burden of
patients. As the chairman of the Division of Dermatol-
ogy at Baylor University Medical Center exclaimed,
“As the first interchangeable biosimilar of adalim-
umab, Cyltezo (adalimumab-adbm) represents an
important step toward bringing patients more afford-
23
U.S. Pharmacist • March 2022 • www.uspharmacist.com
FDA-Approved Medications
Hydroxychloroquine
Leflunomide
Methotrexate
Sulfasalazine
Baricitinib
Tofacitinib
Upadacitinib
Anti-TNF: Non-TNF:
Adalimumab Abatacept
Certolizumab pegol Rituximab
Etanercept Tocilizumab
Golimumab Sarliumab
Infliximab
able treatment options for complex, and often expen-
sive, biologic reference products.”9
VOLTAIRE-RA Trial
The VOLTAIRE-RA trial was completed in 2015,
with the objective to prove the clinical equivalence of
adalimumab-adbm and adalimumab. In a test group
of 645 patients with clinically diagnosed active RA,
this study used a double-blind, randomized, parallel-
group intervention approach.14 It was noted that the
patients were stable on methotrexate and randomized
to continue with either the biosimilar adalimumab-
adbm or adalimumab within a 24-hour treatment
time frame.14 The primary endpoint was illustrated
through the percentage of patients achieving the
American College of Rheumatology 20% response
criteria (ACR20) at Weeks 12 and 24.14 Efficacy,
safety, and immunogenicity were also observed up to
Week 58 of treatment.14
Results show that 67.0% (n = 324) of those who
received adalimumab-adbm and 61.1% (n = 321) of
those who received adalimumab achieved ACR20
(90% CI 0.9-12.7).14 Meanwhile, at the 24th week,
69.0% and 64.5% (95% CI 3.4-12.5) were achieved,
respectively.14 Changes in mean response rates for
ACR20 were similar when re-randomized at 24
weeks.14 The significance of this evidence indicates a
positive outcome for the therapeutic equivalence of the
two agents. Likewise, safety, tolerability, and immu-
nogenicity were similar between the two treatment
groups.
 Anticipating the First Adalimumab Biosimilar
VOLTAIRE-RAext Trial
A phase IIIb VOLTAIRE-RAext trial, based on previ-
ous studies, supported the basis of adalimumab-adbm
and its indications for the treatment of RA. This study
was conducted for 48 weeks using an open, multicenter
interventional approach.15 The sample size was 430
adults with a diagnosis of moderate-to-severe RA who
wished to continue treatment with adalimumab-
adbm.15 These patients were extracted from their par-
ticipation in the VOLTAIRE-RA trial. The patients
received a prefilled, 40-mg syringe of adalimumab-
adbm and administered it every 2 weeks.15 The primary
endpoint was the number of patients with adverse drug
reactions from the start of the trial to the end of the
10-week follow-up period.15
Results were divided into three groups: continuous
administration of adalimumab-adbm, conversion from
adalimumab reference product (RP) to adalimumab-
adbm, and continuous administration of adalimumab
RP in the previous study.15 Among these groups,
20.2% experienced ≥1 drug-related adverse effect, with
a lower proportion of 17.6% in the group with the
switched therapy.15 Secondary endpoints were investi-
gated to assess efficacy using disease activity score 28,
erythrocyte sedimentation rate, and achievement of the
ACR/European League Against Rheumatism
response.15,16 Expansion of this study did not lead to
significant new findings in terms of efficacy, safety, or
immunogenicity.15,16
The positive data from the VOLTAIRE-X
phase III study demonstrated that
interchangeability was achieved:
Adalimumab-adbm was very similar to
adalimumab in terms of safety,
efficacy, and immunogenicity.
VOLTAIRE-X Trial
The positive data from the VOLTAIRE-X phase III study
demonstrated that interchangeability was achieved. The
VOLTAIRE-X trial was designed to assess the pharma-
cokinetic similarity between patients who regularly took
adalimumab and those who alternated between the bio-
similar adalimumab-adbm and adalimumab.11,16 The
treatment groups were clinically diagnosed with moder-
ate-to-severe chronic plaque psoriasis and received 48
weeks of treatment with a 10-week follow-up period.17
24
U.S. Pharmacist • March 2022 • www.uspharmacist.com
A double-blind, randomized, parallel intervention model
was used in this study.17 There were 259 enrolled par-
ticipants between ages 18 and 80 years.17 The primary
endpoint was demonstrated by the pharmacokinetics
measurements of adalimumab over a dosing interval of
Weeks 30 to 32: area under the plasma concentration
(AUC) and maximum observed concentration (Cmax).17
Secondary endpoints were assessed through the effi-
cacy, safety, and immunogenicity profiles, and other
pharmacokinetic measurements, such as minimum
observed plasma concentration (Cmin) and time to
maximum observed plasma concentration (Tmax).17
The results supported the primary and secondary end-
points. There were three endpoint-reporting groups:
run-in period with adalimumab (loading dose on first
day), treatment switching between adalimumab and
adalimumab-adbm, and continued administration of
adalimumab.17 Equivalence was estimated based on a
90.2% CI.16 This interval corresponds to the AUC and
Cmax tests, and CI was calculated based on the ratio of
switching treatments to continuous dosing.17 The results
show that both the primary and secondary endpoints
were satisfied. Adalimumab-adbm was very similar to
adalimumab in terms of safety, efficacy, and immuno-
genicity. This study, along with previous studies, showed
that adalimumab-adbm is a biosimilar and adalimumab
is therapeutically equivalent.
The three trials elaborated here—VOLTAIRE-RA,
VOLTAIRE-RAext, and VOLTAIRE-X—all demon-
strated supporting evidence for the efficacy and safety
profiles of adalimumab-adbm for RA patients. In addi-
tion, the clinical trials also attested to adalimumab-
adbm being an interchangeable biosimilar. However, it
is noted that there are other clinical trials reviewing
adalimumab-adbm’s role and effectiveness compared
with adalimumab in other disease states, such as Crohn’s
(VOLTAIRE-CD).18
Conclusion
With positive evidence exhibited in various studies,
adalimumab-adbm is the first interchangeable mono-
clonal antibody. This citrate-free adalimumab-adbm has
been proven to exude the same efficacy and safety as the
original medication. The introduction of the first inter-
changeable adalimumab biosimilar offers an alternative
and inexpensive option for many and could potentially
lead to other scientific breakthroughs.
References available online at www.uspharmacist.com.
The content contained in this article is for informational purposes
only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is
solely at your own risk.
Vitamins and
Minerals for Pain
Management
ABSTRACT: About one in five U.S.
adults experiences pain daily or on
most days, and for patients struggling
with pain, the toll on their health and
well-being is detrimental and can be
debilitating. Appropriate pain
management has been a growing
concern since the rise of the opioid
epidemic. When prescription
pharmacologic agents do not alleviate
their pain or are not easily accessible,
patients seek alternative therapies.
Vitamins and minerals are one option
that has gained traction and has
attracted researchers’ interest. © Scott Bodell / JobsonHealthcare

Although evidence supporting the use

of these agents is limited, pharmacists are in a position to help patients make educated
decisions on the use of vitamins and minerals.

I n the United States, chronic pain is one of the lead-

ing conditions for which people seek medical treat-
ment, and the toll on their health and well-being is
detrimental and can be debilitating. Based on the
2019 National Health Interview Survey, about one in
five adults in the U.S. experiences pain on most days
or every day.1 Appropriate pain management has been
a growing concern since the rise of the opioid epi-
demic. When prescription pharmacologic agents do
not alleviate their pain or are not easily accessible,
patients seek alternative therapies. In 2011, chronic
pain was reported to have an annual economic bur-
den of $560 billion to $635 billion, of which direct
healthcare costs comprised only $261 billion to $300
billion.2
The International Association for the Study of Pain
(IASP) defines pain as “an unpleasant sensory and
emotional experience associated with, or resembling
that associated with, actual or potential tissue dam-
age.”3 As the definition implies, pain is relative to the
tion (acute or chronic), etiology (malignant or non-
malignant), or anatomical location.4 The goal of
treatment for any type of pain is to improve quality
of life, functioning, and comfort.
Over the past 3 decades, the approach to pain and
its management has been a key focus area.5 In the
1990s, the inadequate assessment and treatment of
pain was recognized as a health emergency and even-
tually labeled as “the 5th vital sign.” In the effort to
improve pain control and in the wake of new phar-
maceutical formulations, liberal opioid prescribing
eventually led to a national opioid crisis. In response,
research and guidelines have aimed to identify alter-
native pain-management modalities.5,6 Most recent
guidelines and best-practice reports have recom-
mended individualized, multimodal, and multidisci-
plinary pain management encompassing medications,
Tara Smith, PharmD Candidate 2023
Brandon Morel, PharmD Candidate 2023

individual afflicted; the optimal treatment depends
on the pain classification. There are four common
pain-classification schemes based on the pathophysi-
ologic mechanism (nociceptive or neuropathic), dura-
Elina Delgado, PharmD, BCPS
Assistant Professor of Pharmacy
William Carey University School of Pharmacy
Department of Pharmacy Practice
Biloxi, Mississippi

25
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Vitamins and Minerals for Pain Management
Table 1
Proposed Mechanisms of Vitamin B12 for Alleviating Neuropathic Pain
• Vitamin B12 may positively affect neural regeneration by inducing axonal growth, neuron-conduction rates, and
Schwann-cell differentiation.
• COX enzymes and prostaglandin production are thought to be counterbalanced by a number of factors, including
vitamin B12 levels.
• Vitamin B12’s homocysteine-depleting mechanism promotes the synthesis of neurotransmitters (such as noradrenaline
and 5-hydroxytryptamine) theorized to play a role in pain relief.
• Vitamin B12 may inhibit pain signaling through TRPV1, which responds to heat, acidity, and capsaicin.
• Vitamin B12 may have a synergistic effect with opiates.

COX: cyclooxygenase; TRPV1: transient receptor potential cation channel subfamily V member 1. Source: Reference 10.

restorative therapies, interventional procedures,
behavioral-health approaches, and complementary
and integrative medicine. One limitation of these
documents, however, is the lack of discussion of the
role that vitamins and minerals may play in pain man-
agement. According to a survey conducted in 2002,
more than one-third of Americans use complementary
and alternative medicine.7 Given that pharmacists are
often the only healthcare professionals available to
answer consumers’ questions about OTC medica-
tions, it is important to understand the possible role
of these agents in pain management.
NEUROPATHIC PAIN
The IASP defines neuropathic pain as “pain caused
by a lesion or disease of the somatosensory nervous
system.”8 This condition encompasses a number of
etiologies, including diabetes, cancer, chronic alcohol
consumption, herpes zoster infection, traumatic nerve
injury, drug toxicity, and central processes including
cerebrovascular accidents, spinal cord injuries, and
multiple sclerosis.9 Broadly, current pharmacologic
treatment strategies include serotonin-norepinephrine
reuptake inhibitors such as venlafaxine and dulox-
etine, tricyclic antidepressants, and the anticonvul-
sants gabapentin and pregabalin as first-line thera-
pies. However, given the complex nature of
neuropathic pain, its spectrum of symptoms, and its
prevalence in up to 10% of the population (according
to validated questionnaires), there is a growing
demand for new treatments.9 Research into vitamin
supplementation—with or without a preexisting defi-
ciency—has been gaining traction.
Vitamin B12
In humans, vitamin B12 functions mainly as a cofactor
for the methyltransferase enzyme known as methio-
nine synthase.10 This allows for the formation of
methionine, which is later converted to S-adenosyl
methionine (SAMe). SAMe is responsible for donat-
26
U.S. Pharmacist • March 2022 • www.uspharmacist.com
ing methyl groups to the formation of myelin sheaths
around neurons. Animal models have exhibited sev-
eral mechanisms through which vitamin B12 is pro-
posed to alleviate neuropathic pain in humans (TABLE
1). A recent systematic review of 325 articles found
that the strongest areas of research on the use of vita-
min B12 in treating peripheral polyneuropathy are
postherpetic neuralgia (PHN), diabetic neuropathy,
and alcohol-related neuropathy.9 This study found no
articles that disproved the utility of vitamin B12 for
neuropathic pain.
Diabetic Neuropathy: Hyperglycemia (and hyperlip-
idemia) cause the increased production of reactive
oxygen species (ROS), advanced glycation end prod-
ucts, and insoluble sugars such as sorbitol.11 All of
these end products induce cellular damage and a pro-
inflammatory environment, particularly affecting the
peripheral neurons. Although there is a positive trend
in the use of vitamin B12 for diabetic neuropathy,
evidence is insufficient because most of the research
trials lacked adequate follow-up periods or sample
sizes and did not have a placebo arm for comparison.
Additionally, many of these studies focused on the
adjunctive use of vitamin B12 with gabapentinoids and
other B vitamins, thereby limiting the assessment of
vitamin B12 on its own.
PHN: PHN is a lingering pain that persists beyond 4
months following a rash induced by herpes zoster.12
Inflammation caused by the virus triggers fibrosis of
nerves and spontaneous activity capable of maintain-
ing pain in the absence of ongoing tissue damage. Five
randomized, controlled trials included in a systematic
review found that vitamin B12 was helpful—whether
as monotherapy or adjunctively—for PHN regardless
of where the pain manifested.9
Alcohol-Related Neuropathy: Vitamin deficiencies
resulting from chronic alcoholism lead to complica-
 Vitamins and Minerals for Pain Management
tions in the demyelination of peripheral neurons and
to slow nerve conduction caused by alcohol-induced
neurotoxicity.13 Symptoms are usually symmetrical
and distal, including paresthesia, cramps, weakness,
and pain. Vitamin supplementation in this case would
help reverse those complications. It has been found
that the addition of vitamin B12 may provide a ben-
efit in pain improvement.9
Zinc
The pathogenesis of chemotherapy-induced periph-
eral neuropathy (CIPN) is not well understood, but
the mechanism appears to involve axonal degradation
from chronic exposure to chemotherapeutic agents.14
One possible cause may be an increase in ROS from
the chemotherapeutic agents, so researchers are inves-
tigating the use of antioxidants to treat or prevent
CIPN. The questionnaire-based Diet, Exercise, Life-
style, and Cancer Prognosis (DELCaP) study found a
correlation between multivitamin use and reduced
incidence of CIPN in stage I–III breast cancer patients
who received doxorubicin, cyclophosphamide, and
paclitaxel, but there was no statistically significant
risk reduction with individual supplement use.15 A
study in mouse models with paclitaxel-induced CIPN
demonstrated dose-dependent reduction of local allo-
dynia following intraplantar zinc administration for
up to 4 days.16 This study found that exogenous zinc
inhibited TRPV1 (transient receptor potential cation
channel subfamily V member 1; a nonselective cation
transport protein), thereby preventing paclitaxel-
induced sensitization of peripheral nociceptors. The
Pathways study found that women who initiated zinc
and other antioxidants after diagnosis were two to
three times more likely to report CIPN at 6-month
follow-up.17 Further research is needed on the use of
zinc for CIPN treatment before any changes to recom-
mendations are made.
Vitamin E
Vitamin E, the primary fat-soluble antioxidant, is
being studied relative to the role of ROS in neuro-
pathic pain. A 2006 study using rat models concluded
that vitamin E administration—as either a high-dose
single injection (0.1, 1, or 5 g/kg with no equivalent
human dose owing to variations in metabolic rates
between species) or repetitive daily low-dose injec-
tions (50 or 100 mg/kg, equating to 3 g in a 60-kg
human)—reduced behaviors associated with mechan-
ical allodynia.18 Similar to the results of the DELCaP
study, a phase III clinical trial in patients receiving
27
U.S. Pharmacist • March 2022 • www.uspharmacist.com
neurotoxic chemotherapy found no difference in
CIPN incidence regardless of whether vitamin E was
administered.14 The researchers found a slight posi-
tive effect on neuropathy duration in patients who
took 400 mg of vitamin E twice daily; however, they
noted that the dose may have been too low to achieve
a statistically significant benefit. A randomized trial
that examined vitamin E supplementation versus pla-
cebo as an adjunct to standard pain management for
diabetic neuropathy concluded that vitamin E was
effective in reducing some pain, but no improvement
was seen in overall quality-of-life scores.19
CHRONIC PAIN
According to the IASP, chronic pain is “pain that
persists or recurs for longer than 3 months.”20 The
principles informing the treatment of neuropathic
pain and chronic pain are subject to overlapping, as
forms of neuropathic pain can become chronic afflic-
tions. The preferred first-line treatment options are
nonpharmacologic therapies (diet, exercise, and
behavioral) and nonopioid prescription medications;
however, given the nature of chronic pain, many of
the affected patients have been prescribed opioids.21
Because chronic pain is the leading cause of disability
in U.S. adults, there has been a significant push for
alternative treatments, including research into vita-
mins and minerals.22
Vitamin C
Vitamin C deficiency (plasma concentrations <11
mcmol/L) manifests as scurvy-related myalgia and
arthralgia in the knees, wrists, and ankles due to
bleeding within these areas.23 Deficiency of this vita-
min is rare in developed countries (<6% in the U.S.),
but the populations primarily affected are hospital-
ized elderly patients, cancer patients, and critically ill
patients. The use of vitamin C has been shown to be
effective in several aspects of pain management.
Complex Regional Pain Syndrome (CRPS): Many ran-
domized, controlled trials have demonstrated that
vitamin C supplementation reduced the incidence of
CRPS in wrist- and ankle-surgery patients, with the
most efficacious dosage being 0.5 g or more per
day.23,24 The same dosage was also administered pro-
phylactically for osteoarthritis in joint-replacement
patients, who were then found to have no incidence
of CRPS.
Rheumatoid Arthritis and Osteoarthritis: It has been
 For your non-immunocompromised members with uncontrolled
mild to moderate atopic dermatitis (AD) 12 years of age and older
NOW APPROVED:
THE ONLY FDA-APPROVED JAK INHIBITOR
DELIVERED IN A CREAM FORMULATION
OPZELURA™ can be applied to affected skin,
up to 20% BSA, including sensitive areas.*
*For topical use only. Not for ophthalmic, oral, or intravaginal use.
INDICATION
OPZELURA is indicated for the topical short-term and non-continuous
chronic treatment of mild to moderate atopic dermatitis in
non-immunocompromised patients 12 years of age and older
whose disease is not adequately controlled with topical prescription
therapies or when those therapies are not advisable.
Limitation of Use:
Use of OPZELURA in combination with therapeutic biologics, other
JAK inhibitors or potent immunosuppressants such as azathioprine or
cyclosporine is not recommended.
IMPORTANT SAFETY INFORMATION
SERIOUS INFECTIONS
Patients treated with oral Janus kinase inhibitors for inflammatory
conditions are at risk for developing serious infections that may lead
to hospitalization or death. Reported infections include:
• Active tuberculosis, which may present with pulmonary or
extrapulmonary disease.
• Invasive fungal infections, including candidiasis and pneumocystosis.
• Bacterial, viral, and other infections due to opportunistic pathogens.
Avoid use of OPZELURA in patients with anactive, serious infection,
including localized infections. If a serious infection develops, interrupt
OPZELURA until the infection is controlled. Carefully consider the
benefits and risks of treatment prior to initiating OPZELURA in
patients with chronic or recurrent infection. Closely monitor patients
for the development of signs and symptoms of infection during and
after treatment with OPZELURA.
No cases of active tuberculosis (TB) were reported in clinical trials
with OPZELURA. Cases of active TB were reported in clinical trials of
oral Janus kinase inhibitors used to treat inflammatory conditions.
Consider evaluating patients for latent and active TB infection prior to
administration of OPZELURA. During OPZELURA use, monitor patients
for the development of signs and symptoms of TB.
Viral reactivation, including cases of herpes virus reactivation (e.g.,
herpes zoster), were reported in clinical trials with Janus kinase
inhibitors used to treat inflammatory conditions including OPZELURA.
If a patient develops herpes zoster, consider interrupting OPZELURA
treatment until the episode resolves.
Hepatitis B viral load (HBV-DNA titer) increases, with or without
associated elevations in alanine aminotransferase and aspartate
aminotransferase, have been reported in patients with chronic
HBV infections taking oral ruxolitinib. OPZELURA initiation is not
recommended in patients with active hepatitis B or hepatitis C.
MORTALITY
Higher rate of all-cause mortality, including sudden cardiovascular
death, has been observed in patients treated with oral Janus kinase
inhibitors for inflammatory conditions.
MALIGNANCIES
Lymphoma and other malignancies have been observed in patients
treated with Janus kinase inhibitors for inflammatory conditions.
Patients who are current or past smokers are at additional increased risk.
Non-melanoma skin cancers, including basal cell and squamous cell
carcinoma, have occurred in patients treated with OPZELURA. Perform
periodic skin examinations during OPZELURA treatment and following
treatment as appropriate.
 Remind
Remind
your commercially
your commercially
insured
insured
patients
patients
aboutabout
the copay
the copay
savings
savings
card for
card
OPZELURA™ .
for OPZELURA™ .
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patients
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IndividualIndividual
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use only with
PAYPAY
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insurance. insurance.
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used if patient
used ifispatient
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in a government-funded

P E RP E R
† †

$ $
prescription
prescription
insuranceinsurance
program or program
if patient
or pays
if patient pays
cash for their
cash prescription.
for their prescription.
Must be used
Mustfor
beanused for an
FDA-approved
FDA-approved
indication.indication.
AdditionalAdditional
Terms andTerms and
T U BTEU B E Conditions Conditions
apply. apply.

