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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+ 50+
ARS YEARS

Indication • In a postmarketing observational study, an


SHINGRIX is a vaccine indicated for prevention increased risk of Guillain-Barré syndrome

X Gray (10K)
of herpes zoster (shingles) in adults aged was observed during the 42 days following
50 years and older. vaccination with SHINGRIX

K.O. (TURN OFF


SHINGRIX is not indicated for prevention of • Syncope (fainting) can be associated with the
primary varicella infection (chickenpox). administration of injectable vaccines, including
Important Safety Information SHINGRIX. Procedures should be in place to

BACKGROUND
avoid falling injury and to restore cerebral
• SHINGRIX is contraindicated in anyone with
perfusion following syncope
a history of a severe allergic reaction (eg,
anaphylaxis) to any component of the vaccine • Solicited local adverse reactions reported in

LAYER WHEN
or after a previous dose of SHINGRIX individuals aged 50 years and older were pain
(78%), redness (38%), and swelling (26%)
• Review immunization history for possible
vaccine sensitivity and previous vaccination- • Solicited general adverse reactions reported in

USING)
related adverse reactions. Appropriate individuals aged 50 years and older were myalgia
medical treatment and supervision must be (45%), fatigue (45%), headache (38%), shivering
available to manage possible anaphylactic (27%), fever (21%), and gastrointestinal
reactions following administration of symptoms (17%)
SHINGRIX
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 there is a reduction in the immunity leads to a sharp
decline in immunity.1 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) Please see Brief Summary of
• The data are insufficient to establish if there Prescribing Information for SHINGRIX
is vaccine-associated risk with SHINGRIX in on the following pages.
pregnant women 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
• It is not known whether SHINGRIX is excreted 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.
in human milk. Data are not available to assess 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,
the effects of SHINGRIX on the breastfed infant et al. Vaccine. 2014;32(15):1745-1753. 9. Patterson-Bartlett J, et al. Vaccine.
or on milk production/excretion 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.
• Vaccination with SHINGRIX may not result 13. Prescribing Information for SHINGRIX.
in protection of all vaccine recipients