Learn
Learn
moremore
at OPZELURAhcp.com.
at OPZELURAhcp.com.
IMPORTANTIMPORTANTSAFETY SAFETY
INFORMATION INFORMATION(continued)(continued) in the clinical in the
trials
clinical
with OPZELURA.
trials with OPZELURA.
Consider the Consider
benefitsthe benefits
MAJOR MAJOR
ADVERSE ADVERSE
CARDIOVASCULAR
CARDIOVASCULAR EVENTS (MACE)and risks for
EVENTS (MACE) andindividual
risks for individual
patients who patients
have awho
known have history
a known history
Higher rate
Higher of MACE
rate of(including
MACE (including
cardiovascular
cardiovascular
death, death, of these events
of thesepriorevents
to initiating
prior totherapy
initiating
with
therapy
OPZELURA.
with OPZELURA.
myocardial
myocardial
infarction, infarction,
and stroke) andhasstroke)
beenhas observed
been observed Perform CBC Perform
monitoring
CBC monitoring
as clinicallyasindicated.
clinicallyIfindicated.
signs and/If signs and/
in patients
in patients
treated withtreatedJanuswith kinase
Janusinhibitors
kinase inhibitors
for for or symptoms or symptoms
of clinicallyofsignificant
clinically significant
thrombocytopenia,
thrombocytopenia,
inflammatory
inflammatory
conditions. conditions.
ConsiderConsider
the benefitsthe and risks andanemia,
benefits risks and anemia,
neutropenia
and neutropenia
occur, patients
occur,should
patients should
for the individual
for the individual
patient priorpatient
to initiating
prior to initiating
or continuing discontinue
or continuing discontinue
OPZELURA. OPZELURA.
therapytherapy
with OPZELURA,
with OPZELURA,particularly
particularly
in patients patients whoLipid Elevations
in who Lipid Elevations
are current
are current
or past smokers
or past smokers
and patientsand patients
with other with other TreatmentTreatment
with oral ruxolitinib
with oral ruxolitinib
has been associated
has been associated
cardiovascular
cardiovascular
risk factors.
risk Patients
factors. Patients
should be should
informed with increases
be informed with increases
in lipid parameters
in lipid parameters
including total
including total
of about theaboutsymptoms
the symptomsof serious ofcardiovascular
serious cardiovascular
events and cholesterol,
events and cholesterol,
low-density low-density
lipoproteinlipoprotein
(LDL) cholesterol,
(LDL) cholesterol,
the stepsthetosteps
take iftothese
take symptoms
if these symptoms
occur. occur. and triglycerides.
and triglycerides.
r to THROMBOSIS
THROMBOSIS Adverse Reactions
Adverse Reactions
ents Thrombosis,
Thrombosis,
including including
deep venous deepthrombosis,
venous thrombosis, The mostThe common
most common
adverse reactions
adverse(≥1%)reactions
are (≥1%) are
pulmonarypulmonary
embolism, embolism,
and arterialandthrombosis
arterial thrombosis
has beenhas beennasopharyngitis
nasopharyngitis
(3%), diarrhea(3%),(1%),
diarrhea
bronchitis
(1%), bronchitis
(1%), ear (1%), ear
observed observed
in patients in patients
treated withtreated
oralwith
Janusoral
kinase
Janus kinase infection infection
(1%), eosinophil
(1%), eosinophil
count increased
count (1%),
increased
urticaria
(1%), urticaria
inhibitors
inhibitors
forinflammatory
forinflammatory
conditions.conditions.
Many of these
Many of these (1%), folliculitis
(1%), folliculitis
(1%), tonsillitis
(1%),(1%),
tonsillitis
and rhinorrhea
(1%), and rhinorrhea
(1%). (1%).
RA. adverseadverse
reactions reactions
were seriouswereand serious
some andresulted
some resulted
in in
Pregnancy Pregnancy
A death. Patients
death. Patients
with symptoms
with symptoms
of thrombosis
of thrombosis
should be should be willThere
There be a pregnancy
will be a pregnancy
registry thatregistry
monitorsthat monitors
promptly promptly
evaluated. evaluated. pregnancy pregnancy
outcomesoutcomesinpregnantinpregnant
persons exposed
persons exposed
Thromboembolic
Thromboembolic events were events
observed
were observed
in clinicalin clinical to OPZELURA to OPZELURA
during pregnancy.
during pregnancy.
Pregnant persons
Pregnant persons
trials with
trials
OPZELURA.
with OPZELURA.
There was There
no clear no clear relationship exposed to
wasrelationship exposed
OPZELURA to OPZELURA
and healthcareand healthcare
providers should
providers should
betweenbetween
platelet count
plateletelevations
count elevations
and thrombotic
and thrombotic report OPZELURA
events. events. report OPZELURA
exposure by exposure
calling 855-4MEDINFO
by calling 855-4MEDINFO
OPZELURA OPZELURA
should be should
used be withused
caution
withincaution
patients inwho
patients who or 855-463-3463.
or 855-463-3463.
may be mayat increased
be at increased
risk of thrombosis.
risk of thrombosis. LactationLactation
Thrombocytopenia,
Thrombocytopenia, Anemia Anemia
and Neutropenia
and Neutropenia Advise womenAdvisenot women
to breastfeed
not to breastfeed
during treatment
during with
treatment with
ar Thrombocytopenia,
Thrombocytopenia, anemia and anemia
neutropenia
and neutropenia
were reported OPZELURA
were reported OPZELURA
and for four and weeks
for four
afterweeks
the last
afterdose
the last dose
se (approximately
(approximately
5 elimination 5 elimination
half-lives). half-lives).

Please
Please
see Brief
see Summary
Brief Summary
of Fullof
Prescribing
Full Prescribing
Information
Information
for OPZELURA™
for OPZELURA™
on the
onfollowing
the following
pages.pages.
risk. BSA, body
BSA,surface
body surface
area; FDA,
area;
FoodFDA,
andFood
Drugand
Administration;
Drug Administration;
JAK, Janus
JAK,
kinase.
Janus kinase.
l Reference:
Reference:
OPZELURA™
OPZELURA™
(ruxolitinib)
(ruxolitinib)
cream. Prescribing
cream. Prescribing
Information.
Information.
Incyte Corporation,
Incyte Corporation,
2021. 2021.
m
ng
OPZELURAOPZELURA
is a trademark
is a trademark
of Incyte.of Incyte.
Incyte and
Incyte
the Incyte
and thelogo
Incyte
are registered
logo are registered
trademarkstrademarks
of Incyte. of Incyte.
© 2021, Incyte
© 2021, Corporation.
Incyte Corporation.
MAT-ONA-00177
MAT-ONA-00177
09/21 09/21