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 identified through National Drug Codes, and potential cases of
any or Grade 3 solicited local reactions between Dose 1 and hospitalized GBS among recipients of SHINGRIX were identified
Dose 2. Headache and shivering were reported more frequently through International Classification of Diseases codes.
by subjects after Dose 2 (28% and 21%, respectively) compared
with Dose 1 (24% and 14%, respectively). Grade 3 solicited The risk of GBS following vaccination with SHINGRIX was assessed
general adverse reactions (headache, shivering, myalgia, and in self-controlled case series analyses using a risk window of 1 to 42
fatigue) were reported more frequently by subjects after Dose 2 days post-vaccination and a control window of 43 to 183 days
(2.3%, 3%, 4%, and 4%, respectively) compared with Dose 1 post-vaccination. The primary analysis (claims-based, all doses)
(1.4%, 1.4%, 2.3%, and 2.4%, respectively). found an increased risk of GBS during the 42 days following
vaccination with SHINGRIX, with an estimated 3 excess cases of
Unsolicited Adverse Events: Unsolicited adverse events that GBS per million doses administered to adults aged 65 years or older.
occurred within 30 days following each vaccination (Day 0 to 29) In secondary analyses, an increased risk of GBS was observed
were recorded on a diary card by all subjects. In the 2 studies, during the 42 days following the first dose of SHINGRIX, with an
unsolicited adverse events occurring within 30 days of estimated 6 excess cases of GBS per million doses administered to
vaccination were reported in 51% and 32% of subjects who adults aged 65 years or older, and no increased risk of GBS was
received SHINGRIX (n = 14,645) or placebo (n = 14,660), observed following the second dose of SHINGRIX. These analyses
respectively (Total Vaccinated Cohort). Unsolicited adverse events of GBS diagnoses in claims data were supported by analyses of
that occurred in ≥1% of recipients of SHINGRIX and at a rate at GBS cases confirmed by medical record review. While the results
least 1.5-fold higher than placebo included chills (4% versus of this observational study suggest a causal association of GBS
0.2%), injection site pruritus (2.2% versus 0.2%), malaise (1.7% with SHINGRIX, available evidence is insufficient to establish a
versus 0.3%), arthralgia (1.7% versus 1.2%), nausea (1.4% versus causal relationship.
0.5%), and dizziness (1.2% versus 0.8%).
8 USE IN SPECIFIC POPULATIONS
Gout (including gouty arthritis) was reported by 0.18% (n = 27)
versus 0.05% (n = 8) of subjects who received SHINGRIX or 8.1 Pregnancy
placebo, respectively, within 30 days of vaccination; available The data are insufficient to establish if there is vaccine-associated
information is insufficient to determine a causal relationship risk with SHINGRIX in pregnant women [see Use in Specific
with SHINGRIX. Populations (8.1) of full prescribing information].
Serious Adverse Events (SAEs): In the 2 studies, SAEs were 8.2 Lactation
reported at similar rates in subjects who received SHINGRIX
(2.3%) or placebo (2.2%) from the first administered dose up to Risk Summary
30 days post-last vaccination. SAEs were reported for 10.1% of It is not known whether SHINGRIX is excreted in human milk. Data
subjects who received SHINGRIX and for 10.4% of subjects who are not available to assess the effects of SHINGRIX on the breastfed
received placebo from the first administered dose up to 1 year infant or on milk production/excretion [see Use in Specific
post-last vaccination. One subject (<0.01%) reported Populations (8.2) of full prescribing information].
lymphadenitis and 1 subject (<0.01%) reported fever greater than
39°C; there was a basis for a causal relationship with SHINGRIX. 8.5 Geriatric Use
Optic ischemic neuropathy was reported in 3 subjects (0.02%) Adults Aged 60 Years and Older
who received SHINGRIX (all within 50 days after vaccination) and Of the total number of subjects who received at least 1 dose of
0 subjects who received placebo; available information is SHINGRIX in Studies 1 and 2 (n = 14,645), 2,243 (15%) were aged
insufficient to determine a causal relationship with SHINGRIX. 60 to 69 years, 6,837 (47%) were aged 70 to 79 years, and 1,921
Deaths: From the first administered dose up to 30 days post-last (13%) were 80 years and older. There were no clinically meaningful
vaccination, deaths were reported for 0.04% of subjects who differences in efficacy across the age groups [see Clinical Studies
received SHINGRIX and 0.05% of subjects who received placebo (14.1, 14.2, 14.3) of full prescribing information].
in the 2 studies. From the first administered dose up to 1 year The frequencies of solicited local and general adverse reactions in
post-last vaccination, deaths were reported for 0.8% of subjects subjects aged 70 years and older were lower than in younger adults
who received SHINGRIX and for 0.9% of subjects who received (aged 50 through 69 years). [See Adverse Reactions (6.1).]
placebo. Causes of death among subjects were consistent with
those generally reported in adult and elderly populations. 17 PATIENT COUNSELING INFORMATION
Potential Immune-Mediated Diseases: In the 2 studies, new onset • Inform patients of the potential benefits and risks of immunization
potential immune-mediated diseases (pIMDs) or exacerbation of with SHINGRIX and of the importance of completing the 2-dose
existing pIMDs were reported for 0.6% of subjects who received immunization series according to the schedule.
SHINGRIX and 0.7% of subjects who received placebo from the first • Inform patients about the potential for adverse reactions that have
administered dose up to 1 year post-last vaccination. The most been temporally associated with administration of SHINGRIX.
frequently reported pIMDs occurred with comparable frequencies in
the group receiving SHINGRIX and the placebo group. • Provide the Vaccine Information Statements, which are available
free of charge at the Centers for Disease Control and Prevention
Dosing Schedule: In an open-label clinical study, 238 subjects 50 (CDC) website (www.cdc.gov/vaccines).
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. Trademarks are owned by or licensed to the GSK group
of companies.
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. Manufactured by GlaxoSmithKline Biologicals
Rixensart, Belgium, U.S. License 1617, and
General Disorders and Administration Site Conditions Distributed by GlaxoSmithKline
Decreased mobility of the injected arm which may persist for 1 or Research Triangle Park, NC 27709
more weeks.
Immune System Disorders ©2021 GSK group of companies or its licensor.
Hypersensitivity reactions, including angioedema, rash, and urticaria. July 2021 SHX:6BRS
Nervous System Disorders
©2021 GSK or licensor.
Guillain-Barré syndrome. SGXJRNA210080 September 2021
Postmarketing Observational Study of the Risk of Guillain-Barré Produced in USA.
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
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
EDITORIAL BOARD OF ADVISORS 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-
Carmen Catizone, RPh
Executive Director,
viduals worldwide.
National Association of In the largest genome study of migraine yet, researchers have more than
Boards of Pharmacy tripled the number of known genetic risk factors for migraine. Among the
Tammie Lee Demler, BS, PharmD,
identified 123 genetic regions are two that contain target genes of recently
MBA, BCGP, BCPP developed migraine-specific drugs.
Clinical Associate Professor and The study involved leading migraine research groups in Europe, Austra-
Director of Psychiatric Pharmacy lia, and the United States working together to pool genetic data from more
Residency Programs
than 873,000 study participants, 102,000 of whom had migraine. The new
University of Buffalo
findings, published in Nature Genetics, also uncovered more of the genetic
Mark Litzinger, RPh architecture of migraine subtypes than previously known.
Market Director,
Migraine is believed to be a neurovascular
Walmart
disorder with disease mechanisms within both
Mario Sylvestri, PharmD, PhD the brain and the blood vessels of the head.
Senior Director,
Previous research has shown that genetic fac-
Medical Sciences Liaison
tors contribute significantly to the migraine
Amylin Pharmaceuticals
risk. However, it has long been debated
Mary Ann E. Zagaria, PharmD, MS, BCGP
whether the two main migraine types—
Clinical Consultant Pharmacist
migraine with and without aura—share similar
and President of MZ Associates, Inc.
genetic backgrounds.
CONTRIBUTING EDITORS To gain more insight into the specific risk
genes, researchers from the International Head- Robert Davidson
Loyd V. Allen, Jr., PhD, RPh
ache Genetics Consortium assembled a large Editor-in-Chief
Emily M. Ambizas, PharmD, MPH, BCGP rdavidson@uspharmacist.com
genetic dataset to conduct a genome-wide asso-
Jack DeRuiter, PhD ciation study, looking for genetic variants that
Ed DeSimone, PhD, RPh
were more common in those who had migraine in general or one of the
two main migraine types. The results demonstrated that migraine sub-
Marlon S. Honeywell, PharmD, ALFP
types have both shared risk factors and risk factors that appear specific to
Joshua J. Neumiller, PharmD, CDCES, one subtype. The analyses highlighted three risk variants that appear to
FADCES, FASC be specific to migraine with aura and two that appear to be specific to
Somnath Pal, BS (Pharm), MBA, PhD migraine without aura.
Furthermore, the results supported the concept that migraine is brought
Manouchehr Saljoughian, PharmD, PhD
about by both neuronal and vascular genetic factors, strengthening the view
Jesse C. Vivian, RPh, JD that migraine truly is a neurovascular disorder. Migraine is globally the sec-
Mea A. Weinberg, DMD, MSD, RPh 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
Send your comments via email
regions containing genes that encode targets for recently developed
rdavidson@uspharmacist.com
migraine-specific therapeutics. One of the newly identified regions contains
Mail: U.S. Pharmacist
genes (CALCA/CALCB) encoding calcitonin gene–related peptide, a mole-
395 Hudson Street, 3rd Floor
cule involved in migraine attacks and blocked by the recently introduced
New York, NY 10014
www.uspharmacist.com calcitonin gene–related peptide inhibitor migraine medications. Another risk
facebook.com/USPharm region covers the HTR1F gene encoding serotonin 1F receptor, also a target
twitter.com/USPharmacist for new migraine-specific medications.
4
U.S. Pharmacist • March 2022 • www.uspharmacist.com
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

NEXT MONTH
SpecialSection: Specialty Pharmacy
Editorial Focus: Specialty Pharmacy News Digest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34
COVID-19

View the Digital Edition of this issue and


Current and Evolving Treatments for HIV PrEP . . . . . . . . . . . . . . . . . . . . . . .38
earn additional CE credits online at: When pre-exposure prophylaxis is used consistently, it is effective at preventing
www.uspharmacist.com
transmission of this viral disease; therefore, pharmacists should encourage adherence
in at-risk patient populations.
Jennifer LaPreze, PharmD, BCACP, CDCES, CPP, and Brooke Nowicki, PharmD, AAHIVP
CUSTOMER SERVICE
CONTINUING EDUCATION (CE) PROGRAMS
Phone: (800) 825-4696 Consult Your Pharmacist
Fax: (212) 219-7849
E-mail:
Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43
cecustomerservice@jobson .com There is currently no curative therapy for this chronic immune-related disorder, and
SUBSCRIPTION SERVICES management focuses on treating relapses, slowing disease progression, providing
Send checks to U .S . Pharmacist, symptomatic relief, and maintaining an acceptable quality of life.
PO Box 91, Congers, NY 10920-0091 Emily M. Ambizas, PharmD, MPH, CGP
Phone: (877) 529-1746 (U .S . only)
or (845) 267-3065
E-mail: 2 CE Credits
uspharmacist@cambeywest .com
Managing Chronic, Noncancer Pain With Opioids . . . . . . . . . . . . . . . . . . . .49
ARTICLE REPRINTS
Contact: Wright’s Media The lowest effective dosage and shortest duration should be employed, and when tapering
Phone: (877) 652-5295 is appropriate, clinicians should use effective communication strategies, frequent follow-up,
E-mail: and validated assessment tools to help reduce withdrawal symptoms.
jobson@wrightsmedia .com
Vorlak Hong, PharmD, and Jennifer LaPreze, PharmD, BCACP, CDCES, CPP
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U.S. Pharmacist • March 2022 • www.uspharmacist.com
EDITORIAL STAFF March 2022
Editor-in-Chief Vol. 47 No. 3
Robert Davidson

Senior Editor
Marjorie Borden

Senior Associate Editor


Colleen King

Consulting Clinical Editor


Mary Gurnee, PharmD, RPh

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Heather Koitzsch (888) 498-1490 Managing Acute Pain in Opioid Use Disorder . . . . . . . . . . . . . . . . . . . . . .HS-2
Too often, patients with this condition experience abrupt drug cessation or inappropriate
Subscription Services pain management when admitted to the hospital or in the postoperative period.
(877) 529-1746 (U.S. only)
or (845) 267-3065 Breanne M. Mefford, PharmD, BCCCP, and J. Chris Donaldson, PharmD, BCCCP

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


Greg Concha
In particular, CYP2D6 polymorphisms may play a substantial role in the safety and efficacy
Production Manager of codeine, hydrocodone, and tramadol.
Mario Iannotta (212) 274-7008 Alexa Zeiger, PharmD; John Andraos, PharmD; Ajay Sharma, BPharm, PhD; and
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Director, Continuing
Departments
Education Processing Editorial
Regina Combs (800) 825-4696 Large Migraine Study Manifests New Genetic Risk Factors . . . . . . . . . . . . 4
A particularly interesting finding reported by researchers was the identification of genomic
Director, Circulation
Jared Sonners risk regions containing genes that encode targets for recently developed migraine-specific
therapeutics.
Vice President, Robert Davidson, Editor-in-Chief
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Industry News . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Trend Watch
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and Nondrug Treatment
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Senior Vice President, Operations Approaches . . . . . . . . . . . . . . . . . . . . . . 14


Jeff Levitz
In federally funded research, 20.4% of studies
Vice President, Human Resources chiefly focused on neurologic/glial aspects, 7.3%
Tammy Garcia examined nondrug aspects, and 5.9% investigated
biobehavioral and psychosocial aspects.
Somnath Pal, BS (Pharm), MBA, PhD

Contemporary Compounding
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PAIN NEWS DIGEST

Rising Opioid-Overdose Death Rates and declining cognitive function that may interfere
Among Older Adults with taking opioids as prescribed. In addition, the
A common stereotype for an “older adult” might body’s ability to metabolize opioids decreases with age,
include early-bird specials, dentures, and tickets to meaning that people are more vulnerable to overdose.
the matinee show.
A new Northwestern Medicine study that analyzed Promoting Safer Pain Relief With
20 years of fatal opioid-overdose data in adults aged New Compounds
55 years and older paints a much different picture. Scientists at Scripps Research in Florida have cre-
Between 1999 and 2019, opioid-related overdose ated a collection of new pain-relieving compounds
deaths increased exponentially in U.S. adults aged 55 that, like morphine and other drugs, provide relief
years and older, from 518 deaths in 1999 to 10,292 via activation of opioid receptors but without
deaths in 2019: a 1,886% increase. inducing many dangerous and unwanted side
“Many of us think drug misuse is a problem of the effects that have driven opioid-related overdose and
young. However, older adults are experiencing an deaths.
explosion in fatal opioid overdoses,” said Maryann Writing in the journal Proceedings of the National
Mason, an associate professor of emergency medi- Academy of Sciences, biochemist Laura Bohn, PhD,
cine at Northwestern University Feinberg School of and colleagues describe a compound called SR-17018,
Medicine. The findings were published in JAMA Net- which activates the same pain-relieving receptor as opi-
work Open. oid drugs, including morphine, oxycodone, and fen-
In the 20-year span, 79,893 people in the U.S. aged tanyl; however, it binds to opioid receptors in a differ-
55 to 80 years died by opioid overdose, with about ent way from those drugs, leaving the opioid receptor
half being between age 55 and 64 years, Dr. Mason open and available to the body’s own natural pain-
said. The annual overall death rate per 100,000 people relieving substances, apparently augmenting pain
aged 55 years and older ranged from a low of 0.9 in relief. In a study by Pantouli et al published in 2021 in
1999 to a high of 10.7 in 2019 and increased annually Neuropharmacology, the group showed that the com-
from 2000 on, the study found. pound performed particularly well in mouse studies of
Lori Post, Buchler Professor of Geriatric Medicine, chemotherapy-induced neuropathic pain, the scientists
said ageism is one of the contributing factors for the write.
increase in fatal opioid overdoses among older adults, In the current report, the authors have made strides
explaining that doctors often do not screen for drug in understanding why these drugs seem so different.
misuse during appointments with older people because “We demonstrate that these compounds bind to a dif-
“it doesn’t fit the stereotype of what it means to be ferent site on the receptor than a typical opioid.
old.” Because of that, they seem to leave the receptor on and
Black men experienced the largest increases in opi- yet still receptive to endogenous opioids,” says Dr.
oid-overdose deaths among older adults since 2013, Bohn, who chairs the Scripps Research Department of
the study found. By 2019, the opioid-overdose fatality Molecular Medicine in Jupiter, Florida. “In neuropa-
rate among non-Hispanic black or black males aged thy pain, we show they are far superior to morphine
55 years and older was 40.03 per 100,000 popula- and oxycodone; moreover, SR-17018 does not
tion—four times greater than the overall opioid fatality decrease breathing.”
rate of others of the same age. The authors also described a related compound
Dr. Mason added that black men are also more that, being more potent, induces respiratory suppres-
likely to have experienced trauma, lack access to health sion but at higher doses than are needed to relieve pain.
insurance and healthcare, not trust healthcare provid- Importantly for safety, this compound, SR-14968,
ers, and be undertreated for pain compared with other proved responsive to the overdose-rescue medication
subpopulations of older adults. naloxone when given at doses high enough to suppress
The study suggested other contributing factors in breathing.
the exponential increase among older adults. They Perhaps most importantly for people with severe
could include social isolation and depression; exposure chronic pain, SR-17018 showed an ability to provide
to medically prescribed opioids for chronic conditions sustained pain relief over time without development of
such as arthritis and cancer, which increase with age; tolerance, the problem of reduced efficacy over time
8
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Pain News Digest