OPZELURA™ (ruxolitinib) cream, for topical use
Brief Summary of FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE: OPZELURA is indicated for the topical short-term
and non-continuous chronic treatment of mild to moderate atopic dermatitis in
non-immunocompromised patients 12 years of age and older whose disease is
not adequately controlled with topical prescription therapies or when those therapies
are not advisable.
Limitation of Use: Use of OPZELURA in combination with therapeutic biologics, other
JAK inhibitors or potent immunosuppressants such as azathioprine or cyclosporine
is not recommended.
WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR
ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS
SERIOUS INFECTIONS
Patients treated with oral Janus kinase inhibitors for inflammatory conditions
are at risk for developing serious infections that may lead to hospitalization or
death [see Warnings and Precautions and Adverse Reactions].
Reported infections include:
• Active tuberculosis, which may present with pulmonary or
extrapulmonary disease.
• Invasive fungal infections, including candidiasis and pneumocystosis.
• Bacterial, viral, and other infections due to opportunistic pathogens.
Avoid use of OPZELURA in patients with an active, serious infection,
including localized infections. If a serious infection develops, interrupt
OPZELURA until the infection is controlled.
The risks and benefits of treatment with OPZELURA should be carefully
considered prior to initiating therapy in patients with chronic or
recurrent infection.
Patients should be closely monitored for the development of signs and
symptoms of infection during and after treatment with OPZELURA [see
Warnings and Precautions].
MORTALITY
Higher rate of all-cause mortality, including sudden cardiovascular death
have been observed in patients treated with oral Janus kinase inhibitors
for inflammatory conditions [see Warnings and Precautions].
MALIGNANCIES
Lymphoma and other malignancies have been observed in patients treated
with Janus kinase inhibitors for inflammatory conditions [see Warnings
and Precautions].
MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE)
Higher rate of MACE (including cardiovascular death, myocardial infarction,
and stroke) has been observed in patients treated with Janus kinase
inhibitors for inflammatory conditions [see Warnings and Precautions].
THROMBOSIS
Thrombosis, including deep venous thrombosis, pulmonary embolism, and
arterial thrombosis has been observed at an increased incidence in patients
treated with oral Janus kinase inhibitors for inflammatory conditions
compared to placebo. Many of these adverse reactions were serious and
some resulted in death. Patients with symptoms of thrombosis should be
promptly evaluated [see Warnings and Precautions].
WARNINGS AND PRECAUTIONS
Serious Infections: Serious and sometimes fatal infections due to bacterial,
mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been
reported in patients receiving oral janus kinase inhibitors. Serious lower respiratory
tract infections were reported in the clinical development program with topical
ruxolitinib. Avoid use of OPZELURA in patients with an active, serious infection,
including localized infections. Consider the risks and benefits of treatment prior to
initiating OPZELURA in patients: with chronic or recurrent infection; with a history of
a serious or an opportunistic infection; who have been exposed to tuberculosis; who
have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
with underlying conditions that may predispose them to infection. Closely monitor
patients for the development of signs and symptoms of infection during and after
treatment with OPZELURA. Interrupt OPZELURA if a patient develops a serious
infection, an opportunistic infection, or sepsis. Do not resume OPZELURA until the
infection is controlled.
Tuberculosis: No cases of active tuberculosis (TB) were reported in clinical trials
with OPZELURA. Cases of active TB were reported in clinical trials of oral Janus
kinase inhibitors used to treat inflammatory conditions. Consider evaluating patients
for latent and active TB infection prior to administration of OPZELURA. During
OPZELURA use, monitor patients for the development of signs and symptoms of TB.
Viral Reactivation: Viral reactivation, including cases of herpes virus reactivation
(e.g., herpes zoster), were reported in clinical trials with Janus kinase inhibitors used
to treat inflammatory conditions including OPZELURA. If a patient develops herpes
zoster, consider interrupting OPZELURA treatment until the episode resolves.
Hepatitis B and C: The impact of Janus kinase inhibitors used to treat inflammatory
conditions including OPZELURA on chronic viral hepatitis reactivation is unknown.
Patients with a history of hepatitis B or C infection were excluded from clinical trials.
Hepatitis B viral load (HBV-DNA titer) increases, with or without associated
elevations in alanine aminotransferase and aspartate aminotransferase, have been
reported in patients with chronic HBV infections taking oral ruxolitinib. OPZELURA
initiation is not recommended in patients with active hepatitis B or hepatitis C.
Mortality: A higher rate of all-cause mortality, including sudden cardiovascular
death was observed in clinical trials of oral Janus kinase inhibitors used to treat
inflammatory conditions. Consider the benefits and risks for the individual patient
prior to initiating or continuing therapy with OPZELURA.
Malignancy and Lymphoproliferative Disorders: Malignancies, including
lymphomas, were observed in clinical trials of oral Janus kinase inhibitors used to
treat inflammatory conditions. Patients who are current or past smokers are at
additional increased risk. Consider the benefits and risks for the individual patient
prior to initiating or continuing therapy with OPZELURA, particularly in patients with
a known malignancy (other than successfully treated non-melanoma skin cancers),
patients who develop a malignancy, and patients who are current or past smokers.
Non-melanoma Skin Cancers: Non-melanoma skin cancers including basal cell and
squamous cell carcinoma have occurred in patients treated with OPZELURA. Perform
periodic skin examinations during OPZELURA treatment and following treatment
as appropriate.
Major Adverse Cardiovascular Events (MACE): Major adverse cardiovascular
events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI),
and non-fatal stroke were observed in clinical trials of Janus kinase inhibitors used
to treat inflammatory conditions. Consider the benefits and risks for the individual
patient prior to initiating or continuing therapy with OPZELURA particularly in
patients who are current or past smokers and patients with other cardiovascular risk
factors. Patients should be informed about the symptoms of serious cardiovascular
events and the steps to take if these symptoms occur.
Thrombosis: Thrombosis, including deep venous thrombosis (DVT), pulmonary
embolism (PE) and arterial thrombosis, has been observed at an increased incidence
in patients treated with oral Janus kinase inhibitors for inflammatory conditions
compared to patients treated with placebo. Many of these adverse reactions were
serious and some resulted in death. Thromboembolic events were observed in
clinical trials with OPZELURA. There was no clear relationship between platelet
count elevations and thrombotic events. OPZELURA should be used with caution in
patients who may be at increased risk of thrombosis.
Thrombocytopenia, Anemia and Neutropenia: Thrombocytopenia, anemia and
neutropenia were reported in the clinical trials with OPZELURA. Consider the
benefits and risks for individual patients who have a known history of these events
prior to initiating therapy with OPZELURA. Perform CBC monitoring as clinically
indicated. If signs and/or symptoms of clinically significant thrombocytopenia,
anemia, and neutropenia occur, patients should discontinue OPZELURA.
Lipid Elevations: Treatment with oral ruxolitinib has been associated with increases
in lipid parameters including total cholesterol, low-density lipoprotein (LDL)
cholesterol, and triglycerides.
ADVERSE REACTIONS
Clinical Trials Experience: Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may not reflect the
rates observed in practice. In two double-blind, vehicle-controlled clinical trials (Trials 1
and 2), 499 subjects 12 years of age and older with atopic dermatitis were treated with
OPZELURA twice daily for 8 weeks. In the OPZELURA group, 62% of subjects were
females, and 71% of subjects were White, 23% were Black, and 4% were Asian. The
adverse reactions reported by ≥ 1% of OPZELURA-treated subjects and at a greater
incidence than in the vehicle arm through week 8 are as follows for OPZELURA
(N=499) vs Vehicle (N=250), respectively: Subjects with any treatment emergent
adverse event (TEAE) 132 (27%) vs 83 (33%), Nasopharyngitis 13 (3%) vs 2 (1%),
Bronchitis 4 (1%) vs 0 (0%), Ear infection 4 (1%) vs 0 (0%), Eosinophil count increased
4 (1%) vs 0 (0%), Urticaria 4 (1%) vs 0 (0%), Diarrhea 3 (1%) vs 1 (<1%), Folliculitis
3 (1%) vs 0 (0%), Tonsillitis 3 (1%) vs 0 (0%), and Rhinorrhea 3 (1%) vs 1 (<1%).
Adverse reactions that occurred in Trials 1 and 2 in < 1% of subjects in the OPZELURA
group and none in the vehicle group were: neutropenia, allergic conjunctivitis, pyrexia,
seasonal allergy, herpes zoster, otitis externa, Staphylococcal infection, and
acneiform dermatitis.
DRUG INTERACTIONS
Drug interaction studies with OPZELURA have not been conducted. Ruxolitinib is
known to be a substrate for cytochrome P450 3A4 (CYP3A4). Inhibitors of CYP3A4
may increase ruxolitinib systemic concentrations whereas inducers of CYP3A4 may
decrease ruxolitinib systemic concentrations.
Strong Inhibitors of CYP3A4: Avoid concomitant use of OPZELURA with strong
inhibitors of CYP3A4 as there is a potential to increase the systemic exposure of
ruxolitinib and could increase the risk of OPZELURA adverse reactions.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Exposure Registry: There will be a pregnancy registry that monitors
pregnancy outcomes in pregnant persons exposed to OPZELURA during pregnancy.
Pregnant persons exposed to OPZELURA and healthcare providers should report
OPZELURA exposure by calling 1-855-463-3463.
Risk Summary: Available data from pregnancies reported in clinical trials with
OPZELURA are not sufficient to evaluate a drug-associated risk for major birth
defects, miscarriage, or other adverse maternal or fetal outcomes. In animal
reproduction studies, oral administration of ruxolitinib to pregnant rats and rabbits
during the period of organogenesis resulted in adverse developmental outcomes at
doses associated with maternal toxicity.
The background risks of major birth defects and miscarriage for the indicated
populations are unknown. All pregnancies carry some risk of birth defects, loss, or
other adverse outcomes. The background risk in the U.S. general population of major
birth defects and miscarriage is 2-4% and 15-20%, respectively.
Data
Animal Data: Ruxolitinib was administered orally to pregnant rats or rabbits during
the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30
or 60 mg/kg/day in rabbits. There were no treatment-related malformations at any
dose. A decrease in fetal weight of approximately 9% was noted in rats at the
highest and maternally toxic dose of 60 mg/kg/day. This dose resulted in systemic
exposure approximately 22 times the clinical systemic exposure at the maximum
recommended human dose (MRHD); the clinical systemic exposure from ruxolitinib
cream, 1.5% applied twice daily to 25-40% body surface area is used for calculation
of multiples of human exposure. In rabbits, lower fetal weights of approximately 8%
and increased late resorptions were noted at the highest and maternally toxic dose
of 60 mg/kg/day. This dose resulted in systemic exposure approximately 70% the
MRHD clinical systemic exposure. In a pre-and post-natal development study in rats,
pregnant animals were dosed with ruxolitinib from implantation through lactation
at doses up to 30 mg/kg/day. There were no drug-related adverse effects on
embryofetal survival, postnatal growth, development parameters or offspring
reproductive function at the highest dose evaluated (3.1 times the MRHD clinical
systemic exposure).
Lactation
Risk Summary: There are no data on the presence of ruxolitinib in human milk, the
effects on the breastfed child, or the effects on milk production. Ruxolitinib was
present in the milk of lactating rats. When a drug is present in animal milk, it is likely
that the drug will be present in human milk. Because of the serious adverse findings
in adults, including risks of serious infections, thrombocytopenia, anemia, and
neutropenia, advise women not to breastfeed during treatment with OPZELURA
and for approximately four weeks after the last dose (approximately 5 elimination
half-lives).
Data: Lactating rats were administered a single dose of [14C]-labeled ruxolitinib
(30 mg/kg) on postnatal Day 10, after which plasma and milk samples were
collected for up to 24 hours. The AUC for total radioactivity in milk was approximately
13 times the maternal plasma AUC. Additional analysis showed the presence of
ruxolitinib and several of its metabolites in milk, all at levels higher than those in
maternal plasma.
Pediatric Use: The safety and effectiveness of OPZELURA for the topical treatment
of atopic dermatitis have been established in pediatric patients aged 12 to 17 years
of age with mild-to-moderate atopic dermatitis. Use of OPZELURA in this age group
is supported by evidence from Trials 1 and 2 which included 92 subjects aged 12 to
17 years. No clinically meaningful differences in safety or effectiveness were observed
between adult and pediatric subjects. The safety and effectiveness of OPZELURA
in pediatric patients younger than 12 years of age have not been established.
Juvenile Animal Toxicity Data: Oral administration of ruxolitinib to juvenile rats
resulted in effects on growth and bone measures. When administered starting at
postnatal day 7 (the equivalent of a human newborn) at doses of 1.5 to 75 mg/kg/day,
evidence of fractures occurred at doses ≥ 30 mg/kg/day, and effects on body weight
and other bone measures [e.g., bone mineral content, peripheral quantitative
computed tomography, and x-ray analysis] occurred at doses ≥ 5 mg/kg/day. When
administered starting at postnatal day 21 (the equivalent of a human 2-3 years of
age) at doses of 5 to 60 mg/kg/day, effects on body weight and bone occurred at
doses ≥ 15 mg/kg/day, which were considered adverse at 60 mg/kg/day. Males were
more severely affected than females in all age groups, and effects were generally
more severe when administration was initiated earlier in the postnatal period. These
findings were observed at systemic exposures that are at least 40% the MRHD
clinical systemic exposure.
Geriatric Use: Of the 1249 total subjects with atopic dermatitis in clinical trials with
OPZELURA, 115 were 65 years of age and older. No clinically meaningful differences
in safety or effectiveness were observed between patients less than 65 years and
patients 65 years and older.
PATIENT COUNSELING INFORMATION
Advise the patient or caregivers to read the FDA-approved patient labeling
(Medication Guide).
Infections: Inform patients that they may be at increased risk for developing
infections, including serious infections, when taking Janus kinase inhibitors. Instruct
patients to tell their healthcare provider if they develop any signs or symptoms of an
infection. Advise patients that Janus kinase inhibitors increase the risk of herpes
zoster, and some cases can be serious.
Malignancies and Lymphoproliferative Disorders: Inform patients that Janus kinase
inhibitors may increase the risk for developing lymphomas and other malignancies
including skin cancer. Instruct patients to inform their health care provider if they
have ever had any type of cancer. Inform patients that periodic skin examinations
should be performed while using OPZELURA.
Major Adverse Cardiovascular Events: Advise patients that events of major adverse
cardiovascular events (MACE) including non-fatal myocardial infarction, non-fatal
stroke, and cardiovascular death, have been reported in clinical studies with Janus
kinase inhibitors used to treat inflammatory conditions. Instruct all patients,
especially current or past smokers or patients with other cardiovascular risk factors,
to be alert for the development of signs and symptoms of cardiovascular events.
Thrombosis: Advise patients that events of DVT and PE have been reported in clinical
studies with Janus kinase inhibitors used to treat inflammatory conditions. Instruct
patients to tell their healthcare provider if they develop any signs or symptoms of
a DVT or PE.
Thrombocytopenia, Anemia and Neutropenia: Advise patients of the risk of
thrombocytopenia, anemia, and neutropenia with OPZELURA. Instruct patients to tell
their healthcare provider if they develop any signs or symptoms of thrombocytopenia,
anemia or neutropenia [see Warnings and Precautions].
Administration Instructions: Advise patients or caregivers that OPZELURA is for
topical use only [see Dosage and Administration].
Advise patients to limit treatment to 60 grams per week.
Pregnancy: Inform patients to report their pregnancy to Incyte Corporation
at 1-855-463-3463 [see Use in Specific Populations].
Lactation: Advise a patient not to breastfeed during treatment with OPZELURA
and for four weeks after the last dose [see Use in Specific Populations].
Manufactured for:
Incyte Corporation
1801 Augustine Cut-off
Wilmington, DE 19803
OPZELURA is a trademark of Incyte. All rights reserved.
U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481;
9079912; 9974790; 10639310; 10610530; 10758543; 10869870
© 2021 Incyte Corporation. All rights reserved
Issued: September 2021 PLR-ONA-00004
 Vitamins and Minerals for Pain Management
noted that patients with rheumatoid arthritis present
with average vitamin C levels less than half the level
in healthy controls.23 One study reported a total
reduction of pain in a single rheumatoid arthritis
patient following twice-weekly infusions of high-dose
vitamin C, and a study in osteoarthritis patients given
1 g of oral calcium ascorbate per day found that the
reduction in pain was less than half of that reported
for nonsteroidal anti-inflammatory drugs.23 These
data may also suggest more efficacy with parenteral
versus oral administration in patients with arthritis.
Orthopedic Pain: Vitamin C exhibits regulatory effects
on bone and collagen formation.23 A study of 16
patients with Paget’s disease showed a reduction in
bone pain following administration of 3 g of oral
vitamin C per day for 2 weeks. However, the pain
reduction was not greater than that observed with
typical calcitonin treatment for the disease.
PHN: Serum levels of vitamin C are much lower in
shingles patients than in healthy persons, and this has
been found to increase the risk of PHN.23 Random-
ized, controlled trials have shown a reduced incidence
of PHN and decreased long-term pain following par-
enteral vitamin C administration.
Cancer Pain: Cancer patients typically have increased
vitamin C requirements and lower circulating levels
than healthy individuals.23 Questionnaire-based stud-
ies examining quality of life showed significant
improvements (>30%) due to decreased pain follow-
ing vitamin C administered orally or parenterally.
Decreased Opioid Requirements: Patients receiving
opioids have been found to exhibit decreased with-
drawal symptoms with coadministration of vitamin
C.23 Several studies have also observed that these
patients required fewer morphine equivalents of opi-
oids compared with patients who did not receive vita-
min C coadministration.
Vitamin D
Vitamin D deficiency is associated with several eti-
ologies of chronic pain, including type 1 diabetes,
hypertension, metabolic syndrome, ischemic heart
disease, falls, broken bones, depression, and cancer.25
More recent studies have also linked vitamin D defi-
ciency to sickle cell disease, aromatase inhibitor–
induced arthralgia, headache, PHN, pain in patients
taking high doses of opioids, and various types of
32
U.S. Pharmacist • March 2022 • www.uspharmacist.com
musculoskeletal and orthopedic pain. In these condi-
tions, higher reported levels of pain and opioid use
occurred in patients with deficient circulating levels
of vitamin D.25,26 In addition to its bone-regulation
and hormonal effects, vitamin D regulates the inflam-
matory responses mediated by the adaptive immune
system.26 Similar to vitamin C supplementation,
administration of vitamin D in these cases prevents
pain associated with a deficiency of the vitamin (<30
nmol/L) and has little effect in patients with adequate
levels. Current evidence is insufficient to change rec-
ommendations regarding vitamin D supplementation,
and more research should be conducted.
Deficiency of vitamin C is rare
in developed countries, but
the populations primarily affected
are hospitalized elderly patients,
cancer patients, and critically
ill patients.
Magnesium
Magnesium is an antagonist of N-methyl-d-aspartate
voltage-gated receptors that exhibits antinociceptive
effects by preventing and attenuating hypersensitivity
to pain.27,28 It is also known to reduce neuromuscular
excitability by antagonizing the effects of calcium on
acetylcholine release.21 Further research must be con-
ducted before changes to recommendations should
be considered, but promising trends have been noted
in the use of magnesium for the following conditions.
Perioperative Pain: In a systematic review of 27 ran-
domized, controlled trials, data trends suggested that
systemic administration of magnesium during general
anesthesia may lessen postoperative pain without
increasing the risk of adverse effects.27 The usual
regimen is a loading dose of 30 mg/kg to 50 mg/kg
followed by a maintenance dose of 6 mg/kg to 20 mg/
kg per hour. Magnesium has also been associated with
increased hemodynamic stability during surgery as
well as reduced anesthetic and opioid use. It has been
found to be largely ineffective for attenuating pain
associated with cesarean delivery, hysterectomy,
inguinal hernia repair, and varicose vein surgery;
however, it is worth noting that the studies reporting
these results used a single dose rather than a loading
 Vitamins and Minerals for Pain Management
dose plus continuous infusion.28
Migraine: Hypomagnesemia has been observed in
patients who develop migraines, but the etiology of
this condition is not fully understood.27 Magnesium
supplementation has yielded inconsistent results in
preventing and treating migraines. This may be due
to differences in magnesium formulation, dosing, and
administration as well as migraine subtype.
Fibromyalgia: Patients with fibromyalgia have been
found to have lower magnesium levels and magne-
sium intake.27 Magnesium supplementation has been
suggested to be beneficial because it reduces levels of
substance P, which correlates to a decrease in fibro-
myalgia pain.
PHN: IV magnesium sulfate administered at 30 mg/kg
over 30 minutes was shown to lessen or completely
resolve pain in patients with PHN.28 Studies have
suggested that it is as effective as ketamine for reduc-
ing pain associated with PHN, but more research
should be conducted before it is recommended as a
treatment option.27
REFERENCES
1. Yong RJ, Mullins PM, Bhattacharyya N. Prevalence of chronic pain
among adults in the United States. Pain. 2022;163(2):e328-e332.
2. Smith TJ, Hillner BE. The cost of pain. JAMA Netw Open.
2019;2(4):e191532.
3. International Association for the Study of Pain. Definition of pain.
www.iasp-pain.org/resources/terminology/#pain. Accessed January 2,
2022.
4. Abd-Elsayed A, Deer TR. Different types of pain. In: Abd-Elsayed
A, ed. Pain: A Review Guide. Cham, Switzerland: Springer Nature
Switzerland; 2019:15-16.
5. HHS.gov/Opioids. Pain Management Best Practices Inter-Agency
Task Force report. www.hhs.gov/sites/default/files/pain-mgmt-best-
practices-draft-final-report-05062019.pdf. Accessed January 2, 2022.
6. Institute for Clinical Systems Improvement. Pain: assessment, non-
opioid treatment approaches and opioid management care for adults.
www.icsi.org/wp-content/uploads/2021/11/Pain-Interactive-7th-
V2-Ed-8.17.pdf. Accessed January 2, 2022.
7. Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complemen-
tary and alternative medicine use among adults: United States, 2002.
Adv Data. 2004;(343):1-19.
8. Murnion BP. Neuropathic pain: current definition and review of
drug treatment. Aust Prescr. 2018;41(3):60-63.
9. Julian T, Syeed R, Glascow N, et al. B12 as a treatment for periph-
eral neuropathic pain: a systematic review. Nutrients.
2020;12(8):2221.
10. Buesing S, Costa M, Schilling JM, Moeller-Bertram T. Vitamin
B12 as a treatment for pain. Pain Physician. 2019;22:e45-e52.
11. Feldman EL. Pathogenesis of diabetic neuropathy. UpToDate.
Waltham, MA: UpToDate Inc. www.uptodate.com. Accessed January
2, 2022.
12. Ortega E. Postherpetic neuralgia. UpToDate. Waltham, MA:
UpToDate Inc. www.uptodate.com. Accessed January 2, 2022.
13. Charness ME. Overview of the chronic neurologic complications
of alcohol. UpToDate. Waltham, MA: UpToDate Inc. www.uptodate.
com. Accessed January 2, 2022.
14. Kottschade LA, Sloan JA, Mazurczak MA, et al. The use of vita-
min E for the prevention of chemotherapy-induced peripheral neurop-
athy: results of a randomized phase III clinical trial. Support Care
Cancer. 2011;19(11):1769-1777.
33
U.S. Pharmacist • March 2022 • www.uspharmacist.com
CIPN: A 2004 study reported that infusions of cal-
cium and magnesium (Ca2+/Mg2+) before and after
administration of oxaliplatin could prevent the
development of CIPN.27,28 Metanalyses and system-
atic reviews have yielded inconsistent results, and
although their effectiveness remains inconclusive,
these infusions have been adopted into clinical prac-
tice anyway.
CONCLUSION
Pain is a complex and multifaceted health condition
that has variable effects on different individuals.
Although a number of pharmacologic therapies are
available to help manage pain, no uniform regimen
works for all patients. Vitamins and minerals may
be an alternative option for pain relief, particularly
for neuropathic and chronic pain. Although evi-
dence supporting the use of vitamins and minerals
is limited, pharmacists are well positioned to help
patients make educated decisions on the use of these
nutrients.
The content contained in this article is for informational purposes
only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is
solely at your own risk.
15. Zirpoli GR, McCann SE, Sucheston-Campbell LE, et al. Supple-
ment use and chemotherapy-induced peripheral neuropathy in a coop-
erative group trial (S0221): the DELCaP study. J Natl Cancer Inst.
2017;109(12):djx098.
16. Luo J, Bavencoffe A, Yang P, et al. Zinc inhibits TRPV1 to allevi-
ate chemotherapy-induced neuropathic pain. J Neurosci.
2018;38(2):474-483.
17. Greenlee H, Hershman DL, Shi Z, et al. BMI, lifestyle factors and
taxane-induced neuropathy in breast cancer patients: the Pathways
Study. J Natl Cancer Inst. 2016;109(2):djw206.
18. Kim HK, Kim JH, Gao X, et al. Analgesic effect of vitamin E is
mediated by reducing central sensitization in neuropathic pain. Pain.
2006;122(1-2):53-62.
19. Rajanandh MG, Kosey S, Prathiksha G. Assessment of antioxi-
dant supplementation on the neuropathic pain score and quality of
life in diabetic neuropathy patients—a randomized controlled study.
Pharmacol Rep. 2014;66(1):44-48.
20. Treede RD, Rief W, Barke A, et al. Chronic pain as a symptom or
a disease: the IASP Classification of Chronic Pain for the International
Classification of Diseases (ICD-11). Pain. 2019;160(1):19-27.
21. CDC. About CDC’s opioid prescribing guideline. www.cdc.gov/
opioids/providers/prescribing/guideline.html. Accessed January 2,
2022.
22. Zelaya CE, Dahlhamer JM, Lucas JW, Connor EM. Chronic pain
and high-impact chronic pain among U.S. adults, 2019. NCHS Data
Brief. 2020;(390):1-8.
23. Carr AC, McCall C. The role of vitamin C in the treatment of
pain: new insights. J Transl Med. 2017;15(1):77.
24. Zollinger PE, Tuinebreijer WE, Breederveld RS, Kreis RW. Can
vitamin C prevent complex regional pain syndrome in patients with
wrist fractures? J Bone Joint Surg Am. 2007;89(7):1424-1431.
25. Nadolski CE. Vitamin D and chronic pain: promising correlates.
US Pharm. 2012;37(7):42-44.
26. Helde-Frankling M, Björkhem-Bergman L. Vitamin D in pain
management. Int J Mol Sci. 2017;18(10):2170.
27. Shin HJ, Na HS, Do SH. Magnesium and pain. Nutrients.
2020;12(8):2184.
28. Na HS, Ryu JH, Do SH. The role of magnesium in pain. In: Vink
R, Nechifor M, eds. Magnesium in the Central Nervous System. Ade-
laide, Australia: University of Adelaide Press; 2011.
 SPECIAL SECTION: SPECIALTY PHARMACY
Specialty Pharmacy News Digest
Could One Autoimmune Disease
Lead to Another?
Researchers at the University of Colorado Anschutz
Medical Campus have discovered that having one
kind of autoimmune disease can lead to another. The
scientists serendipitously found that mice with anti-
body-induced rheumatoid arthritis in their joints
went on to develop spinal lesions similar to those in
axial spondyloarthritis (AxSpA), which causes fusion
of the vertebrate and curvature, or bending, of the
backbone. The study was published in the journal
Immune Network.
“This interesting disease association may be due
to the binding of anti-collagen autoantibodies to the
spine, or to some alteration of the immune system
that requires further investigation,” said the study’s
lead author, Nirmal Banda, PhD, professor in the
division of rheumatology at the University of Colo-
rado School of Medicine.
These same anticollagen antibodies are also pres-
ent in humans with arthritis. They directly attack
joint cartilage, resulting in inflammation and pain.
Dr. Banda noted that every mouse injected with col-
lagen antibody–induced arthritis developed arthritis
and then curvature of the spine consistent with
AxSpA.
“I began to notice the proliferation of bone in the
spine and fusing of the vertebrate,” he said. “The
normal spaces between the spine vertebrate in certain
locations were disappearing. This is similar to what
happens to humans with AxSpA.”
The connection, he said, has not been made in any
other study he has seen. But exactly how one autoim-
mune disease could trigger another remains a mystery,
one that Dr. Banda hopes to investigate. “I want to
know what the mechanism is,” he said. In the mean-
time, he suggested that those with an autoimmune dis-
ease be vigilant in case they develop another.
Common Virus May Pose Serious Threat
to Transplant Patients
A common virus that causes no harm in most people
may be a danger to organ-transplant recipients and
other immunocompromised people, say researchers
at Columbia University Irving Medical Center.
34
U.S. Pharmacist • March 2022 • www.uspharmacist.com
The researchers found that a human polyomavi-
rus (HPyV9) was associated with the deaths of three
solid-organ transplant recipients who developed a
severe skin rash and then died about a year later
from pulmonary and multiorgan failure.
The study, published in JAMA Dermatology, was
led by Stephanie Gallitano, MD, assistant professor
of dermatology at Columbia University Vagelos Col-
lege of Physicians and Surgeons, and Nischay
Mishra, PhD, assistant professor of epidemiology at
Columbia’s Mailman School of Public Health and
Center for Infection and Immunity.
The deaths of the organ-transplant recipients were
initially a mystery. Some viruses can cause life-threat-
ening diseases in transplant recipients and other
immunocompromised people, but none of these were
found in the three patients.
To identify a culprit, the researchers turned to Vir-
CapSeq-VERT, a technique developed by researchers
in the Center for Infection and Immunity, that detects
all known vertebrate viruses. Using these techniques,
the researchers detected HPyV9 and found that the
virus was present in the skin, blood, and lungs of the
three patients. Additional tests showed that the virus
was not just present in the patients but was actively
replicating, causing the initial skin rash and damaging
the lungs.
Because of the newly identified risk, the research-
ers say organ-transplant recipients and other immu-
nocompromised patients should be routinely tested
for HPyV9 infection. (VirCapSeq-VERT recently
received approval for clinical use from the New York
State Department of Health.)
Although HPyV9 has been found in the blood of
transplant recipients and may be present in up to
30% of the general population, it has not been previ-
ously linked to a human disease. “Since HPyV9 is
not routinely tested in clinical settings, we may find it
is more common than we realize,” says Dr. Mishra.
“And as we begin to use VirCapSeq-VERT in clinical
microbiology, we can anticipate finding other patho-
genic viruses that we cannot otherwise predict.”
Earlier detection with the new technique may
improve clinical outcomes. A fourth patient with
HPyV9 identified by the researchers is currently
 Specialty Pharmacy News Digest
being screened for viral load to monitor disease pro-
gression and is receiving treatment.
“Our study is the first to describe immunosup-
pressed transplant recipients infected with HPyV9,
so the risk of developing HPyV9 infection is still
unknown,” Dr. Gallitano says. “As we learn more
about the pathogenesis of this disease, targeted novel
forms of antiviral therapy and/or modification of
immunosuppressive drug regimens may improve
patient outcomes.”
“Kick and Kill” Strategy Aims to
Eliminate HIV-Infected Cells
In a study using mice, a UCLA-led team of research-
ers have improved upon a method they developed in
2017 that was designed to kill HIV-infected cells.
The advance could move scientists a step closer to
being able to reduce the amount of virus, or even
eliminate it, from infected people who are dependent
on lifesaving medications to keep the virus from mul-
tiplying and illness at bay.
The strategy, described in Nature Communica-
tions, uses cells that are naturally produced by the
immune system to kill infected cells that hide in the
body, potentially eradicating them, said Dr. Jocelyn
Kim, an assistant professor of medicine in the divi-
sion of infectious diseases at the David Geffen School
of Medicine at UCLA.
“These findings show proof-of-concept for a ther-
apeutic strategy to potentially eliminate HIV from
the body, a task that had been nearly insurmountable
for many years,” said Dr. Kim, the study’s lead
author. “The study opens a new paradigm for a pos-
sible HIV cure in the future.”
Worldwide, there are currently 38 million people
living with HIV, and an estimated 36 million have
died of HIV-related diseases in the decades since HIV
began circulating, according to UNAIDS.
Patients with HIV take antiretroviral medication
to keep the virus at bay. But HIV has the ability to
elude antiretrovirals by lying dormant in cells called
CD4+ T cells, which signal another type of T cell, the
CD8, to destroy HIV-infected cells. When a person
with HIV stops treatment, the virus emerges from
those reservoirs and replicates in the body, weaken-
ing the immune system and raising the likelihood of
opportunistic infections or cancers that can lead to
illness or death.
The UCLA-led study continues research on a
strategy called “kick and kill,” which many of the
same scientists first described in a 2017 paper. The
35
U.S. Pharmacist • March 2022 • www.uspharmacist.com
approach coaxes the dormant virus to reveal itself in
infected cells, so it can then be targeted and killed. In
the earlier study, the researchers gave antiretroviral
drugs to mice whose immune systems had been
altered to mimic those of humans and then infected
with HIV. They then administered a synthetic com-
pound called SUW133, which was developed at
Stanford University, to activate the mice’s dormant
HIV. Up to 25% of the previously dormant cells that
began expressing HIV died within 24 hours.
But a more effective way to kill those cells was
needed. In the new study, while the mice were receiv-
ing antiretrovirals, the researchers used SUW133 to
flush HIV infected cells out of hiding. They then
injected healthy natural killer cells into the mice’s
blood to kill the infected cells. The combination of
SUW133 and injections of healthy natural killer
immune cells completely cleared the HIV in 40% of
the HIV-infected mice.
The researchers also analyzed the mice’s spleens
because the spleen harbors immune cells and is a
favorable place to look for latent HIV-infected cells.
They did not detect the virus there, suggesting that
cells harboring HIV were eliminated. In addition, the
combination approach performed better than either
the administration of the latency reversing agent
alone or the natural killer cells alone.
Dr. Kim said the researchers’ next objective is to fur-
ther refine the approach to eliminate HIV in 100% of
the mice they test in future experiments. “We will also
be moving this research toward preclinical studies in
nonhuman primates with the ultimate goal of testing
the same approach in humans,” she said.
Researchers Find Protein Trove That
May Influence Cystic Fibrosis
Researchers at the University of Toronto (U of T)
have identified hundreds of new proteins that could
play a role in cystic fibrosis and which may shed light
on why some patients respond better than others to
current therapies.
Many of these proteins, part of a group of drugga-
ble molecules called membrane proteins, interact
with the CFTR protein, which when missing or
faulty leads to the buildup of mucos in the lungs and
other organs that is often fatal in cystic fibrosis.
“We identified more than 400 proteins associated
with either healthy or mutant CFTR and have shown
that some of them could predict the variability seen
in patient symptoms and treatment responses,” said
Igor Stagljar, principal investigator on the study and
 Specialty Pharmacy News Digest
a professor in the Donnelly Centre for Cellular and
Biomolecular Research at U of T’s Temerty Faculty
of Medicine.
“With a more comprehensive view of the CFTR
protein interaction network, we can identify novel
drug targets that should enable more patient-specific
therapies,” Dr. Stagljar said. The journal Molecular
Systems Biology published the findings.
To help identify protein-protein interactions
involving CFTR, the researchers developed a new
technology based on a platform they designed in
2014. The approach is a high-throughput version of
their Mammalian Membrane Two-Hybrid system
that allows for screening of many more membrane
proteins associated with a specific protein.
“The earlier design was array-based, and we
could only screen about 200 proteins at a time,” said
Dr. Stagljar, who is also a professor of biochemistry
and molecular genetics at U of T. “With this new
technology, we’ve introduced several changes that
allow us to screen thousands of protein targets simul-
taneously, in a pooled manner.”
Dr. Stagljar and his laboratory used the technol-
ogy to find several overlooked proteins, including
many membrane proteins that may play a role in
CFTR function and cystic fibrosis. Membrane pro-
teins account for roughly one-third of all proteins in
cells and about 65% of all drug therapy targets.
One especially promising candidate the team found
is the fibrinogen-like 2 protein, thought to play a role
in hepatitis, liver disease, and immune function.
Downregulation of this protein, the team showed,
leads to increased expression of CFTR in organoids,
3D in vitro models that show how cells interact in an
organ, in this case with patient-derived gut tissues.
“We think fibrinogen-like 2 protein is a valuable
drug target for cystic fibrosis, and we’re now work-
ing with our collaborators to validate other proteins
that turned up in this study and in genome-wide
association studies,” Dr. Stagljar said.
Cystic fibrosis affects over 90,000 people globally.
The disease can arise when children inherit two
mutated CFTR genes, one from each parent, result-
ing in defective CFTR proteins on the surface of cells
in the lungs and other organs.
Study Links Gut Fungi to Crohn’s
Inflammation
Results of a new study by researchers at Case West-
ern Reserve University represent a step toward
improving our understanding of Crohn’s disease and
36
U.S. Pharmacist • March 2022 • www.uspharmacist.com
the factors that cause its intestinal inflammation.
Crohn’s disease can lead to chronic inflammation
of the entire digestive tract. Symptoms include diar-
rhea, pain and cramping, fatigue, weight loss, and
more. There is no cure for Crohn’s disease, but
patients can alleviate symptoms with current treat-
ment options, and new treatment options for
Crohn’s disease patients may be on the horizon
thanks to the research linking a common fungal
pathogen to inflammatory bowel disease.
The study recently appeared in Cellular and
Molecular Gastroenterology and Hepatology. This
new research from the Case Western Reserve School
of Medicine focuses on the role of the fungus Can-
dida tropicalis in triggering chronic inflammation
within the gut microbiome. The gut microbiome is a
complex ecosystem of fungus and bacteria found
within the digestive tract.
Researchers introduced the fungi into animal
models and induced colitis (inflammation of only the
large intestine) through a chemical compound. The
models infected with C tropicalis showed severe
inflammation and significant imbalance of the gut
microbiome with changes in bacteria levels.
Researchers say the findings show that this imbal-
ance of fungi and bacteria can create a predisposi-
tion to inflammatory bowel disease. Past studies
have shown that people with Crohn’s disease have
higher levels of C tropicalis compared with healthy
individuals.
Understanding the impact of C tropicalis on a per-
son’s health, therefore, will play a role in developing
treatments for Crohn’s disease.
Researchers Restore Function in Liver
Cancer–Suppressing Gene
A team of researchers from Massachusetts General
Hospital (MGH) and Brigham and Women’s Hospital
(BWH) has reprogrammed the tumor microenviron-
ment of liver cancer by using mRNA nanoparticles.
This technology, similar to the one used in COVID-19
vaccines, restored the function of the p53 master
regulator gene, a tumor suppressor mutated in not
just liver but also other types of cancer. When used in
combination with immune checkpoint blockade
(ICB), the p53 mRNA nanoparticle approach not
only induced suppression of tumor growth but also
significantly increased antitumor immune responses
in hepatocellular carcinoma (HCC) laboratory mod-
els. The results of the study were published in Nature
Communications.
 Specialty Pharmacy News Digest
“The reprogramming of the cellular and molecular
components of the tumor microenvironment could be
a transformative approach for treating HCC and other
cancers,” said cosenior author Jinjun Shi, PhD, with
the Center for Nanomedicine at BWH, who developed
the platform with MGH liver cancer biologist and
cosenior author Dan G. Duda, DMD, PhD. “By using
this new approach, we’re targeting specific pathways
in tumor cells with mRNA nanoparticles. These tiny
particles provide the cells with the instructions to build
proteins, which, in the case of HCC, delayed tumor
growth and rendered the tumor more responsive to
treatment with immunotherapy.”
HCC is the most prevalent form of liver cancer,
characterized by a high mortality rate and dismal
prognosis. Immune checkpoint blockers, a revolu-
tionary new class of drugs that enable the body’s
immune system to recognize and attack cancer cells,
have shown efficacy in treating HCC, but most
patients do not benefit. To overcome this resistance,
multiple strategies are being developed to improve
ICBs by combining them with other existing thera-
pies, such as anti-VEGF drugs and radiotherapy.
However, even these approaches are expected to ben-
efit only a small number of patients, creating an
urgent need for new combination therapies.
Encouraged by the success of mRNA in COVID-
19 vaccines, Dr. Shi decided to apply the technology
(with certain modifications) to targeting cancer cells.
He teamed up with Dr. Duda, whose MGH labora-
tory had already created sophisticated animal models
to analyze the microenvironment of liver tumors in
response to immunotherapy. They developed and
optimized an mRNA nanoparticle strategy to restore
loss of function of p53, a tumor-suppressor gene
whose function is lost in more than one-third of
HCC cases. In doing so, they uncovered evidence
that p53 regulates the tumor microenvironment by
modulating the interaction of cancer cells with
immune cells as part of ICB therapy.
“In our previous work we had developed
nanoparticles to target CXCR4—a chemokine recep-
tor expressed by liver cancer cells—and selectively
codeliver drugs such as kinase inhibitors,” explained
Dr. Duda. “We’ve now adapted this platform to use
CXCR4 as a kind of ZIP code to selectively target
the tumor with nanoparticles encapsulating thera-
peutic mRNAs. When we combined this nanomedi-
cine with anti–programmed death receptor 1 (PD-1)
antibodies, a standard immunotherapy for HCC
patients, it induced global reprogramming of the
37
U.S. Pharmacist • March 2022 • www.uspharmacist.com
tumor microenvironment and tumor response by
restoring p53 expression.”
How Exercise Could Help People
With Asthma
Interventions aimed at promoting physical activity in
people with asthma could improve their symptoms
and quality of life, according to new research from
the University of East Anglia (UEA).
Researchers looked at whether interventions such
as aerobic and strength or resistance training had
helped participants with asthma. Although they
found that these interventions worked, patients with
asthma may have had difficulty undertaking them
because of their challenge of travel to fitness groups
or because the interventions were not suitable for
people with additional health conditions.
But the team say that digital interventions—such
as video appointments, smartwatches, and mobile
apps—could remove some of these barriers and
enable patients to carry out home-based programs.
Dr. Andrew Wilson, from UEA’s Norwich Medi-
cal School, said, “Being physically active is widely
recommended for people with asthma. Doing more
than 150 minutes a week of moderate to vigorous
physical activity has extensive benefits including
improved lung function and asthma control. But
research has shown that people living with asthma
engage in less physical activity and are more seden-
tary than people without asthma.”
The team studied interventions that were designed
to promote physical activity in adults with asthma.
They looked at 25 separate studies from around the
world involving 1,849 participants with asthma to
see whether their symptoms and quality of life were
changed thanks to the interventions.
Postgraduate researcher Leanne Tyson, also from
UEA’s Norwich Medical School, said, “We found
that interventions that promote physical activity
had significant benefits in terms of increasing physi-
cal activity, decreasing time spent sedentary,
improving quality of life, and decreasing asthma
symptoms.
“This is really important because helping patients
make significant behavior changes could really
improve their outcomes in the long term. Our review
also highlights the potential use of digital interven-
tions, which were notably absent.”
The content contained in this article is for informational purposes
only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is solely
at your own risk.
 SPECIAL SECTION: SPECIALTY PHARMACY