that requires increased dosages, increasing the danger pain questionnaires were filled out and x-rays were
of overdose. taken as well as a blood test for infection. If needed,
Going forward, the team is continuing to refine and patients were referred for ongoing treatment. In addi-
test the compounds so that they could eventually be tion, patients received up to six phone calls over the
tested in a clinical setting. next 12 months, making sure they had their referral
“Severe and chronic pain associated with surgery, and to check on how they were doing.
nerve damage, and trauma require strong pain
relief,” Dr. Bohn says. “Safer solutions are needed. Might a Dangerous Microbe Offer a
We believe these new compounds are a big step in the New Way to Suppress Pain?
right direction.” Anthrax has a scary reputation. Widely known to
cause serious lung infections in humans and
New Treatment Reduces Long-Term Pain unsightly, albeit painless, skin lesions in livestock
Following Knee Surgery and people, the anthrax bacterium has even been
With one in five people experiencing ongoing pain used as a weapon of terror.
long after knee-replacement surgery, new research, Now the findings of a new study suggest that the
led by the University of Bristol and North Bristol dreaded microbe also has unexpected beneficial poten-
NHS Trust in the U.K. and published in The Lancet tial—one of its toxins can suppress multiple types of
Rheumatology, has shown a way to help reduce pain in animals.
continuing pain that could also save the NHS time The research reveals that this specific anthrax toxin
and money.
Each year, 100,000 knee-replacement surgeries are
The findings of a new study suggest
carried out in the U.K. Most of these operations take
place to treat pain related to osteoarthritis. Unfortu- that the dreaded microbe [anthrax]
nately, every year around 20,000 people who have
knee-replacement surgery to relieve their pain find that
also has unexpected beneficial
they have moderate to severe pain 3 months or longer potential—one of its toxins can
after their operation, which impacts their everyday
lives.
silence multiple types of pain
The study found the STAR (support and treatment in animals.
after joint replacement) care pathway reduces pain
severity, the amount pain interferes with people’s lives, works to alter signaling in pain-sensing neurons and,
and is cost effective. The new treatment could poten- when delivered in a targeted manner into neurons of
tially save the NHS up to £14 million ($19 million) per the central and peripheral nervous system, can offer
year through reduced inpatient admissions. relief to animals in distress.
The study found that patients who received the The work, led by investigators at Harvard Medical
STAR care pathway had less pain severity and impact School (HMS) in collaboration with industry scientists
on daily life at both 6 and 12 months after treatment (9 and researchers from other institutions, was published
and 15 months after surgery); half the number of hos- in Nature Neuroscience.
pital readmissions; reduced length of hospital stay for Furthermore, the team combined parts of the
any inpatient admissions 3 months after surgery; and anthrax toxin with different types of molecular cargo
less unpaid time off work. and delivered it into pain-sensing neurons. The tech-
The program looked at how likely patients are to nique can be used to design novel precision-targeted
experience ongoing knee pain after their operation and pain treatments that act on pain receptors but without
discovered why they avoid seeking help. The research the widespread systemic effects of current pain-relief
team developed a new treatment—a care pathway— drugs, such as opioids.
and compared how patients did on the STAR care “This molecular platform of using a bacterial toxin
pathway when compared with a control group who to deliver substances into neurons and modulate their
had the usual care. function represents a new way to target pain-mediating
As part of the STAR care pathway, 3 months after neurons,” said study senior investigator Isaac Chiu,
surgery patients attended an hour-long clinic run by associate professor of immunology in the Blavatnik
specially trained healthcare professionals, and detailed Institute at HMS.
9
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Pain News Digest