Current and Evolving

Treatments for HIV PrEP
ABSTRACT: Preexposure prophylaxis (PrEP) is a medication therapy regimen provided to HIV-
negative persons at high risk of acquiring HIV. Current FDA-approved oral therapies are
emtricitabine-tenofovir disoproxil fumarate (FTC/TDF) and emtricitabine-tenofovir alafenamide
(FTC/TAF). Recently, the FDA approved the first injectable therapy, cabotegravir long-acting
injectable (CAB-LA), which could provide an advantage to certain patient populations. When PrEP
therapy is taken consistently, it is very effective at preventing HIV. This article will discuss who is a
candidate for PrEP, available therapy options, and additional therapies that are actively being
studied. Pharmacists can help provide education to these patients to help promote adherence
within high-risk populations.

I n 2019, 36,801 individuals received a new diagnosis

of HIV in the United States.1 Approximately 1,189,700
people over the age of 13 years are living with HIV infec-
tion, and up to 13% of these individuals may be undi-
agnosed.1 Occurrences are highest in men who have sex
with men (MSM), Black, and Hispanic patients.1 At this
time, there is no vaccine available to prevent HIV trans-
mission. Nonpharmacologic and pharmacologic inter-
ventions are needed to successfully reduce HIV acquisi-
tion. Nonpharmacologic methods include, but are not
limited to, counseling regarding safe sex practices, access
to harm-reduction strategies such as syringe service pro-
grams to decrease sharing syringes, and circumcision in
some situations.2 Pharmacologic methods for HIV pre-
vention focus on postexposure prophylaxis (PEP), pre-
exposure prophylaxis (PrEP), and treatment as preven-
tion (TasP).3 PEP is starting antiretroviral therapy (ART)
within 72 hours of potential exposure to HIV.3,4 PrEP is
utilizing ART to prevent HIV infection in HIV-negative
individuals who are at a greater risk of HIV.3,5 TasP is
effective at preventing HIV transmission when the
infected person takes ART as prescribed to reduce viral
loads to nondetectable levels.3 The focus of this article
will be to discuss who is a candidate for PrEP, available
treatment options, recommended monitoring, and pipe-
line therapies.
The use and consistent adherence of PrEP have been
estimated to reduce the occurrence of HIV by 99% for
MSM, 90% or more for women, and 74% among indi-
viduals who inject drugs.5,6 Currently, there are two
FDA-approved, once-daily oral tablet PrEP therapies
available to prevent HIV infection in adolescents and
adults weighing at least 35 kilograms: emtricitabine-
tenofovir disoproxil fumarate (FTC/TDF) and emtric-
itabine-tenofovir alafenamide (FTC/TAF).5,7,8 FTC/TDF
is recommended to prevent HIV infection in all indi-
viduals at risk through injection drug use or sex.7 In
clinical trials, FTC/TDF showed a 92% to 100% risk
reduction in acquiring HIV among adherent indi-
viduals.9,10 The DISCOVER trial showed that
FTC/TAF was noninferior to FTC/TDF in reducing
the risk of acquiring HIV among men and trans-
gender women who have sex with men.11 FTC/TAF
is FDA-approved to prevent HIV infection among
individuals at risk through sex, excluding indi-
viduals at risk through receptive vaginal sex due to
the lack of available clinical data.5,8

Jennifer LaPreze, PharmD, BCACP, CDCES, CPP

Clinical Staff Pharmacist
Atrium Health
Fort Mill, South Carolina

Brooke Nowicki, PharmD, AAHIVP

Clinical Pharmacist
© gettyimages.com / JobsonHealthcare
Walgreens Clinical Pharmacy
Durham, North Carolina

38
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Current and Evolving Treatments for HIV PrEP

Indications for PrEP Therapy

Table 1

means primary care providers can prescribe PrEP.5 Dur-

ing the visit, a thorough past medical history should be
Men who have • HIV-positive sexual partner conducted, and a complete medication review, risk
sex with men • High number of sex partners
assessment for acquiring HIV, risk assessment for drug
• Anal intercourse with inconsistent
or no condom use or alcohol abuse, and resources and education should
• Commercial sex work be provided to aid in reducing HIV acquisition.5,13 Prior
• Recent STI with gonorrhea, to initiating either therapy, individuals should be tested
chlamydia, or syphilis and confirmed HIV negative to prevent resistant HIV. If
an individual is HIV positive, additional ART is needed
Heterosexual • HIV-positive sexual partner
men and • High number of sex partners for effective management, which is not discussed in this
women • History of inconsistent or no article. Laboratory work includes a complete metabolic
condom use panel, liver enzymes, renal function, hepatitis serology,
• Commercial sex work and screening for sexually transmitted infections
• Recent STI with gonorrhea or
(STIs).13,15 TABLE 2 provides recommendations for labo-
syphilis
• High HIV prevalence area or ratory monitoring at baseline and for subsequent follow-
network up visits.13 Follow-up screening for STIs is based on an
individual’s risk of STIs.15 Patients should follow up
Individuals • HIV-positive injecting partner
every 3 months for laboratory monitoring, medication
who inject • Sharing any injection equipment
drugs adherence, and screening for medication toxicity.13
When selecting a regimen, shared decision-making
PrEP: pre-exposure prophylaxis; STI: sexually transmitted with patient and provider is important. Providers should
infection. Source: Reference 13.
discuss with patients regarding the need for frequent
visits and expenses related to necessary monitoring.
Monitoring Recommendations for Common adverse effects for FTC/TDF and FTC/TAF
Table 2

PrEP Therapy include nausea, gastrointestinal upset, and headache

HIV antibody/ At baseline, every 3 months, and
antigen after discontinuation of therapy
Creatinine At baseline, 3 months, then every 6
clearance months
Pregnancy At baseline, every 3 months, and
testing after discontinuation of therapy
HBV screening At baseline
Vaccinate and/or continue to
monitor if individual is not immune
Hepatitis C At baseline, then annually
antibody
STI screening At baseline, then every 3-6 months
as deemed appropriate
PrEP: preexposure prophylaxis; STI: sexually transmitted
infection. Source: References 13, 15.
The CDC determined that more than 1.2 million
individuals met eligibility criteria for PrEP in 2015.12,13
TABLE 1 provides indications for PrEP for patients at high
risk of acquiring HIV.13 The U.S. Preventive Services
Task Force has given PrEP a “grade A recommendation”
that prescribers offer PrEP to patients at high risk of
acquiring HIV.14 A specialization in infectious diseases
or HIV medicine is not required for prescribing, which
39
U.S. Pharmacist • March 2022 • www.uspharmacist.com
(which usually resolves after a few weeks).7,8 Clinicians
may consider prescribing supportive therapy, such as
antiemetics, to help with adverse effects. Changes in
bone mineral density and renal function are associated
with FTC/TDF and are usually reversible after a certain
time period following discontinuation.7 FTC/TDF is
appropriate for patients with renal function >60 mL/min
while FTC/TAF is approved for ≥30 mL/min based on
the Cockcroft-Gault equation.7,8 In patients who have
difficulty swallowing larger tablets, FTC/TAF may be
preferred given its smaller size than FTC/TDF. Prescrib-
ers and clinicians can consult the National Clinician
Consultation Center PrEP Line at 1-855-448-7737 for
additional prescribing information.5
Alternative Dosing Strategy
On-Demand Oral PrEP: The only FDA-approved, oral
once-daily therapies are FTC/TDF and FTC/TAF. On-
demand oral PrEP is another strategy prescribers are
utilizing against the adherence barrier prevalent in many
individuals’ PrEP therapy. Although on-demand PrEP—
also known as “nondaily PrEP,” “event-driven PrEP,” or
“2-1-1 PrEP”—is not FDA-approved or CDC-recom-
mended, it has been studied and is currently being utilized
in clinics worldwide.16 This approach replaces daily oral
PrEP therapy with PrEP therapy at times of a sexual
 Current and Evolving Treatments for HIV PrEP
encounter. This means that a patient would take two
tablets of oral PrEP 2 to 24 hours prior to sex, followed
by a third tablet 24 hours after the initial double dose,
and then a fourth tablet 48 hours after the initial double
dose.15,16 In a multisex scenario, the patient would con-
tinue to take one tablet every 24 hours until 48 hours
after the last sexual encounter.15,16 If there are fewer than
7 days between sexual episodes, the patient would need
to take one tablet to restart the cycle. If there are more
than 7 days between sexual episodes, the patient would
need to start again with the two-PrEP-tablet cycle.15,16
The IPERGAY trial compared on-demand PrEP with
placebo and found an 86% reduction rate of HIV infec-
tion in the on-demand PrEP group.17 Study limitations
included the low participant population and the median
number of doses (15 tablets per month); this is very close
to the four tablets per week that has been known to
produce high levels of protection during attempted daily
dosing.17 This brings to light the question of whether the
high rate of dosing was a main contributor to the HIV-
acquisition reduction rate.17 Current guidelines for on-
demand PrEP are conflicting, and more data will be
needed before we have a clear understanding of the impli-
cations of on-demand dosing in PrEP therapy.
Recent FDA Approval
Cabotegravir Long-Acting Injectable (CAB-LA): CAB-LA
was recently approved by the FDA in December 2021
for PrEP in at-risk adults and adolescents weighing at
least 35 kilograms to reduce the risk of sexually acquired
HIV.18 Prior to initiation and each subsequent injection,
individuals must produce a negative HIV-1 test result.19
Shared decision-making with healthcare provider and
patient should occur to determine the use of oral cabo-
tegravir 30 mg once-daily lead-in for a month prior to
administration of CAB-LA or to start CAB-LA without
an oral lead-in.19
CAB-LA is a 600-mg injection given 1 month apart
for 2 consecutive months and subsequent injections every
2 months thereafter administered by a healthcare pro-
vider via gluteal intramuscular injection. If an oral lead-
in of cabotegravir is used, initiation injections should be
administered on the last day or within 3 days of oral
cabotegravir. CAB-LA can be administered 7 days before
or after the scheduled date to receive the injection.19 If
individuals miss subsequent injections, discussions with
their healthcare provider are warranted to explore addi-
tional options. The most common adverse reactions with
CAB-LA include injection site reactions, diarrhea, head-
ache, fatigue, and pyrexia.19 Hepatoxicity has been
reported with CAB-LA; regular monitoring of hepatic
40
U.S. Pharmacist • March 2022 • www.uspharmacist.com
function is recommended, and if hepatotoxicity occurs,
to discontinue use.19
CAB-LA was studied in two randomized, double-
blind, controlled, multinational trials: HIV Prevention
Trials Network (HPTN) 083 and HPTN 084. HPTN
083 compared CAB-LA to FTC/TDF. The primary out-
come was the prevalence of HIV transmission in high-
risk men who have sex with men and transgender
women. Individuals were to be followed for 153 weeks
and were randomly assigned to either CAB-LA or FTC/
TDF. The study was stopped early due to the HIV infec-
tion rate being significantly lower in the CAB-LA group.
In total, 52 of the 4,566 participants contracted HIV—
39 participants in the FTC/TDF group and 13 in the
CAB-LA group. This study was the first to show great
promise for the use of an injection as an alternative to
daily PrEP therapy.20
Furthermore, the HPTN 084 trial compared CAB-LA
to FTC/TDF in adult women in sub-Saharan South
Africa who were at high risk of being infected with HIV.
This trial was also stopped early due to the HIV infection
rate being significantly lower in the CAB-LA group.
Thirty-eight of the 3,223 participants contracted HIV—
34 participants in FTC/TDF group and four in the CAB-
LA group.20 Primary analysis showed an 88% reduction
in the risk of acquiring HIV-1 infection with CAB-LA.19
The availability of a long-acting injectable PrEP
option will be an effective tool against current usage and
adherence barriers in at-risk populations. Adjustments
will need to be made in pharmacies and provider offices
to establish workflow processes that are safe and efficient
in billing and provide monthly and bi-monthly PrEP
injections.
PrEP Therapies in the Pipeline
The protective effects of FTC/TDF and FTC/TAF rely on
optimal adherence, which can be a barrier for at-risk
patient populations. To combat this, clinical trials are in
progress exploring alternative treatment options to daily
oral PrEP therapy.
Islatravir (ISL) Once-Monthly Oral Tablet: Impower-022
and Impower-024 are both phase III trials comparing ISL
with FTC/TDF and FTC/TAF in different patient popu-
lations. The primary end point will be the incidence of
HIV infections. Both are estimated to be completed in
2024.22,23
Dapavirine Long-ActingVaginal Ring (DPR-VR): DPR-VR
is a long-acting vaginal ring system dosed once-monthly
that is in clinical trials to offer PrEP therapy for women
 Current and Evolving Treatments for HIV PrEP

in developing countries who are at substantial risk of
acquiring HIV.
Two separate phase III clinical trials showed that
DPR-VR significantly reduced the risk of HIV transmis-
sion compared with placebo. The Ring Study showed a
risk reduction of 31%, and the ASPIRE trial showed a
risk reduction of 27%.24,25
DPR-VR received positive scientific opinion from the
European Medicines Agency in 2020 for use in adult
women in developing countries, recommendations from
the World Health Organization (WHO) in 2021, and
approval in Zimbabwe in July 2021.26,27 DPR-VR also
has regulatory reviews pending in additional countries
in Africa and is currently under review by the FDA.26
Although these results are promising and trials are
still in process, approval of DPR-VR in developing coun-
tries would need to act as a supplement to existing HIV-
prevention practices. The ring could be another expan-
sion in our “PrEP toolbox” to fight the global rate of
HIV infection.
Other delivery systems in the pipeline include addi-
tional topical products, implants, and transdermal
devices. The goal of these new delivery systems is to
and educate patients to notify prescribing clinicians when
starting a new medication—whether it is an herbal sup-
plement, OTC medication, or prescription therapy—to
avoid potential interactions. Pharmacists can also pro-
vide counseling on PrEP therapy to discuss potential
adverse effects, as well as management, importance of
optimal adherence, and need for routine follow-up for
monitoring. Pharmacists may be able to identify repeat
PrEP patients as candidates for PrEP therapy and recom-
mend follow-up with a prescriber. Additionally, pharma-
cists may be able to assist with resources available to
make PrEP therapy more affordable, including co-pay
cards and patient-assistance programs.
Impact of COVID-19
COVID-19 has impacted healthcare and individuals’
access to PrEP. Some offices may have been able to
expand telehealth services to patients, while other offices
may have reduced their hours or closed. The CDC con-
tinues to recommend quarterly HIV testing for patient
safety and prefers laboratory-only visits for assessment.29
However, if laboratory-only visits are not available, there
USPH-LineTracing-Right-3.50-5.00-B.125-QR-PRESS.pdf 1 4/27/2020

expand the availability of PrEP and to appeal to a wide

variety of populations globally, therefore increasing the
percentage of eligible patients on PrEP therapy and ulti-
mately decreasing the rate of HIV infections.28

Medication Affordability
The average cost of oral PrEP therapy is approximately
$1,845 per month; cost can be a barrier to getting at-risk
patients on therapy.15 There are several forms of assis-
tance to help combat this barrier. Most health insurance
and state-funded Medicaid plans cover PrEP therapy for C

little or no charge.29 To assist with high copays, Gilead, M

the manufacturer of FTC/TDF and FTC/TAF, offers Y

copay cards to bring the patient’s cost down even further. CM

For those who do not have insurance, most states have MY

patient-assistance programs.29 Pending patient qualifica-

CY

tion, these programs assist in getting PrEP for free or at

a reduced cost to the patient.
CMY

Many insurance companies require patients to use K

specialty pharmacies to fill these medications. Specialty

pharmacies have resources dedicated to cost assistance
and education for these medications. Physician offices
that specialize in PrEP therapy can assist patients with
these enrollment processes as well.

Role of the Pharmacist

Pharmacists can complete comprehensive medication
reviews, identify drug interactions with PrEP therapy,
41
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 Current and Evolving Treatments for HIV PrEP
are two options: home specimen collection kits for HIV
and STI infection to test urine or blood, where the patient
mails the kit back to the laboratory and test results are
provided to the prescribing provider, or self-testing via
an oral swab–based test. The latter is used if other
options are not available, given its lower sensitivity to
detect recent HIV infection.30 Once HIV-negative status
is confirmed, the prescriber could consider writing
90-day prescriptions instead of 30-day prescriptions. If
a clinic is changing services or closing, it should provide
individuals with other services or clinics for continuity
of care and access to PrEP.30
Some clinics may have created flexible care plans to
extend laboratory work and utilized telemedicine when
in-person visits were not possible. One study showed
a 44% reduction in new PrEP starts and a 0% decrease
in follow-up visits for PrEP.31 Another study showed a
REFERENCES
1. CDC. HIV Surveillance Report. www.cdc.gov/hiv/statistics/over-
view/index.html. Accessed November 1, 2021.
2. CDC. HIV: Protect yourself if you inject drugs. www.cdc.gov/hiv/
basics/hiv-prevention/inject-drugs.html. Accessed November 3, 2021.
3. Heendeniya A, Bogoch I. Antiretroviral medications for the
prevention of HIV infection: a clinical approach to preexposure
prophylaxis, postexposure prophylaxis, and treatment as prevention.
Infect Dis Clin North Am. 2019;33(3):629-646.
4. CDC. HIV: About PEP. www.cdc.gov/hiv/basics/pep/about-pep.
html. Accessed November 3, 2021.
5. CDC. HIV: Pre-exposure prophylaxis (PrEP) www.cdc.gov/hiv/
clinicians/prevention/prep.html. Accessed November 1, 2021.
6. Beymer M, Holloway I, Pulsipher C, et al. Current and future
PrEP medications and modalities: on demand, injectables, and
topicals. Curr HIV/AIDS Rep. 2019;16(4):349-358.
7. Truvada (emtricitabine and tenofovir disoproxil fumarate) pack-
age insert. Foster City, CA: Gilead Sciences, Inc; Revised June 2020.
8. Descovy (emtricitabine and tenofovir alafenamide) package insert.
Foster City, CA: Gilead Sciences, Inc; Revised March 2021.
9. Grand RM, Lama JR, Anderson PL, et al. Preexposure chemo-
prophylaxis for HIV prevention in men who have sex with men. N
Engl J Med. 2010;363(27):2587-2599.
10. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophy-
laxis for HIV infection among African women. N Engl J Med.
2012;367(5):411-422.
11. Hare C, Coll J, Ruane P, et al. The phase 3 DISCOVER study:
daily F/TAF or F/TDF for HIV pre-exposure prophylaxis. Presented
at the Conference on Retroviruses and Opportunistic Infections,
Seattle, WA. March 2019.
12. Smith DK, Van Handel M, Wolitski RJ, et al. Vital signs: esti-
mated percentages and numbers of adults with indications for
preexposure prophylaxis to prevent HIV acquisition–United States,
2015. MMWR Morb Mortal Wkly Rep. 2015;65(46):1291-1295.
13. CDC. Preexposure prophylaxis for the prevention of HIV infec-
tion in the United States–2017 update: a clinical practice guideline.
www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf.
Accessed November 5, 2021.
14. U.S. Preventive Services Task Force. Preexposure prophylaxis
for the prevention of HIV infection: US Preventive Services Task
Force Recommendation Statement. JAMA. 2019;321(22):2203-2213.
15. Baker J, Rolls J. Update on HIV prevention and preexposure
prophylaxis. JAAPA. 2020;33(6):12-17.
16. Saberi P, Scott H. On-demand oral pre-exposure prophylaxis
with tenofovir/emtricitabine: what every clinician needs to know. J
Gen Intern Med. 2020;35(4):1285-1288.
17. Beymer M, Holloway I, Pulsipher C, Landovitz RJ. Current and
future PrEP medications and modalities: on demand, injectables,
and topicals. Curr HIV/AIDS Rep. 2019;16(4):349-358.
18. FDA. FDA approves first injectable treatment for HIV preex-
posure prevention. December 20, 2021. www.fda.gov/news-events/
press-announcements/fda-approves-first-injectable-treatment-hiv-pre-
42
U.S. Pharmacist • March 2022 • www.uspharmacist.com
191% increase in PrEP refill lapses and a 72.1%
decrease in new PrEP starts. Continued emerging data
will show the impact of COVID-19 on PrEP therapy,
and additional research is needed to assess the full
impact of COVID-19 and PrEP therapy.32
Conclusion
PrEP is effective at reducing HIV transmission when used
consistently. Pharmacists can provide education to
patients to help continue therapy. There are new thera-
pies in development that may further prevent HIV.
COVID-19 continues to impact healthcare, and addi-
tional research will be needed to be conclude the impact
on PrEP usage.
The content contained in this article is for informational purposes
only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is solely
at your own risk.
exposure-prevention. Accessed February 19, 2022.
19. Apretude (cabotegravir extended-release injectable suspension)
package insert. Research Triangle Park, NC: GlaxoSmithKline.
Published December 2021.
20. Landovitz RJ, Donnell D, Clement M, et al. Cabotegravir for
HIV prevention in cisgender men and transgender women. N Engl
J Med. 2021;385:595-608.
21. World Health Organization. Trial results reveal that long-acting
injectable cabotegravir as PrEP is highly effective in preventing HIV
acquisition in women. www.who.int/news/item/09-11-2020-trial-
results-reveal-that-long-acting-injectable-cabotegravir-as-prep-is-
highly-effective-in-preventing-hiv-acquisition-in-women. Accessed
November 28, 2021.
22. Clinicaltrials.gov. Oral islatravir (MK-8591) once-monthly as
preexposure prophylaxis (PrEP) in men and transgender women who
have sex with men and are at high risk for HIV-1 infection (MK-
8591-024) (Impower-024). www.clinicaltrials.gov/ct2/show/
NCT04652700. Accessed November 27, 2021.
23. Clinicaltrials.gov. Oral ISL QM as PrEP in cisgender women at
high risk for HIV-1 infection (MK-8591-022) (Impower-022). www.
clinicaltrials.gov/ct2/show/NCT04644029. Accessed November 27,
2021.
24. Nel A, van Niekerk N, van Baelen B, et al. Safety, adherence,
and HIV-1 seroconversion among women using the dapivirine
vaginal ring (DREAM): an open-label, extension study. Lancet HIV.
2021;8(2):e77-e86.
25. Baeten J, Palanee-Phillips T, Brown E, et al. Use of a vaginal
ring containing dapivirine for HIV-1 prevention in women. N Engl
J Med. 2016;375:2121-2132.
26. International Partnership for Microbicides. A long-acting ring
for women’s HIV prevention. www.ipmglobal.org/content/ring-
backgrounder-0. Accessed November 28, 2021.
27. World Health Organization. Consolidated guidelines on HIV
prevention, testing, treatment, service delivery and monitoring:
recommendations for a public health approach. www.who.int/
publications/i/item/9789240031593. Accessed November 28, 2021.
28. Coelho L, Torres T, Veloso V, et al. Preexposure prophylaxis
2.0: new drugs and technologies in the pipeline. Lancet HIV.
2019;6:e788-e799.
29. CDC. HIV: Paying for PrEP. www.cdc.gov/hiv/basics/prep/paying-
for-prep/index.html. Accessed November 21, 2021.
30. CDC. PrEP during COVID-19. 2020. www.cdc.gov/nchhstp/
dear_colleague/2020/dcl-051520-PrEP-during-COVID-19.html.
Accessed December 1, 2021.
31. Rogers B, Tao J, Maynard M, et al. Characterizing the impact
of COVID-19 on pre-exposure prophylaxis (PrEP) care. AIDS Behav.
2021;25:3754-3757.
32. Krakower DS, Solleveld P, Levine K, et al. Impact of COVID-19
on HIV preexposure prophylaxis care at a Boston community health
center. NATAP. 2020. www.natap.org/2020/IAC/IAC_75.htm. Accessed
December 1, 2021.
 CONSULT YOUR PHARMACIST