“There’s still a great clinical need for developing surgery at Pitt. “When you get up from a sitting posi-
non-opioid pain therapies that are not addictive but tion or from sleeping, it’s a sharp, searing pain that
that are effective in silencing pain,” said study first some people describe as being like a nail going right
author Nicole Yang, HMS research fellow in immunol- through their heel.”
ogy in the Chiu Laboratory. “Our experiments show The acute form of PF can be treated with stretching,
that one strategy, at least experimentally, could be to shoe orthotics, or cortisone injections. But about 10%
specifically target pain neurons using this bacterial of patients progress to the chronic form in which the
toxin.” foot’s collagen degenerates and the plantar fascia thick-
The researchers caution, however, that for now, this ens. For these patients, surgical release of the plantar
approach remains purely experimental and still needs fascia with a small cut can help, but this surgery comes
to be tested and further fine-tuned in more animal with risks, according to Dr. Beth Gusenoff.
studies and, eventually, in humans. “Recently, there has been a plea among podiatrists
For the current study, they started out by trying to to stop cutting the plantar fascia because some peo-
determine how pain-sensing neurons may be different ple get a lot of scar tissue, which causes pain,” she
from other neurons in the human body. To do so, they explained. “And if too much is cut, the foot can
first turned to gene-expression data. One of the things become destabilized, so people end up with almost
that caught their attention: Pain fibers had receptors like a floppy foot.” Inspired by the regenerative
for anthrax toxins, whereas other types of neurons did properties of fat stem cells, the Gusenoffs developed
not. In other words, the pain fibers were structurally a technique that uses fat from a patient’s belly or
primed to interact with the anthrax bacterium. They other body area.
wondered why. To test this method, the team recruited 14 patients
The newly published research sheds light on that with chronic PF and split them into two groups. Group
question while also pointing to novel avenues for
drug development beyond the traditional small-mole- In a pilot study led by a wife-and-
cule therapies that are currently being designed across
laboratories. husband team, the fat-injection
“Bringing a bacterial therapeutic to treat pain raises
procedure improved symptoms of
the question ‘Can we mine the natural world and the
microbial world for analgesics?’” Dr. Chiu said. plantar fasciitis in patients, laying
“Doing so can increase the range and diversity of the
types of substances we look to in search for solutions.”
the groundwork for a larger
clinical trial.
Fat Could Inject Relief Into Patients With
Plantar Fasciitis Pain 1 participants received the procedure at the beginning
A novel technique that transplants a patient’s own fat of the study and were followed for 12 months, and
into the sole of the foot could offer relief to those suf- their Group 2 counterparts received the procedure
fering from a common and painful condition called after a 6-month observation period and were followed
plantar fasciitis (PF), according to University of Pitts- for an additional 6 months.
burgh (Pitt) School of Medicine researchers. “We found that Group 1 had improvements in
In a pilot study in Plastic and Reconstructive Sur- quality of life and sports activity, decreased plantar fas-
gery and led by a wife-and-husband team, the fat-injec- cia thickness, and reduced pain levels,” said Dr. Jeffrey
tion procedure improved symptoms of PF in patients, Gusenoff. “And a lot of the measures that were
laying the groundwork for a larger clinical trial. improving 6 months after the procedure got even bet-
“We developed this procedure to harness the regen- ter by 12 months.”
erative properties of fat,” said Jeffrey Gusenoff, MD,
professor of plastic surgery at Pitt. “In this proof-of- Pain and Anxiety Affect Breathing on
concept study, we showed that fat injections into the a Cellular Level
foot reduced heel pain, helped patients get back to Why people’s breathing rate increases dramati-
doing sports and activities, and boosted quality of life.” cally when they are hurting or anxious was not
“Plantar fasciitis is exceptionally painful,” said Beth previously understood. Now, a team of Salk Insti-
Gusenoff, DPM, clinical assistant professor of plastic tute scientists has uncovered a neural network in
10
U.S. Pharmacist • March 2022 • www.uspharmacist.com
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Pain News Digest

the brain that coordinates breathing rhythm with Soft Tissue Destruction and
feelings of pain and fear. Along with contributions Lower Back Pain
to the fields of pain management, psychological Back pain affects many people at some point in
theories of anxiety, and philosophical investiga- their lives, and a common cause is damage to the
tions into the nature of pain, these findings could squishy discs or flexible, rubbery tissues of the
lead to development of an analgesic that would spine. However, observing this damage at an early
prevent opioid-induced respiratory depression stage is difficult with current imaging methods.
(OIRD), the disrupted breathing that causes over- Now, researchers reporting in ACS Nano can see
dose deaths. microscopic soft tissue destruction in animal spines
In the study published in Neuron, the Salk group by targeting denatured collagen with fluorescent
focused on a group of neurons in the brainstem molecules.
called the lateral parabrachial nucleus, which is Any area along the spine, from the neck to tail
arranged in a core-shell configuration. They found bone, can become uncomfortable when its soft and
that neurons in the core project to the amygdala, an protective tissues, including the cartilage and jelly-
area of the brain that processes fear and the emo- like intervertebral discs, become damaged and lose
tional experience of pain. Neurons in the shell proj- their structure. Daily wear and tear, as well as some
ect to the pre–Bötzinger complex, a region that gen- disorders, such as facet joint osteoarthritis or anky-
erates breathing rhythm. The core and shell neurons losing spondylitis, can degrade and unfurl the colla-
influence each other according to inputs from these gen proteins that give these tissues their bounce and
areas, making people breathe faster when they flexibility. Detecting compromised collagen early
experience pain or anxiety. could help patients get relief before the pain becomes
“We are the first group to demonstrate how the lat- severe, but this is very difficult to do with existing
eral parabrachial nucleus coordinates breathing and medical technologies, such as x-rays and MRI.
pain,” says the paper’s senior author, Sung Han, assis- Previously, Yang Li and colleagues developed a col-
tant professor in Salk’s Clayton Foundation Laborato- lagen hybridizing peptide (CHP) probe that specifically
ries for Peptide Biology. “By understanding the circuits binds unfurled collagen molecules, which happens
in this brain region, we may be able to tease apart when they deteriorate and lose their ability to cushion
breathing regulation and pain regulation to develop a vertebrae. So, Li, Kuibo Zhang, Hong Shan, and col-
medication that inhibits feelings of pain without leagues wanted to test if CHP labeled with fluorescent
repressing breathing, like OIRD.” tags could be used as an imaging method to identify
In OIRD, opioids repress breathing as well as pain; collagen destruction in the body.
it is the major cause of death from opioids. In previous To make the peptide probe more stable in the body,
work, Dr. Han’s laboratory showed that opiates like the researchers modified CHP by substituting a
morphine repress breathing by triggering specific hydroxyl group with fluorine and then attaching a flu-
receptors, called mu-opioid receptors (MORs), leading orescent dye to it. When healthy mice and rats were
to the inhibition of neurons that express them. It also injected with the fluorescent dye–labeled CHP and
showed that reactivating the cells that express MORs imaged with near-infrared fluorescence, the team con-
can reverse OIRD. The current work suggests addi- firmed that the fluorescing molecules accumulated on
tional approaches for preventing OIRD, possibly by the soft tissues between the vertebrae.
inhibiting neurons in the region’s core (blunting fear/ The researchers then removed a portion of the ani-
anxiety) while exciting similar neurons in the shell mals’ spines and imaged them with light sheet fluores-
(supporting breathing). cence microscopy. This technique produced precise 3D
Dr. Han is eager to see the team’s discovery applied maps, which revealed denatured collagen. Because
translationally. “The biggest problem these days is that CHP is known to target damaged collagen, the team
opioids reduce pain but also reduce breathing, so peo- says their imaging experiments show that even healthy
ple die,” says Dr. Han, holder of the Pioneer Fund animals can have a modest degree of deteriorated col-
Development Chair. “By understanding those two lagen around load-bearing joints, especially in the
mechanisms in our research, maybe we can manipulate lower back.
certain populations of neurons by pharmacological The content contained in this article is for informational purposes
intervention so that we can control pain without only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is
changing the breathing.” solely at your own risk.

12
U.S. Pharmacist • March 2022 • www.uspharmacist.com
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 Breanne M. Mefford, PharmD, BCCCP
Critical Care Pharmacist, Medical Intensive Care Unit
into three different waves. An increase in the pre- Department of Pharmacy
scribing of opioids in the 1990s constituted the first University of Kentucky Medical Center
wave; the second wave, which began in 2010, was Lexington, Kentucky
defined by rapid increases in overdose deaths J. Chris Donaldson, PharmD, BCCCP
involving heroin; and 2013 saw the beginning of Critical Care Pharmacist, Medical Intensive Care Unit
Department of Pharmacy
the third wave, characterized by substantial University of Kentucky Medical Center
increases in overdose deaths related to synthetic 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- buprenorphine’s high affinity causes it to rapidly
out a compelling cause should be discouraged. Too displace opioid agonist–bound mu receptors,
often, however, patients with OUD experience thereby hastening withdrawal.9
abrupt cessation or inappropriate management of Buprenorphine provides analgesia at low-to-
acute pain when admitted to the hospital or in the moderate doses and is approximately 25 to 100
postoperative period. Many clinicians are unfamil- times more potent than morphine.10 Furthermore,
iar with OAT and the treatment of acute pain in buprenorphine exhibits a ceiling effect, so doses
patients with OUD. Additionally, many providers exceeding 32 mg do not produce a greater analgesic
are concerned with manipulative or drug-seeking effect.11 Providers typically are more inclined to use
behavior, and this may deter the use of opioid buprenorphine for OUD because of its decreased
agents to treat acute pain. This review aims to potential for abuse and because, in contrast to
describe the pharmacology of OAT agents and dis- methadone, it enables the provision of office-based
cuss current considerations for the treatment of treatment. Additionally, buprenorphine has a lower
acute pain in patients receiving OAT. risk of respiratory depression than methadone, and
it has the ability to treat opioid-induced hyperal-
Treatment of OUD gesia through kappa-receptor antagonism. 11
Buprenorphine and methadone are commonly used Because buprenorphine antagonizes the action of
for the treatment of OUD. The pharmacologic mu agonists, the practice of withholding buprenor-
properties of these agents differ substantially, as phine before surgery has become widespread. Pre-
highlighted below. clinical and clinical studies have shown that the
administration of buprenorphine and mu agonists
Buprenorphine: This agent is a semisynthetic partial produces an additive analgesic response at analge-
opioid analgesic that binds to mu-, kappa-, and sic doses of buprenorphine. However, little is
delta-opioid receptors. Its analgesic effect is via known about the interaction between buprenor-
high-affinity binding to the opiate receptors in the phine and opioid agonists when buprenorphine is
central nervous system. Buprenorphine displays used to treat OUD.9 The difficulties of managing
partial mu-agonist and weak kappa-antagonist pain in patients taking buprenorphine, combined
activity, but its agonist activity at the delta receptor with the pharmacologic properties noted above,
is not well understood. The half-life of buprenor- have led to conflicting views on how to optimally
phine is variable, ranging from 3 hours for IV treat acute pain in these patients.
administration to 24 to 60 hours for sublingual
administration. 9 The dissociation from binding
sites is slow, leading to a longer duration of action
The difficulties of managing pain in
than that of other opioids. This slow dissociation patients taking buprenorphine,
allows for prolonged therapeutic effects in treating
opioid dependence and chronic pain.10 Buprenor-
combined with the pharmacologic
phine’s high binding affinity and slow mu-opioid properties noted above, have led to
receptor dissociation make the use of mu-opioid
receptor antagonists, such as naloxone, difficult. conflicting views on how to optimally
Multiple buprenorphine formulations are FDA treat acute pain in these patients.
approved for the treatment of OUD, including sub-
lingual tablet, sublingual film, buccal film, Methadone: Methadone, a synthetic full mu-recep-
implant, and extended-release injection. The tor agonist, is structurally unrelated to other opi-
buprenorphine concentration of these formula- oids; it exhibits N-methyl-d-aspartate (NMDA)
tions has euphoric effects when administered IV; receptor antagonist activity. Available formula-
accordingly, naloxone is added because its effect tions are racemic mixtures of two isomers. The
is significantly increased when injected IV, antago- R-isomer is an NMDA receptor antagonist that
nizing buprenorphine’s euphoric effects and pre- inhibits the uptake of norepinephrine and sero-
cipitating immediate withdrawal, thus discourag- tonin, and the S-isomer is a mu- and delta-opioid
ing misuse.9 Patients should show signs of opioid receptor agonist.12 Historically, an influx of heroin
withdrawal prior to starting buprenorphine, as into U.S. metropolitan areas following World War
HS-4
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Health Systems Edition
Managing Acute Pain in Opioid Use Disorder

II resulted in increased rates of illicit drug use, It is recommended to continue the patient’s home
leading to the establishment of narcotic-mainte- MMT and employ short-acting opioids to manage
nance programs that used methadone as the pri- acute breakthrough pain.14 Given methadone’s
mary opioid-replacement agent based on its slow unique pharmacologic profile, dose conversion to
onset of action (3-5 days) and long elimination an alternative opioid often is inaccurate, limiting
half-life (8-59 hours). 11 In higher doses, metha- the practicality of alternative regimens. In addition,
done may have serious side effects including respi- nonopioid analgesics—including nonsteroidal anti-
ratory depression, arrhythmias due to prolonged inflammatory agents and acetaminophen—should
QT interval, and drug-drug interactions from be used when appropriate. If a patient is unable to
CYP450 metabolism. A study of maintenance take oral medications, the methadone dose may be
methadone found that patients were cross-tolerant administered IV or subcutaneously as one-half to
to the analgesic effects of morphine and that pain two-thirds of the maintenance dose divided into
relief, when achieved, did not last as long as two to four equal doses.14 Importantly, the patient’s
expected.13 Cross-tolerance between opioids may methadone clinic should always be contacted in
explain why patients receiving OAT require higher order to confirm the patient’s MMT regimen as
and more frequent doses of opioid analgesics for well as to inform the staff of the patient’s hospital-
adequate pain control. These are all important ization, as these clinics routinely perform urine
considerations in the management of acute pain in drug screens.
the setting of methadone OAT.