Multiple Sclerosis
M ultiple sclerosis (MS) is a chronic immune-
mediated, inflammatory neurologic disease
affecting the brain, spinal cord, and optic nerve.
overall daily activities. As MS progresses,
patients experience increased disability. More
than half of those who have MS will experience
It is a condition characterized by demyelination walking impairments within 10 years of disease
and axonal loss, resulting in interruption of nerve onset. There is also a significant reduction in life
impulses, causing a multitude of symptoms, such expectancy by 7 to 14 years in patients with MS
as sensation loss, compared with the
muscle weakness, general population.
vision loss, incoordi- Currently, there is no
nation, cognitive cure for MS, and
impairment, fatigue, lifelong treatment is
and bladder and required. Current
bowel disturbances. treatment involves a
The pathological multidisciplinary
hallmark of MS is approach and con-
the accumulation of sists of disease-modi-
demyelinating lesions fying therapies
found in the white (DMTs), symptom-
and gray matter of atic treatment, life-
the brain and spinal style modifications,
cord. It is estimated psychological sup-
that nearly 1 million port, and rehabilita-
MS affects the brain, spinal cord, and optic nerve.
adults are living with tion interventions. As
MS in the United medication experts,
States. It is a very costly condition; in 2019 the pharmacists serve as a resource for patients and
total economic burden of MS was estimated to their caregivers, aiding in the discussion about
be $85.4 billion, with the majority of this attrib- the importance of therapy, adherence, and of
uted to direct medical costs. 1-6
proper administration techniques.2,7,8
MS is one of the most common causes of non-
traumatic disability in young adults, with inci- Four Clinical Courses of MS
dences peaking between the ages of 20 and 40 The clinical course of MS is defined by periods
years, with a higher prevalence in women. It is a of relapse and/or disease progression. A relapse is
debilitating disease that diminishes quality of life; the occurrence of new symptoms or worsening of
mobility is impaired in up to 90% of patients old symptoms in the absence of fever or infection
with MS, fatigue affects up to 95% of patients, lasting more than 24 hours and separated from
and pain is reported in up to 86% of patients. the previous attack by at least 30 days. Some
People with MS often have difficulty working, common presentations of relapses include optic
pursuing leisurely activities, and participating in neuritis, sensory deficits, cerebellar dysfunctions,
or severe fatigue. Disease progression is worsen-
Emily M. Ambizas, PharmD, MPH, CGP
ing of signs and symptoms over at least 6 months
Interim Assistant Dean, Experiential Pharmacy Education despite having periods of relapse or remissions.9
Associate Clinical Professor Patients with MS can be classified or grouped
St. John's University, College of Pharmacy & Health Sciences
into four major categories based on their disease
Queens, New York
Clinical Specialist, Walgreens Pharmacy course: relapsing-remitting MS (RRMS), second-
Whitestone, New York ary progressive MS (SPMS), primary progressive
43
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Multiple Sclerosis
Table 1
Risk Factors for MS
Environmental • Epstein-Barr virus infection
• Geographical latitude
Genetics • First-degree relative
• Polymorphisms on HLA-
DRB1*15:01 allele
Modifiable Factors • Tobacco exposure
• Obesity
• Sodium intake
• Low sun exposure
• Night work
• Low vitamin D levels
HLA: human leukocyte antigen; MS: multiple sclerosis.
Source: References 1, 3, 10.
MS (PPMS), and progressive relapsing MS
(PRMS). The most common form of MS at dis-
ease onset is RRMS, composing almost 90% of
cases. This disease pattern is characterized by
periods of symptom flareups, or relapses, fol-
lowed by periods of partial or complete remis-
sion. There is no evidence of disease progression
between attacks. For some patients, relapses
decrease in frequency over time and sometimes
completely disappear. However, in most patients,
neuronal damage becomes clinically evident, and
usually within 10 to 20 years after disease onset,
patients progress to SPMS. A steady worsening
of neurologic deficits occurs. Periods of relapses
typically lead to further progression. About 10%
of patients will present with PPMS at disease
onset; symptoms continue to worsen from the
beginning. Patients do not experience periods of
relapses or remissions but may experience occa-
sional plateaus. The mean age of onset is about
40 years, and it seems to more frequently affect
men. PRMS is rare, affecting fewer than 5% of
patients. It is progressive from the beginning and
is characterized by a continual decline in neuro-
logic functioning with occurrences of superim-
posed relapses.3,5,9,10
Risk Factors
The exact cause of MS is still unknown, but epi-
demiologic data suggest environmental and
genetic factors both play a role (see TABLE 1).
Genetics seem to play a role in the development
of MS. The recurrence rate of MS in families is
about 13% to 20%, but the risk decreases with
44
U.S. Pharmacist • March 2022 • www.uspharmacist.com
increasing genetic distance. In first-degree rela-
tives, MS risk is 2.77%. This risk drops to
1.02% in second-degree relatives and to 0.88%
in third-degree relatives. The risk in monozygotic
twins is 25% to 30% compared with 3% to 5%
in dizygotic twins. More than 200 genetic risk
variants have been identified for MS, with the
human leukocyte antigen (HLA) region represent-
ing the strongest MS susceptibility locus; the
presence of the HLA-DRB1*15:01 allele
increases MS risk threefold.1,3,9,10
Many environmental and lifestyle factors have
been identified that may increase an individual’s
risk for MS development. The timing of expo-
sure to these risk factors may be important;
migration studies have shown that key environ-
mental exposures associated with adult-onset MS
occur before age 15 years. Environmental expo-
sure and MS risk may also depend on the
genetic background of the individual. The most
well-established environmental risk factors
include Epstein-Barr virus (EBV), tobacco expo-
sure, low sun exposure, low vitamin D levels,
and adolescent obesity.3,9-12
Exposure to the EBV, including infectious
mononucleosis, especially in adolescence, has
been associated with an increased risk of MS.
Almost 100% of patients with MS are positive
for EBV antibodies. Smoking has consistently
been shown to increase the risk of MS. The risk
is dose-dependent, with both a higher amount of
smoking and cumulative smoking associated with
an increased risk. The age at which a person
starts smoking does not seem to affect risk, but
smoking cessation regardless of the cumulative
dose has been correlated with a gradual decline
in risk, with the risk approaching zero after 10
years of quitting. Passive exposure to smoking
has been associated with an increased risk as
well. Smoking has also been linked to a faster
disease severity progression, increasing the risk
of conversion from RRMS to SPMS and disabil-
ity progression. MS appears to be more prevalent
in geographical regions that are further from the
equator. Sun exposure, which decreases with
increasing latitude, has been inversely correlated
to MS risk. Sun exposure is also a major deter-
minant of vitamin D levels; low levels of vitamin
D have been shown to increase the risk of MS
and disease activity. Vitamin D supplementation
may lower the risk of MS in susceptible individu-
 Multiple Sclerosis

als. Adolescent obesity

Table 2

Available Disease-Modifying Therapies for MS doubles the risk of devel-

Level of Frequent/Serious oping MS—especially in
Medication Indication Activity Route Adverse Events females—and has been cor-
related with an earlier age
Avonex (inter- RRMS Modest IM Injection-site reac-
at the onset of MS.9-12
feron beta-1a) tions, flu-like symp-
toms, mood disor-
Rebif (interferon RRMS Modest SC ders, suicidal Clinical Presentation
beta-1a) ideation, liver trans- Symptoms of MS are not
aminase elevations, unique to the disease itself;
Plegridy RRMS Modest SC hepatotoxicity, leuko- almost any neurologic sign
(pegylated inter- penia
or symptom can result
feron beta-1a)
from MS. The clinical pre-
Betaseron RRMS Modest SC sentation of MS varies
(interferon widely and is dependent on
beta-1b) where the demyelination
Copaxone, RRMS Modest SC Immediate post occurs. Some patients will
Glatopa (glat- injection-site reac- present with cognitive
iramer acetate) tion (flushing, anxi- changes, while others may
ety, chest pain, pal- experience prominent
pitations) ataxia, hemiparesis or
Tysabri RRMS High IV Fatigue, headache,
paraparesis, depression, or
(natalizumab) infusion allergic reactions, visual symptoms. In most
infections, risk of PML patients, disease onset
involves a clinically iso-
Lemtrada RRMS High IV Infusion reactions,
lated syndrome consisting
(alemtuzumab) infusion leukopenia, autoim-
mune reactions, infec- of an unpredictable neuro-
tions, malignancies logic dysfunction due to
demyelinating lesions
Ocrevus RRMS High IV Infusion reactions, occurring either in the
(ocrelizumab) and infusion leukopenia, infec- optic nerve, brainstem, or
PPMS tions, decreased
immunoglobulin lev-
cerebellum, or the cerebral
els, malignancies hemisphere. The initial
attack is generally mild and
Kesimpta RRMS High SC Injection-site reac- self-limiting and is usually
(ofatumumab) tion, systemic and recognized as the initial
local infections,
decreased immuno-
presentation in retrospect
globulin levels once a diagnosis of MS has
been determined.10,13
Novantrone RRMS High IV Nausea, dose-related Visual impairment due
(mitoxantrone) and infusion cardiomyopathy, pro- to optic neuritis is a com-
SPMS myelocytic leukemia
mon initial symptom. Optic
Gilenya RRMS Moder- Oral Bradycardia, hepato- neuritis is the first neuro-
(fingolimod) ate toxicity, AV block, logic episode in almost
macular edema, infec- 25% of patients. This is
tions, liver transami- characterized by partial or
nase elevations,
hypertension, malig-
total vision loss in one eye
nancies, risk of PML with a blind spot in the
visual field, color vision
Continued deficiency, and orbital pain

45
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Multiple Sclerosis
Table 2
ski sign, paresis, and hyper-
Available Disease-Modifying Therapies for MS (Cont.) reflexia—are the initial
Level of Frequent/Serious presenting symptoms in up
Medication Indication Activity Route Adverse Events to 40% of patients and will
affect almost everyone dur-
Mayzent RRMS Moder- Oral Bradycardia, liver
ing the course of the dis-
(siponimod) and ate transaminase eleva-
SPMS tions, macular ease. Brainstem and cerebel-
edema, hypertension, lar symptoms affect almost
infections, basal cell 70% of MS patients. These
carcinoma symptoms include ocular
movement impairments,
Zeposia RRMS Moder- Oral Liver transaminase
(ozanimod) and ate elevations, diplopia, ataxia and gait
SPMS decreased blood imbalance, slurred speech,
lymphocyte counts, and dysphagia. Sphincter
infections, bradycar- and sexual dysfunctions are
dia, macular edema, dependent upon the degree
hypertension
of lower extremity impair-
Mavenclad RRMS Moder- Oral Headaches, infec- ment and will eventually
(cladribine) ate tions, lymphocytope- affect all patients with MS.
nia, malignancies, Other symptoms include
acute cardiac failure
cognitive impairment,
Tecfidera RRMS Moder- Oral Flushing, diarrhea, fatigue, affective distur-
(dimethyl ate nausea, infections, bances, and depression.10,13
furarate) lymphopenia, ana-
phylaxis, angio-
Management
edema, hepatotoxic-
ity, PML Currently, there is no cura-
tive treatment for MS.
Aubagio RRMS Moder- Oral Headache, diarrhea, Treatment is focused on
(teriflunomide) ate alopecia, hepatotox- treating relapses, modify-
icity, leukopenia,
ing or slowing disease pro-
hypertension, acute
renal failure, serious gression, providing symp-
skin reactions tomatic relief, and
maintaining an acceptable
Ponvory RRMS Moder- Oral Infections, liver
quality of life. Acute
(ponesimod) ate transaminase eleva-
tions, hypertension, relapses are commonly
bradycardia, QT pro- managed with a short
longation, macular course of corticosteroids,
edema, cutaneous such as methylpredniso-
malignancies lone or dexamethasone
AV: atrioventricular; PML: progressive multifocal leukoencephalopathy; PPMS: primary administered IV or orally.
progressive multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary Disease-modifying thera-
progressive multiple sclerosis. Source: References 10, 15, 22, 23. pies (DMTs) have been
shown to reduce the fre-
that is worsened by eye movement. Sensory quency and severity of relapses, and reduce the
symptoms including paresthesia, Lhermitte sign accumulation of lesions, and they can stabilize,
(sensations of electric shocks radiating down the delay, or modestly improve disability. Treatment
spine on neck flexion), and decreased pain and with DMTs should be initiated as early as pos-
light touch perception are experienced by up to sible, ideally within 5 years of clinical symptom
43% of patients initially presenting with MS. onset to reduce the risk of disease progression.
Motor manifestations—characterized by pyrami- Currently, there are several injectable, infusion,
dal signs that include spasticity, weakness, Babin- and oral DMTs available for the treatment of MS

46
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Multiple Sclerosis
(see TABLE 2). These agents have immunosuppres-
sive and immunomodulatory effects targeting
lymphocyte number, proliferation, trafficking,
and cytokine production, reducing central ner-
vous system inflammation, and preventing dis-
ease progression. They have all been found to
be effective in RRMS only, except for ocreli-
zumab, which is the only agent indicated for
the management of PPMS as well. They are cat-
egorized as moderately effective or highly effec-
tive based on their impact on relapses. The
selection of the most appropriate DMT for a
patient can be challenging and is based on a
multitude of factors, including clinical symp-
toms, MRI activity, agent efficacy, side-effect
profile, and patient considerations, which
include convenience, cost, and preference. Cur-
rently, the dominant treatment strategy used is
the escalation regimen. Therapy is started with
a less-effective agent and is switched to another
lower efficacy agent if the patient experiences
intolerable side effects and to a higher-efficacy
DMT when disease activity worsens. Common
management of MS symptoms, including spas-
ticity, pain, fatigue, cognitive impairment, walk-
ing impairment, and bladder and bowel issues,
should include a combination of pharmacologic
and nonpharmacologic agents. The management
of these symptoms is important to improving
the quality of life in MS patients and requires a
multidisciplinary approach. 5,10,13-18
Role of the Pharmacist
An important role of the pharmacist in the
management of MS is medication safety, iden-
tifying any contraindications to therapy and
adverse event risks, and providing patient edu-
cation about MS and its management. Many
agents will require complete blood counts and
liver function tests. Other agents will require
yearly skin exams to detect malignancies, such
as melanoma. Many monitoring parameters are
outlined by regulatory agencies, and pharma-
cists can ensure that the recommended and
required monitoring parameters are completed
at baseline and before refill authorizations.
Before initiating a DMT, a patient’s comorbid
conditions should be taken into consideration.
For example, interferons should be avoided in
patients with a history of depression, and fin-
golimod should be used with caution or
47
U.S. Pharmacist • March 2022 • www.uspharmacist.com
avoided in patients with cardiac complications.
By completing a comprehensive medication
review for all patients, pharmacists can help
identify such conditions that may worsen with
the addition of specific DMTs. A comprehen-
sive review also provides the pharmacist an
opportunity to speak with the patient one-on-
one about MS, the importance of early treat-
ment, and adhering to their regimen. Once
therapy has been initiated, pharmacists play an
important role in counseling the patient on the
appropriate use and adverse effects of the
medication. 19,20
Pharmacists may also help the healthcare team
understand more about the patient’s needs, assess
potential drug interactions, and identify potential
barriers to adherence. One factor that can affect
treatment adherence is cost. MS therapies are very
costly, with annual expenses anywhere from
$90,000 to $195,000. Many insurance providers
require prior authorizations for these products,
which can delay treatment start. Most manufac-
turers provide financial assistance through copay
assistance programs to help with out-of-pocket
expenses but require submission of documenta-
tion. Pharmacists are in a unique position to help
patients navigate this very confusing process by
assisting them in selecting the most cost-effective
option based on the patient’s insurance coverage
and financial needs and serving as an advocate for
patients to obtain their medications promptly.19-21
Conclusion
MS is a chronic progressive disease with no cure.
Management is focused on delaying the disease
process. The use of DMTs is the cornerstone of
treatment, and pharmacists can be an invaluable
resource to both the patient and the interdisci-
plinary healthcare team. Pharmacists can help
patients manage their disease state more effec-
tively by providing education about their therapy,
help patients and their caregivers understand the
risks and benefits of DMTs and the possible
adverse effects, and assist patients in navigating
the confusing landscape of insurance prior autho-
rizations and copay assistance programs to
obtain their medications in a timely manner.
References available online at www.uspharmacist.com.
The content contained in this article is for informational pur-
poses only. The content is not intended to be a substitute for pro-
fessional advice. Reliance on any information provided in this
article is solely at your own risk.
 ✁
PATIENTINFORMATION

What Is Multiple Sclerosis?

Multiple sclerosis (MS) is a chronic autoimmune disease where the body

© gettyimages.com / JobsonHealthcare
attacks and damages nerve cells in the brain, spinal cord, and optic nerves.
This damage causes communication problems between your brain and the rest
of your body. There are different forms of MS. Relapsing-remitting MS is the
most common form. Symptoms come and go. You will experience periods,
also known as relapses, when you have new symptoms or your old symptoms
get worse. Then there is a recovery period when symptoms get better or go
away. Some people who have relapsing-remitting MS will eventually go on to
secondary progressive MS, when symptoms steadily get worse. Primary pro-
gressive MS is a form of MS where the disease starts getting worse from the
beginning, with few or no periods of relapses or remissions.

What Are the Symptoms of MS?
This condition can cause many symptoms,
depending on where the nerve damage is. Symp-
toms may differ greatly from person to person.
Common symptoms include numbness, tingling,
and feeling of pins and needles; muscle weak-
ness or spasms; vision problems such as double
vision, blurriness, partial color blindness, and
eye pain; fatigue; trouble with coordination and
balance; trouble walking or speaking; trouble
thinking clearly; sensitivity to heat; trouble con-
trolling your bowels or bladder; vaginal dryness
in women and erectile dysfunction in men; and
electric shock sensations when you move your
head a certain way.
What Causes MS?
We do not know the exact cause of MS, but it is
likely due to genetic and environmental factors.
Women are more likely to be affected than men.
If one of your parents or siblings has MS, you
may be at greater risk. Certain viral infections,
such as Epstein-Barr, can trigger the condition.
MS is more common in areas that are farther
away from the equator. Having low levels of
vitamin D and low exposure to sunlight can
increase your risk. Smokers are also at higher
risk for MS than nonsmokers.
How Is MS Treated?
There is currently no cure for MS. Different
medicines can be given at different times to help
with symptoms. Corticosteroids, such as methyl-
prednisolone, are often used to help manage
relapses. To help manage other symptoms such
as muscle spasms, urinary problems, pain,
depression, and constipation, medicines that are
normally taken to help with these conditions are
utilized.
The main class of medicines used works at
slowing down the disease process. This class of
medications is known as disease-modifying ther-
apies. If you have MS, you want to start these
medications as soon as possible to prevent fur-
ther progression and help prevent disability.
Many of these medications have significant
health risks associated with their use. It is very
important that you speak with your healthcare
team, including your pharmacist, about the
associated risks, adverse effects, and monitoring
needs.
Where Can I Go for More Information?
You can contact the following organizations for
additional support and resources:
Multiple Sclerosis Foundation (MSF):
https://msfocus.org/ or 888-MSFOCUS.
National Multiple Sclerosis Society (NMSS):
https://www.nationalmssociety.org/ or
800-344-4867.
Multiple Sclerosis Association of America
(MSAA): https://mymsaa.org/ or 800-532-7667.
PHARMACY STAMP

Remember, if you have questions, Consult Your Pharmacist.

48
U.S. Pharmacist • March 22 • www.uspharmacist.com
 2 CE Credits

Managing Chronic,
Noncancer Pain
With Opioids
ABSTRACT: In recent years, there have
been recommendations to decrease
prescribing of opioids for noncancer pain.
Chronic pain should primarily be managed
by nonpharmacologic or nonopioid
pharmacologic therapy. A thorough medical © Getty images/ JobsonHealthcare

history and proper diagnosis assist with

appropriate management. When using opioids for pain management, the lowest effective
dosage and shortest duration should be utilized. If tapering opioids is appropriate, the provider
needs to utilize effective communication strategies, follow up frequently, and utilize validated
assessment tools to help reduce withdrawal symptoms. Telemedicine can be employed during
the COVID-19 pandemic to ensure continued medication access and to provide regular follow-up.