Managing Acute Pain in OUD Chronic opioid exposure results in


The approach to managing acute pain—including opioid- and NMDA-receptor
perioperative pain—in patients receiving OAT is a
common clinical conundrum. As aforementioned, trafficking, which contributes to
clinicians may be less familiar with OAT, poten-
tolerance and hyperalgesia and
tially leading to the undertreatment of acute pain.
Undertreatment is often perpetuated by some pro- minimizes the analgesic properties
viders’ fear of adverse effects, including respiratory
and cognitive suppression, and by the misinterpre-
of chronic OAT.
tation of patient-reported pain as drug-seeking
behavior. Furthermore, the misconception that Buprenorphine Management: Guidelines published
patients derive sustained analgesia from OAT may in 2004 by the Department of Health and Human
play a role in the undermanagement of acute pain. Services’ Center for Substance Abuse Treatment
Chronic opioid exposure results in opioid- and recommended the discontinuation of home
NMDA-receptor trafficking, which contributes to buprenorphine OAT.19 In conjunction with limited
tolerance and hyperalgesia and minimizes the anal- evidence, this recommendation was largely based
gesic properties of chronic OAT.14 Therefore, it is on the considerations that buprenorphine is a par-
important for clinicians to familiarize themselves tial opioid receptor agonist and that it impairs the
with the management of acute pain in patients effectiveness of other opioids. However, clinical
receiving OAT. studies in the perioperative setting have since
shown that the use of additional opioids for acute
Methadone Management: Adequate analgesia may pain plus maintenance of the patient’s home
be more challenging to achieve in patients on meth- buprenorphine OAT is an effective strategy. 20,21
adone maintenance therapy (MMT), as there is Furthermore, clinical studies have demonstrated
often a degree of opioid cross-tolerance.13,15,16 Ret- that patients whose home buprenorphine OAT was
rospective studies have demonstrated that patients held perioperatively had increased opioid require-
on MMT frequently have higher opioid require- ments as well as increased pain scores relative to
ments in the setting of acute perioperative pain. 17,18 patients whose home buprenorphine OAT was
Furthermore, methadone has an analgesic duration continued.22,23
of action of 4 to 8 hours, which is substantially As with methadone, patients who are on
shorter than the suppression of opioid withdrawal. buprenorphine prior to admission may still have
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U.S. Pharmacist • March 2022 • www.uspharmacist.com
Health Systems Edition
Managing Acute Pain in Opioid Use Disorder

higher opioid requirements relative to patients not of the buccal film is 46% to 65% and that of the
on chronic opioids. This has led some institutions to sublingual tablet is 29%, so this may be taken into
implement perioperative protocols that either hold consideration in establishing an IV dose.27
or wean buprenorphine products; however, this
likely adds unnecessary complexity including rein- Conclusion
troduction and may increase the risk of with- Many patients with OUD are receiving OAT with
drawal.11,18,19 Discontinuation of buprenorphine has methadone or buprenorphine. Therefore, clinicians
also been associated with higher rates of illicit opioid may encounter patients receiving OAT who have
use.24 Accordingly, many experts now recommend acute pain during hospitalization or in the postop-
continuing home buprenorphine OAT periopera- erative setting. Providers should familiarize them-
tively and in other acute-pain settings.14,19,25,26 selves with OAT pharmacology and determine the
Short-acting opioid agonists are recommended appropriate regimen for acute pain by continuing
for management of acute pain, keeping in mind that OAT with short-acting agents as needed. As the
these patients will have some degree of cross-toler- opioid epidemic continues, it is of paramount
ance. The total daily buprenorphine dose may be importance to ensure appropriate acute pain treat-
divided into three or four doses, with each dose ment while managing OUD. Pharmacists can play
taken every 6 to 8 hours.19 Most patients likely can a key role in managing OAT in the setting of acute
tolerate transmucosal or sublingual administration, pain and in determining the appropriate administra-
but for those who cannot, buprenorphine may be tion route, dose, and frequency of home OAT.
administered IV. Dose equivalence between trans- The content contained in this article is for informational purposes
mucosal or sublingual and IV administration is not only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is solely
well established; however, the oral bioavailability at your own risk.

REFERENCES Ann Intern Med. 2006;144(2):127-134.