I n 2012, 259 million prescriptions for opioid pain

medications were written.1 It is estimated that 20%
of patients with noncancer pain receive an opioid
prescription.1 Approximately 10.1 million people
misused prescription opioids in 2020, and 1.6 million
people had an opioid use disorder in the past year.2
In 2017, the U.S. Department of Health and Human
Services (HHS) declared a public health emergency
and released a five-point opioid strategy as described
in TABLE 1 to combat the opioid epidemic.2,3
With the current opioid epidemic, there are ques-
tions regarding what is considered a safe dose of
opioids, the role of opioids in chronic pain manage-
ment, and the risk of overdose or abuse. Multiple
guidelines have recommended that opioid prescrip-
tions for noncancer pain not exceed 50 morphine
equivalents due to the risk associated with abuse.1,4,5
This article will discuss validated tools that clinicians
can use to help assess a patient’s pain and, if appro-
priate, determine a plan to taper the opioid.
Effective treatment for pain starts with an accu-
rate diagnosis. Pain is usually described as either
Vorlak Hong, PharmD
Clinical Pharmacy Specialist
Spectrum Health
Grand Rapids, Michigan
Jennifer LaPreze, PharmD, BCACP, CDCES, CPP
Clinical Pharmacist
Atrium Health
Fort Mill, South Carolina
nociceptive or neuropathic; however, symptoms may
overlap and may not be easily categorized. A thor-
ough history and physical examination should occur.
A pharmacist can help gather a detailed medication
history from the patient. This should include medica-
tions currently being used, past medications, sam-
ples, supplements, and any other OTC medications.
During this discussion, the pharmacist can also
inquire about substance abuse.30 Having the right
diagnosis and medication history will help the pro-
vider make a more informed decision on treatment
options.
Chronic pain is most commonly defined as pain
that lasts longer than 3 months or past the time of
normal healing.1 The focus on treatment should shift
U.S. Pharmacist Continuing Education
GOAL: To educate pharmacists about the manage-
ment of noncancer pain.
OBJECTIVES: After completing this activity, the
participant should be able to:
1. Review guidelines regarding prescribing opioids
for noncancer pain.
2. Describe current recommendations for tapering
noncancer pain opioid management.
3. Describe effective communication strategies to
discuss the benefits and harms of opioids with
patients.
4. Discuss the impact of COVID-19 on the opioid
epidemic.

49
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Managing Chronic, Noncancer Pain With Opioids
Table 1
Five-Point Opioid Strategy
• Improve access to prevention, treatment, and
recovery support services.
• Target the availability and distribution of overdose-
reversing drugs.
• Strengthen public health data reporting and
collection.
• Support cutting-edge research on addiction and pain.
• Advance the practice of pain management.
References: 2, 3.
Table 2
Nonopioid Pharmacologic Therapy for
Various Diagnoses
Type of Pain Nonopioid Pharmacologic Therapy
Back pain Acetaminophen, NSAIDs, muscle relaxers, pain
injections, and surgery
Migraines Preventive: antihypertensive
(propranolol, verapamil,
losartan), antidepressant
(amitriptyline, duloxetine),
anticonvulsant (topiramate,
gabapentin, carbamazepine,
oxcarbazepine, lamotrigine),
injectable CGRPs (Nurtec, Boto)
Fibromyalgia Duloxetine, TCAs (amitriptyline, nortriptyline),
gabapentin, pregabalin, topiramate
CGRPs: calcitonin gene–related peptides; MAOI: monoamine oxidase
inhibitors; NSAIDs: nonsteroidal anti-inflammatory drugs; TCAs: tricyclic
antidepressants. References: 1, 4, 5.
from completely eliminating pain to minimizing the
impact of pain on quality of life.6
In 2016, A Compact to Fight Opioid Addiction
focused on reducing inappropriate prescribing of
opioids, and many states have enacted opioid-limit-
ing legislation.7
Given that pain is multifactorial, nonpharmaco-
logic therapies for pain include cognitive behavioral
therapy, such as mindfulness or relaxation techniques
and physical therapy. If pharmacologic therapy is
appropriate, TABLE 2 shows some nonopioid phar-
macologic therapy options for some causes of pain.
For instance, acetaminophen is first-line therapy for
osteoarthritis.1 Neuropathic pain first- and second-
line medications include anticonvulsants, tricyclic
antidepressants, and serotonin and norepinephrine
reuptake inhibitors (SNRIs).1 Patients with chronic
U.S. Pharmacist • March 2022 • www.uspharmacist.com
pain may have depression, which can exacerbate pain
and worsen physical symptoms; pain may also ben-
efit from antidepressant medication use.1 If opioid
therapy is warranted, it is recommended to combine
it with nonpharmacologic therapy and nonopioid
pharmacologic therapy and the lowest necessary dose
for the shortest duration.1,4 Immediate-release opi-
oids are preferred over extended-release/long-acting
formulations.1
Clinicians should discuss appropriate treatment
regimens with patients and set realistic goals for pain
function at each visit. There are assess-
ment tools that are useful for assessing
daily function and pain, potential risk
of addiction before starting opioids, or
abuse potential while on long-term opi-
oids (TABLE 3). The validated assess-
ment tools in TABLE 3 are not all inclu-
sive, and more tools are available that
can be utilized in practice.4 It is recom-
Abortive: triptans,
mended that this process, which sets
oral CGRPs,
MAOIs, Reyvow standards for opioid prescribing,
should be the same for all patients,
regardless of abuse history.8 The pro-
vider should be aware of legal require-
ments that are necessary to satify prior
to prescribing opioids. An example
would be the state of Michigan, where
providers are required to have a con-
versation with the patient about risks
versus benefits of opioids prior to pre-
scribing them to establish a patient-
provider relationship. Part of this pro-
cess includes the review of the
Prescription Drug Monitoring Program (PDMP) to
assess history of opioid use and urine drug-screen
monitoring. Community pharmacists can help in the
monitoring process by checking in with the patient
when dispensing opioids and with monitoring
(adhering to the PDMP). Pharmacists can notify
prescribing providers if there is a question of abuse
or drug interactions.30
Tools that can be used to determine if the opioid
is improving function and pain are the Pain, Enjoy-
ment of Life and General Activity (PEG) scale and
the Two-Item Graded Chronic Pain Scale.4 Both
scales help assess a patient’s pain and functionality
and should be assessed at each visit.
The PEG was developed based on the Brief Pain
Inventory (BPI) scale to make it easier to use in the
primary care setting. The BPI scale for assessing pain
50
 Managing Chronic, Noncancer Pain With Opioids
intensity/functional impairment and pain-related
interference in daily activity and the healthcare famil-
iarity with a 0 to 10 scale were used to create the
PEG.9 The PEG is comparable to the BPI in assessing
patients’ pain, and the resulting three-question PEG
tool allows clinicians to quickly assess function and
pain while checking for other conditions.9
The Two-Item Graded Chronic Pain Scale was
created from a longer graded chronic scale. The
original scale was a six-item question that asked
patients about their pain and interference in activity
for multiple time periods, which made scoring com-
plicated and more time-consuming. It was simplified
to just two questions to help determine pain intensity
and interference, proving to be an effective tool dur-
ing a primary care visit.10
Clinicians should not continue to prescribe opi-
oids if there is not a clinically meaningful improve-
ment in function or pain interference during the acute
pain phase.1,4 Each state has its own PDMP, which
should be checked to verify that a patient’s controlled
substance history is consistent with prescribing.1 Two
tools that can be used to assess for abuse potential
are the Opioid Risk Tool (ORT) and the Screener and
Opioid Assessment for Patients with Pain (SOAPP-
R). The ORT is a five-item clinician self-administered
tool that can be used to help predict abuse-related
behaviors in patients with chronic pain.4 It focuses
on family/personal history of substance/alcohol/pre-
scription abuse and mental disorders. The original
assessment was a 10-item questionnaire that was
developed by Dr. Lynn Webster to serve as another
tool to help with opioid-use assessments. Preadoles-
cent sexual abuse is only weighted for females since
when reviewed, researchers did not observe any dif-
ference in the response when weighted in men. Scores
greater than 8 indicate a high risk for potential abuse,
4 to 7 means moderate risk, and scores 3 or less indi-
cate low risk.11 The ORT was condensed to five ques-
tions.12 In the study, the revised version was found
to be 85.4% sensitive, with 85.1% specificity.12 One
benefit of the ORT is that it is part of MDCalc.8 The
ORT may not absolutely predict potential abuse by
itself, but it can help guide clinicians in their deci-
sions concerning appropriate treatment for the
patient.8
The SOAPP-R was developed to help screen
patients who are at risk for long-term opioid abuse.
This tool was developed with the help of an expert
panel of pain and addiction specialists, identifying
the characteristics of opioid abuse and rating their
51
U.S. Pharmacist • March 2022 • www.uspharmacist.com
hierarchy. It is a 24-question, self-administered tool
with a sensitivity of 81% and a specificity of 68%.13
The maximum score is 96. A score of 18 or greater
means the patient is at higher risk for abuse of opi-
oids.8 This tool should be used with clinical assess-
ments to help guide the clinician’s treatment pro-
gram. When comparing ORT and SOAPP for
predicting risk of abuse in patients taking opioids for
chronic pain, SOAPP with clinical assessment was
more sensitive.14
When meeting with patients on long-term opioids,
providers should determine if opioid tapering is rec-
ommended and use the clinical assessment tools that
have been discussed previously.15 The guidelines rec-
ommend discontinuation of opioids if there is no
clinically meaningful improvement in pain and func-
tion, treatment resulted in a severe adverse event, or
the patient has a history or current substance-use
disorder, excluding tobacco.4 In patients who are not
showing abuse behavior or there is a concern for
harm to the patient, tapering may not be appropriate.
There is concern for providers being pressured,
whether by insurance companies or guidelines stating
that patients are at increased risk of overdose if they
are over a certain morphine equivalent. Other con-
siderations for tapering of opioids are patients con-
currently treated with a benzodiazepine and a hyp-
notic, which puts them at increased risk of
overdose.1,14
Patients should be made aware of the long-term
complications of opioids, as shown in TABLE 4. These
complications include constipation, nausea, somno-
lence, memory loss, increase risk of falls, respiratory
depression, effects on hormones that can lead to
infertility, sexual dysfunction, osteoporosis, depres-
sion, hyperalgesia, and mortality.1,16
Providers should enter the conversation with no
bias. A study showed that patients who have a sub-
stance use disorder feel they are not treated the same
as others and desire the same respect that is extended
to other patients.30 The conversation should be gen-
eralized and without emotions.8 The following com-
ponents were found to be helpful when discussing
the tapering process with patients.17
Rationale for Tapering
Explaining the reasoning for tapering to the patient
makes it individualized.17 The Canadian National
Pain Centre at McMasters has a good, patient-
friendly document that discusses points for tapering.
Patients may feel they were being punished when told
 Managing Chronic, Noncancer Pain With Opioids
Table 3

Validated Tools
Administration Time to Complete Length Comments

Assessment for Function and Pain

Pain PEG Self-reported <1 min 3 questions

2-Item Graded Clinician or self- <1 min 2 questions

Chronic Pain Scale reported

Assessment for Abuse Potential

ORT Clinical or self- <5 min 5 questions Included in MDCalc

reported (Y/N)

SOAPP-R Self-reported <10 min 24 questions Requires licensing

agreement

Assessment of Withdrawals

CINA Clinician <5 mins 11 questions

COWS Clinician <5 mins 11 questions

CINA: Clinical Institute Narcotic Assessment; COWS: Clinical Opiate Withdrawal Scale; ORT: Opioid Risk Tool; PEG:
Pain, Enjoyment of Life and General Activity scale; SOAPP-R: Screener and Opioid Assessment for Patients with Pain.
Source: Reference 4.

they need to taper, even if they were taking the med-
ications as prescribed.17 Most of the studies and com-
mentary reports making the conversation specific to
the patient. Clinicians should explain to the patient
the tools and assessments used to determine why
there was a need for tapering. A common theme also
was to not tell the patient the tapering is the result of
the opioid crisis; to them, this means nothing. Using
either the ORT or SOAPP-R to start the conversa-
tion, the provider can then assess for patients who
are at increased risk of abuse. The use of these tools
does not predict abuse; rather, they indicate that
these patients have risk factors that can make them
more sensitive to abuse issues, whether environmen-
tal or genetic.13
withdrawal and treatment options available for
symptom management.1,4,5 The last set of assessment
tools that can be beneficial when tapering down
patients on their opioid dose are the Clinical Opiate
Withdrawal Scale (COWS) and the Clinical Institute
Narcotic Assessment (CINA). Both are 11-item scales
that assess questions based on patients’ behaviors
and observation by clinician to tell how severe with-
drawal is. The CINA scores range from 0 to 31, and
the higher the score, the more severe withdrawal is.
Scores using the COWS range from 0 to 47, and 5 to
12 are considered mild, 13 to 24 are moderate, 25 to
36 are moderately severe, and >36 is considered
severe withdrawal.18 There is potential for bias since
patients report how they feel.18

Shared Decision-Making Assessment and Screening Tools

Including the patient as part of the process helps to Taking the time to explain the tools being used to
establish trust between provider and patient.2 There assess for withdrawals and what to expect can help
are a lot of fears around the process of tapering.17 the patient. The pharmacist has more time to answer
Patients wonder if their pain will be controlled.17 questions about withdrawals and treatment options
Withdrawals can be difficult to explain, and patients than the provider.30,31 The pharmacist should discuss
may be hesitant, especially if they have experienced with the patient what the realistic goals of pain man-
prior withdraws.17 A pharmacist can help with pain- agement are. Again, it is important to reiterate to
management education to help establish that trust patients that the focus of their treatment is to help
with the patient.30 TABLE 5 shows the symptoms of better control pain so they feel that they are func-
52
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Managing Chronic, Noncancer Pain With Opioids

between the provider and patient should be respect-

Table 4

Long-Term Risks of Opioids ful and demonstrate understanding.31 Motivational

Opioid overdose Can potentially be fatal. Increase interviewing can help the tapering discussion when
in deaths reported there is a disagreement.20

Respiratory May cause or worsen Assurance and Mental Health

problems sleep apnea Abandonment can be detrimental to the patient.
Abandonment can cause more harm to the patient
Physical Suddenly stopping the medication
dependence can cause withdrawal symptoms
and result in withdrawal due to opioids not being
prescribed, causing further mental stress and even
Opioid-induced Makes the pain worse, contributing to the patient being suicidal.14 Assuring
hyperalgesia especially at higher doses that the provider did not abandon the patient in this
process is important. The patient’s mental health is
Drowsiness Potentially causes falls and also to be addressed for successful weaning.1,16
broken bones
Patients who have underlying mental health condi-
Constipation Causes abdominal discomfort
tions should be assessed for therapy. Making sure
that providers treat that aspect of the disease helps
Low testosterone Leads to low energy, depression, ensure a successful process. The ORT is also a good
and low sex drive tool to use for assessing mental health history.
Patients can be further screened using the PHQ-9, an
Low estrogen Increase risk of osteoporosis,
assessment for depression, or GAD-7, an assessment
and progesterone infertility, low sex drive
tool for anxiety. All of the guidelines state that if
References: 1, 16. these conditions are not treated appropriately, opioid
use or tapering can be negatively impacted.1,5 Some
of the patients who are affected by opioid use disor-
tional, emotionally and physically. These expecta- der can be from groups who are already sensitive to
tions can include improvements in cognition and issues such as discrimination due to race, substance-
pain/functionality. abuse history, and economic hardships.31 Due to
multiple comorbid conditions, it is recommended
Negotiation that a multidisciplinary approach may be beneficial
Negotiating when there is a disagreement between in the tapering process.5 A pharmacist can touch base
the provider and patient may be necessary. Disagree- with patients between visits to assess withdrawal or
ments can happen when the patient and provider are answer any medication questions. A therapist can
not at a mutual point in the tapering plan. The pro- help with behavioral therapy for patients with men-
vider needs to be willing to offer explanations while tal health needs. Finally, a social worker can help
engaging the patient and reassuring the patient that address some of the inequities and connect these
it is a partnership.1,16 One study showed than when patients with resources from the community.
the provider and patient talked and listened to each Other aids to assist with tapering include video-
other, they were able to come to a consensus.17 The recorded narrative clips discussing opioid tapering.
disagreement may also stem from a urine drug screen Greater patient engagement with the clip, but not age
and how the provider interprets or discusses the or gender concordance with the storyteller, was asso-
results of an unexpected detection in the screening. ciated with greater perceived persuasiveness for pro-
A resource that providers can use is My Top Care.19 moting opioid tapering. Patient narratives that are
This website helps provides information for false engaging and clinically relevant are likely to be per-
positives and other scenarios. suasive, regardless of storyteller demographics.21
Abandonment can come in the form of a false-
positive urine screen.17 Again, communication is key Tapering Methodology
between the provider and the patient. Additionally, There are multiple methods that can be considered
the disagreement can arise when the patient is not when tapering. Immediate discontinuation may be
ready to taper down to the next dose and the clinician needed if diversion is involved.4 A rapid taper over
feels that it is time to decrease. These discussions a 2- to 3-week time frame may be appropriate if
53
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Managing Chronic, Noncancer Pain With Opioids
Table 5
Symptoms of Withdrawal and Treatment Strategies
Symptoms of
Withdrawal Treatment Options
Diarrhea/cramping • Start loperamide 4 mg then
2 mg by mouth 4X a day prn
Dicyclomine 10-20 mg by mouth
4X a day prn
Myalgias • Ibuprofen 400 mg-600 mg by
mouth 4X a day prn
• Acetaminophen 1,000 mg by
mouth every 8 hours prn
Anxiety/agitation Clonidine 0.1 mg daily to
2X a day
Hydroxyzine 25 mg by mouth
3X a day prn
Propranolol 10-20 mg by mouth
3X a day prn
Buspirone 5-15 mg by mouth
3X a day prn
Insomnia Trazodone 50-100 mg by mouth
prn for sleep
Melatonin 5-10 mg by mouth
at night
Hydroxyzine can also be used
Nausea Ondansetron 8 mg by mouth 2X
a day prn
Tremors Propranolol 10-20 mg by mouth
3X a day prn
Diaphoresis Clonidine 0.1 mg daily to 2X a
day prn
Source: References 1, 16.
the patient has a substance use disorder.4 A slow
taper can start with less than 10% of the original
dose per week with regular monitoring. Another
strategy is an understanding that an opioid
decrease is made with the agreement between the
provider and patient. In this strategy, the patient
would be informed that once the decrease is made
an increase from that dose will not occur.4 Other
taper strategies include reduction of doses by 5%
to 10% every 1 to 2 months, depending on how
the patient tolerates it.1,4,5,16 Use the PEG to assess
how patients are at each reduction and the COWS
scale to assess for withdrawal. If withdrawal symp-
toms are present, mitigating them will help with
the wean. TABLE 5 shows treatment options for
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Comments
• Loperamide has abuse potential
• Dicyclomine can also be used for abdominal cramping
• Take ibuprofen with food and monitor renal function
• Acetaminophen (if liver impairment, do not exceed 2,000 mg)
Monitor blood pressure for clonidine and propranolol
If patient ends up using clonidine more than prn, consider
weaning off of it once withdrawal is over
Consider gabapentin if appropriate; may not be appropriate
in patients with a substance-abuse history
Propranolol and buspirone can also be used to help
transition the patient to sleep
Other agents to consider: mirtazapine or tricyclic
antidepressants
Monitor QTC interval
Monitor blood pressure
symptoms.1,3 Acute opioid withdrawal in ambula-
tory patients is not considered lethal, but the symp-
toms can be bothersome.1
Patients who do not tolerate the tapering process
may be designated for a slower taper. Patients can
feel some side effects from tapering even after they
are off opioids up to 6 months post discontinuation,
so a slow taper may be beneficial.4 Buprenorphine
may have a role in patients unable to tolerate the
wean. It is a partial mu-receptor agonist that has an
advantage over other opioids in that the risk of
respiratory depression plateaus as the dose
increases.14 Buprenorphine can be a good option for
patients with poor pain control. 14 The patch is
approved for the treatment of pain. Providers need
54
 Managing Chronic, Noncancer Pain With Opioids
specialized training and a waiver from the DEA to
prescribe other forms of buprenorphine (a waiver
is not required for the patch formulation).14
After discussing the plan and what the patient
can expect, the provider can bring in other disci-
plines to help manage the process. The pharmacist
can help the provider check in with the patient,
answer questions regarding the taper, and make
interventions as appropriate. One study showed
that a pharmacist can be the communicator
between the patient and provider. The pharmacist
met with the patient, and if an intervention was
identified, the provider was contacted to discuss
the intervention. Furthermore, the pharmacist con-
tacted the patient to make the intervention after
discussion with the provider.21 Local community
pharmacists may also help in this process. They can
educate and ask questions when the patients pick
up their medications. They can help review drug
interactions for patients who have multiple provid-
ers prescribing medications. Also, community phar-
macists can dispense naloxone in many states, if
needed.30
Tapering requires a lot of communication, fre-
quent assessment, and frequent follow-up appoint-
ments. Some concerns with the role of the pharma-
cist in this process have been identified. Pharmacists
are thought of as accessible; however, one study
looking at patients’ perspectives revealed that phar-
macists are sometimes thought of as too busy, so
patients may not seek advice. Additionally, patients
may not be aware of the clinical role a pharmacist is
able to perform, including drug knowledge and
counseling.31 Some patients feel that community
pharmacists may not have enough time to provide
effective education.31
Naloxone
Naloxone is a highly competitive, mu-opioid recep-
tor antagonist that reverses the central and periph-
eral effects of exogenous and endogenous opioids
within 2 to 5 minutes of administration. Naloxone
can be administered through several different
routes, including IM, SC, and intranasal.22,23 The
CDC provides guidance in offering naloxone and
overdose-prevention education for patients and
their household for patients who are taking at least
50 morphine milligram equivalents a day.1 There
has been a decreased risk of death by opioid over-
dose since community-based programs have distrib-
uted naloxone.1
55
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Impact of COVID-19
The coronavirus disease 2019 (COVID-19) pandemic,
which was declared by the WHO on March 11, 2020,
has impacted the medical care provided to patients.
Mental health concerns and substance use–related
harms have risen amid the global pandemic due to a
variety of factors, including stay-at-home orders, social
distancing, fear of sickness and death, loss of employ-
ment, economic stress, and loss of family and friends
due to illness.24 In April 2020, one in seven adults in the
U.S. reported serious psychological distress.25
Another study showed that 13.3% of adults had
started or increased substance use to cope with stress
or emotions related to the pandemic, while 30.9%
had symptoms of anxiety or depressive disorders and
10.7% had considered suicide in the past month.25
People with opioid use disorder may be at higher risk
of complications from COVID-19 given the immu-
nosuppressive nature of opioids.26,27
In March 2020, the Office for Civil Rights at the
HHS allowed the use of nonpublic-facing audio or
video communication products. Medicare now allows
reimbursement for telehealth services. Since COVID-
19, a face-to-face visit for controlled substances is no
longer required, and telemedicine is allowed to pre-
scribe these medications. The opportunity to use tele-
medicine has the potential to manage more people and
expand access to care.28 The federal Substance Abuse
and Mental Health Services Administration allowed
stable patients with opioid use disorder in opioid-
treatment programs to take home a 28-day supply of
medication or a 14-day supply for less stable patients.26
One study showed a reduction in prescriptions for
opioid analgesics, and buprenorphine use for opioid
use disorder decreased among new patients during the
pandemic (but not among existing patients receiving
therapy).28 The ORT and SOAPP-R assessment tools
can be conducted through telemedicine. An in-person
visit is recommended if a patient scores greater than 18
on the SOAPP-R and greater than 8 on the ORT.29
Patients who use chronic opioids and are hospi-
talized for COVID-19 and who need to be intubated
may require prolonged time on mechanical ventila-
tors, and this may make extubating a greater chal-
lenge due to decreased respiration. Patients using
chronic opioids require opioids during hospitaliza-
tion to prevent opioid-withdrawal syndrome, and
there is an increased risk of opioid-induced respira-
tory depression. Additionally, patients needing opi-
oids have potential interactions with other necessary
medications, including certain antibiotics or other
 Managing Chronic, Noncancer Pain With Opioids
drugs, which may be associated with prolongation
of the QT c and require closer monitoring during
hospitalization. Clinicians may want to consider
providing studied nonopioid alternatives and non-
drug approaches for pain management in light of the
COVID-19 pandemic in patients with opioid use
disorder. Additional research is needed to assess the
impact of COVID-19 on long-term opioid use.27
Conclusion
The opioid epidemic has caused a shift in the pre-
scribing of opioids. It has changed the way clini-
REFERENCES
1. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing
opioids for chronic pain–United States, 2016. MMWR Recomm Rep.
2016;65(1):1-49. Erratum in: MMWR Recomm Rep.
2016;65(11):295.
2. U.S. Department of Health and Human Services. What is the U.S.
opioid epidemic? www.hhs.gov/opioids/about-the-epidemic/index.
html. Accessed December 1, 2021.
3. U.S. Department of Health & Human Services. HHS Acting Secre-
tary declares public health emergency to address national opioid cri-
sis. www.hhs.gov/about/news/2017/10/26/hhs-acting-secretary-
declares-public-health-emergency-address-national-opioid-crisis.html.
Accessed December 4, 2021.
4. Washington State Agency Medical Directors’ Group (AMDG).
Interagency guideline on prescribing opioids for pain. 2015. https://
agencymeddirectors.wa.govFiles/2015AMDGOpioid
Guideline.pdf. Accessed November 23, 2021.
5. Busse JW, Craigie S, Juurlink DN, et al. Guideline for opioid ther-
apy and chronic noncancer pain. CMAJ. 2017;189:E659-E666.
6. Wenger S, Drott J, Fillipo R, et al. Reducing opioid use for
patients with chronic pain: an evidence-based perspective. Phys Ther.
2018;98(5):424-433.
7. Austin RC, Fusco CW, Fagan EB, et al. Teaching opioid tapering
through guided instruction. Fam Med. 2019;51(5):434-437.
8. Ducharme J, Moore S. Opioid use disorder assessment tools and
drug screening. Mo Med. 2019;116(4):318-324.
9. Krebs EE, Lorenz KA, Bair MJ, et al. Development and initial val-
idation of the PEG, a three-item scale assessing pain intensity and
interference. J Gen Intern Med. 2009;24(6):733-738.
10. Von Korff M, DeBar LL, Krebs EE, et al. Graded chronic pain
scale revised: mild, bothersome, and high-impact chronic pain. Pain.
2020;161(3):651-661.
11. Brott NR, Peterson E, Cascella M. Opioid Risk Tool. [Updated
2021 May 19]. In: StatPearls [Internet]. Treasure Island, FL: Stat-
Pearls Publishing; 2022.
12. Cheatle MD, Compton PA, Dhingra L, et al. Development of the
revised opioid risk tool to predict opioid use disorder in patients
with chronic nonmalignant pain. J Pain. 2019;20(7):842-851.
13. Butler SF, Fernandez K, Benoit C, et al. Validation of the revised
Screener and Opioid Assessment for Patients with Pain (SOAPP-R). J
Pain. 2008;9(4):360-372.
14. Moore TM, Jones T, Browder JH, et al. A comparison of com-
mon screening methods for predicting aberrant drug-related behavior
among patients receiving opioids for chronic pain management. Pain
Med. 2009;10(8):1426-1433.
15. Covington EC, Argoff CE, Ballantyne JC, et al. Ensuring patient
protections when tapering opioids: Consensus Panel Recommenda-
tions. Mayo Clin Proc. 2020;95(10):2155-2171.
16. Oxford Pain Management Centre. Guidance for opioid
reduction in primary care. 2017. www.ouh.nhs.uk/services/refer-
rals/pain/documents/gp-guidance-opioid-reduction.pdf. Accessed
56
U.S. Pharmacist • March 2022 • www.uspharmacist.com
cians provide pain relief in noncancer pain. Provid-
ers are not required to assess pain as a chronic
disease. When seeing patients, they should reassess
the need for the pain medication and, if appropri-
ate, use validated tools to taper therapy. Commu-
nication plays a large part in establishing trust and
a partnership with the patient, resulting in a more
successful taper. Pharmacists have a role in this
process.
The content contained in this article is for informational purposes
only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is solely
at your own risk.
February 18, 2022.
17. Matthias MS, Johnson NL, Shields CG, et al. “I’m not gonna
pull the rug out from under you”: patient-provider communication
about opioid tapering. J Pain. 2017;18(11):1365-1373.
18. Nuamah J, Sasangohar F, Erraguntla M, Mehta RK. The past,
present and future of opioid withdrawal assessment: a scoping review
of scales and technologies. BMC Med Inform Decis Mak. 2019;
19:113.
19. Clinicians resources and Tools. My Top Care. www.mytopcare.
org/. Accessed December 21, 2021.
20. Hah JM, Trafton JA, Narasimhan B, et al. Efficacy of motiva-
tional-interviewing and guided opioid tapering support for patients
undergoing orthopedic surgery (MI-Opioid Taper): a prospective,
assessor-blind, randomized controlled pilot trial. EClinicalMedicine.
2020;28:100596.
21. Lagisetty P, Smith A, Antoku D, et al. A physician-pharmacist
collaborative care model to prevent opioid misuse. Am J Health Syst
Pharm. 2020;7(10):771-780.
22. Kim HK, Nelson LS. Reducing the harm of opioid overdose with
the safe use of naloxone: a pharmacologic review. Expert Opin Drug
Saf. 2015;14(7):1137-1146.
23. Rzasa Lynn R, Galinkin JL. Naloxone dosage for opioid reversal:
current evidence and clinical implications. Ther Adv Drug Saf.
2018;9(1):63-88.
24. Marroquin B, Vine V, Morgan R. Mental health during the
COVID-19 pandemic: effects of stay-at-home policies, social distanc-
ing behavior, and social resources. Psychiatry Res. 2020;293:113419.
25. Czeisler ME, Lane RI, Petrosky E, et al. Mental health, substance
use, and suicidal ideation during the COVID-19 pandemic–United
States, June 24-30, 2020. MMWR Morb Mortal Wkly Rep.
2020;69(32):1049-1057.
26. Mitchell M, Shee K, Champlin K, et al. Opioid use disorder and
COVID-19: implications for policy and practice. JAAPA.
2021;34(6):1-4.
27. Shah R, Kuo YF, Baillargeon J, Raji MA. The impact of long-
term opioid use on the risk and severity of COVID-19. J Opioid
Manag. 2020;16(6):401-404.
28. Currie JM, Schnell MK, Schwandt H, Zhang J. Prescribing of
opioid analgesics and buprenorphine for opioid use disorder during
the COVID-19 pandemic. JAMA Netw Open. 2021;4(4):e216147.
29. Ogilvie CB, Jotwani R, Joshi J, et al. Review of opioid risk
assessment tools with the growing need for telemedicine. Pain
Manag. 2021;11(2):97-100.
30. Murphy L, Ng K, Isaac P, et al. The role of the pharmacist in the
care of the patients with chronic pain. Integr Pharm Res Pract.
2021;10:33-41.
31. Fatani S, Blake D, D’Eon M, El-Aneed A. Qualitative assessment
of patients’ perspectives and needs from the community pharmacists
in substance use disorder management. Subst Abuse Treat Prev Pol-
icy. 2021;16(1):38.
 Managing Chronic, Noncancer Pain With Opioids

Disclosure Statements:
Drs. Hong and LaPreze have no actual or potential conflicts of interest in relation to this activity.
Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the
material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors
may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of
scientific data.

Disclaimer:
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional
development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures,
medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without
evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product
information, and comparison with recommendations of other authorities.

Examination

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Managing Chronic, Noncancer Pain With Opioids

1. What tool is used to help predict opioid-risk 6. What are key points to discuss with the patient
potential in patients taking opioids? regarding opioid tapering?
A. Pain, Enjoyment of Life and General Activity A. Patient education
(PEG) scale B. Engagement of the patient
B. Clinical Opiate Withdrawal Scale (COWS) C. A and B
C. Brief Pain Inventory (BPI) Scale D. Stop the opioid as soon as possible
D. Opioid Risk Tool (ORT)
7. In the process of tapering opioids, what other
2. What assessment tool was developed with the help comorbidities should providers monitor?
of an expert panel of addiction specialists? A. Weight loss
A. COWS B. Depression/anxiety
B. Screener and Opioid Assessment for Patients with C. Hypertension
Pain (SOAPP-R) D. Diabetes
C. ORT
D. Clinical Institute Narcotic Assessment (CINA) 8. What is the advantage of switching to buprenorphine?
A. As dose increases, respiratory depression plateaus so
3. What tool was developed based on the BPI score? there is lower risk of respiratory issues
A. Two-Item Graded Pain Scale B. Increase in respiratory concerns
B. COWS C. It is not indicated for pain in any form
C. PEG D. Providers do not need special training to prescribe it
D. BPI
9. What are some withdrawal symptoms patients may
4. What are some concerns with using a scale to assess experience?
withdrawals? A. Increase in pain
A. Relies heavily on the patient’s response B. Nausea/vomiting
B. Clinicians can assess physical behaviors C. Diaphoresis
C. Can be biased if patient’s cognition is impaired D. All of the above
D. All of the above
10. What are some concerns that patients have with
5. What are the long-term complications of opioid use? tapering of opioids?
A. Osteoporosis A. Fear of withdrawals
B. Erectile dysfunction B. Increase in pain
C. Hyperalgesia C. Abandonment
D. All of the above D. All of the above

57
U.S. Pharmacist • March 2022 • www.uspharmacist.com
 Managing Chronic, Noncancer Pain With Opioids
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 CONTEMPORARY COMPOUNDING
Morphine Sulfate 5 mg/0.1 mL Nasal Solution
An advantage of this formulation is that the dose
administered can be easily changed depending on the
number of squeezes of the calibrated container.
Method of Preparation: Calculate the
FORMULA
required quantity of each ingredient
for the total amount to be prepared.
Accurately weigh or measure each
ingredient. Dissolve all of the ingre-
dients in sufficient purified water to
final volume and mix well. Package
in a calibrated nasal-spray container
that delivers 0.1 mL per squeeze
(i.e., activation).
Use: This preparation is used in the treatment of
moderate-to-severe pain. The dose is easily
adjusted depending on the number of activations,
or squeezes, administered.
Packaging: Package in tight, light-resistant
containers.
Labeling: Keep out of reach of children. Discard
after ____ [time period].
Stability: A beyond-use date of up to 30 days
may be used for this formulation as a topical
preparation.1
Quality Control: Quality-control assessment can
include weight/volume, pH, specific gravity, active
drug assay, color, clarity, rheologic properties/
pourability, physical observation, physical stability
(discoloration, foreign materials, gas formation,
mold growth), and preservative-effectiveness
test.2,3
Discussion: Morphine sulfate has been used for
decades to treat moderate-to-severe pain. The
advantage of this dosage form is that the dose to
be administered can be easily changed based on
the number of squeezes of the calibrated nasal-
spray container.
Morphine sulfate ((C17H19NO3)2·H2SO4·5H2O,
Loyd V. Allen, Jr., PhD, RPh
Professor Emeritus, College of Pharmacy
University of Oklahoma, Oklahoma City
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Morphine Sulfate 5 mg/0.1 mL Nasal Solution
Rx Ingredient Quantity
(for 100 Morphine sulfate 5g
mL): Benzalkonium chloride 10 mg
Sodium chloride 200 mg
Purified water qs 100 mL
MW 758.83) is a phenanthrene-derivative opiate
agonist used in the treatment of severe acute pain
or moderate-to-severe chronic pain. It is odorless
and occurs as white, feathery, silky crystals; cubi-
cal masses of crystals; or a white, crystalline pow-
der. Morphine sulfate gradually loses water of
hydration when exposed to air, and it darkens on
prolonged exposure to light. Morphine sulfate is
soluble in water, freely soluble in hot water, and
slightly soluble in alcohol. It is available as injec-
tions, solutions, suppositories, and tablets, and as
extended-release oral capsules and tablets.1
Benzalkonium chloride is a bactericidal antimi-
crobial agent commonly used as a preservative in
many ophthalmic, otic, nasal, and parenteral for-
mulations. It occurs as a white or yellowish-
white amorphous powder, a thick gel, or gelati-
nous pieces/flakes with a characteristic mild
aromatic odor, soapy touch, and very bitter taste.
Benzalkonium chloride is highly soluble in water,
alcohol, and acetone. It is hygroscopic, and a
10% w/v aqueous solution has a pH in the range
of 5 to 8. Benzalkonium chloride is composed of
a mixture of straight-chain homologues that pos-
sess different physical, chemical, and microbio-
logic properties. The proportions of these homo-
logues in the mixture determine its effectiveness
as a preservative and disinfectant. As a preserva-
tive in ophthalmics, benzalkonium chloride is
used in concentrations from 0.004% to 0.02%,
with the 0.01% concentration being common.1,4
Sodium chloride (NaCl, MW 58.44) is avail-
able as a white, crystalline powder and colorless
crystals with a saline taste. It is used in a variety
of parenteral and nonparenteral pharmaceutical
59
 ContemporaryCompounding

formulations. In parenteral, ophthalmic, and serum, and its solutions are stable.5
nasal preparations, sodium chloride is used to Purified water is water that is obtained by dis-
prepare isotonic solutions. It is also used as a tillation, ion exchange, reverse osmosis, or
capsule diluent and as a lubricant; to control another suitable process. Water has a specific
drug release from some microcapsules and to gravity of 0.9971 at room temperature, a melting
control micelle size; and to adjust the viscosity of point of 0°C, and a boiling point of 100°C. It is
some polymer dispersions by altering the ionic miscible with most polar solvents and is chemi-
character of the formulation. The pH of a satu- cally stable in all physical states (ice, liquid, and
rated solution ranges from 6.7 to 7.3, and it is steam).6
soluble in water (1 g in 2.8 mL), glycerin (1 g in The content contained in this article is for informational pur-
10 mL), and 95% ethanol (1 g in 250 mL). A poses only. The content is not intended to be a substitute for pro-
fessional advice. Reliance on any information provided in this
0.9% w/v aqueous solution is iso-osmotic with article is solely at your own risk.

REFERENCES
1. U.S. Pharmacopeia/National Formulary [current revision]. Rock-
ville, MD: U.S. Pharmacopeial Convention, Inc; February 2022.
2. Allen LV Jr. Summary of quality-control testing for sterile and
nonsterile compounded preparations, part 1: physical and chemical
testing. IJPC. 2019;23(3):211-216.
3. Allen LV Jr. Summary of quality-control testing for sterile and
nonsterile compounded preparations, part 2: microbiological test-
ing. IJPC. 2019;23(4):299-303.
4. Kibbe AH, Quinn ME. Benzalkonium chloride. In: Sheskey PJ,
Hancock BC, Moss GP, Goldfarb DJ, eds. Handbook of Pharma-
ceutical Excipients. 9th ed. London, England: Pharmaceutical Press;
2020:132-135.
5. Watters M. Sodium chloride. In: Sheskey PJ, Hancock BC, Moss
GP, Goldfarb DJ, eds. Handbook of Pharmaceutical Excipients. 9th
ed. London, England: Pharmaceutical Press; 2020:945-949.
6. Dubash D, Shah U. Water. In: Sheskey PJ, Hancock BC, Moss
GP, Goldfarb DJ, eds. Handbook of Pharmaceutical Excipients. 9th
ed. London, England: Pharmaceutical Press; 2020:1111-1115.

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