1. CDC. Mortality data. WONDER [online database]. http://wonder. 15. Athanasos P, Smith CS, White JM, et al. Methadone maintenance
cdc.gov. Accessed January 31, 2022. patients are cross-tolerant to the antinociceptive effects of very high
2. CDC. Vital signs: overdoses of prescription opioid pain relievers— plasma morphine concentrations. Pain. 2006;120(3):267-275.
United States, 1999-2008. MMWR Morb Mortal Wkly Rep. 16. Hay JL, White JM, Bochner F, Somogyi AA. Antinociceptive effects
2011;60(43):1487-1492. of high-dose remifentanil in male methadone-maintained patients. Eur
3. Rudd RA, Paulozzi LJ, Bauer MJ, et al. Increases in heroin overdose J Pain. 2008;12(7):926-933.
deaths—28 states, 2010 to 2012. MMWR Morb Mortal Wkly Rep. 17. Chan FJ, Schwartz AM, Wong J, et al. Use of chronic methadone
2014;63(39):849-854. before total knee arthroplasty. J Arthroplasty. 2017;32(7):2105-2107.
4. Gladden RM, Martinez P, Seth P. Fentanyl law enforcement submissions 18. Hansen LE, Stone GL, Matson CA, et al. Total joint arthroplasty in
and increases in synthetic opioid-involved overdose deaths—27 states, patients taking methadone or buprenorphine/naloxone preoperatively
2013-2014. MMWR Morb Mortal Wkly Rep. 2016;65(33):837-843. for prior heroin addiction: a prospective matched cohort study. J Arthro-
5. Degenhardt L, Whiteford H, Hall WD. The Global Burden of Disease plasty. 2016;31(8):1698-1701.
projects: what have we learned about illicit drug use and dependence 19. Haber LA, DeFries T, Martin M. Things We Do for No ReasonTM:
and their contribution to the global burden of disease? Drug Alcohol discontinuing buprenorphine when treating acute pain. J Hosp Med.
Rev. 2014;33(1):4-12. 2019;14(10):633-635.
6. Kaskutas LA, Borkman TJ, Laudet A, et al. Elements that define 20. Kornfeld H, Manfredi L. Effectiveness of full agonist opioids in
recovery: the experiential perspective. J Stud Alcohol Drugs. 2014;75(6):999- patients stabilized on buprenorphine undergoing major surgery: a case
1010. series. Am J Ther. 2010;17(5):523-528.
7. Connery HS. Medication-assisted treatment of opioid use disorder: 21. Harrison TK, Kornfeld H, Aggarwal AK, Lembke A. Perioperative
review of the evidence and future directions. Harv Rev Psychiatry. considerations for the patient with opioid use disorder on buprenorphine,
2015;23(2):63-75. methadone, or naltrexone maintenance therapy. Anesthesiol Clin.
8. Santo T Jr, Clark B, Hickman M, et al. Association of opioid agonist 2018;36(3):345-359.
treatment with all-cause mortality and specific causes of death among 22. Macintyre PE, Russell RA, Usher KAN, et al. Pain relief and opioid
people with opioid dependence: a systematic review and meta-analysis. requirements in the first 24 hours after surgery in patients taking
JAMA Psychiatry. 2021;78(9):979-993. buprenorphine and methadone opioid substitution therapy. Anaesth
9. Quaye ANA, Zhang Y. Perioperative management of buprenorphine: Intensive Care. 2013;41(2):222-230.
solving the conundrum. Pain Med. 2019;20(7):1395-1408. 23. Quaye A, Potter K, Roth S, et al. Perioperative continuation of
10. Khanna IK, Pillarisetti S. Buprenorphine—an attractive opioid with buprenorphine at low-moderate doses was associated with lower post-
underutilized potential in treatment of chronic pain. J Pain Res. 2015;8:859- operative pain scores and decreased outpatient opioid dispensing compared
870. with buprenorphine discontinuation. Pain Med. 2020;21(9):1955-1960.
11. Anderson TA, Quaye ANA, Ward EN, et al. To stop or not, that is 24. Ling W, Hillhouse M, Domier C, et al. Buprenorphine tapering
the question: acute pain management for the patient on chronic buprenor- schedule and illicit opioid use. Addiction. 2009;104(2):256-265.
phine. Anesthesiology. 2017;126(6):1180-1186. 25. Lembke A, Ottestad E, Schmiesing C. Patients maintained on
12. Fredheim OMS, Moksnes K, Borchgrevink PC, et al. Clinical phar- buprenorphine for opioid use disorder should continue buprenorphine
macology of methadone for pain. Acta Anaesthesiol Scand. 2008;52(7):879- through the perioperative period. Pain Med. 2019;20(3):425-428.
889. 26. Goel A, Azargive S, Weissman JS, et al. Perioperative Pain and
13. Doverty M, Somogyi AA, White JM, et al. Methadone maintenance Addiction Interdisciplinary Network (PAIN) clinical practice advisory
patients are cross-tolerant to the antinociceptive effects of morphine. for perioperative management of buprenorphine: results of a modified
Pain. 2001;93(2):155-163. Delphi process. Br J Anaesth. 2019;123(2):e333-e342.
14. Alford DP, Compton P, Samet JH. Acute pain management for 27. Buprenorphine. In: Lexi-Drugs. Hudson, OH: Lexi-Comp, Inc; 2022.
patients receiving maintenance methadone or buprenorphine therapy. https://online.lexi.com. Accessed January 31, 2022.

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U.S. Pharmacist • March 2022 • www.uspharmacist.com
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
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Pharmacogenomic Considerations in Opioid Therapy

sible for activating a prodrug to its active metabolite (NSAIDs), antidepressants such as serotonin-norepi-
for the therapeutic effect (e.g., codeine and CYP2D6). nephrine reuptake inhibitors (SNRIs) and tricyclic
Given the rapid decline in the cost of pharmacoge- antidepressants (TCAs), antiepileptic medications
nomic testing and growing clinical evidence on the such as gabapentinoids, and topical analgesics such
impact of pharmacogenomics on pharmacotherapy, as lidocaine and capsaicin.
pharmacists are ideally positioned to identify how
pharmacogenomics affects a given pharmacotherapy CYP2D6 Polymorphism
and to recommend and interpret pharmacogenomic CYP2D6, which is one of the major CYP450 enzymes
test results in order to optimize therapy. in human hepatocytes, is responsible for the metabo-
The Clinical Pharmacogenetics Implementation lism of a variety of central nervous system (CNS)–
Consortium (CPIC) publishes guidelines on the active drugs, including many centrally acting analgesics
impact of pharmacogenomics on a drug’s efficacy or such as opioids. The CYP2D6 gene is highly polymor-
risk of side effects based on prospective clinical evi- phic, with single nucleotide allelic variations resulting
dence.2 Recommendations may include close moni- in reduced or no enzyme activity. Additionally,
toring, altering the dose, or avoiding a drug alto- CYP2D6 is unique in that it can have multiple copies
gether. This article is a critical review of recently of these alleles. The CPIC recommends a scoring sys-
published CPIC guidelines on opioid use based on tem based on clinical studies to help translate CYP2D6
pharmacogenomic variations.3 genotypes into phenotypes. In this scoring system,
CYP2D6 alleles are given an activity score from 0 (no
Opioid Use in Pain Management activity) to 1 (normal activity). The sum of the alleles’
Opioids are among the most common medications activity scores constitutes the activity score, which
used in the treatment of pain, and they carry many corresponds to the patient’s ability to metabolize
serious risks if used inappropriately. In the manage- CYP2D6 substrates. In the presence of multiple copies,
ment of both acute and chronic noncancer pain, pal- the allele activity score is multiplied by the number of
liative care, or end-of-life pain, opioids are intended CYP2D6 copies the patient has, and the sum of these
to be used after nonpharmacologic interventions and scores is the patient’s activity score. Multiplication in
nonopioid pharmacologic treatment options have genes with normal activity can result in higher activity
failed or proved insufficient.4 Nonpharmacologic scores and increased metabolism. Ultimately, CYP2D6
treatment options that may be attempted prior to polymorphisms are categorized into “ultrarapid,”
opioid therapy include cognitive-behavioral therapy, “normal,” “intermediate,” “poor,” and “indetermi-
exercise therapy, physical therapy, and weight loss.4 nate” metabolizer phenotypes.3,6
For the treatment of active cancer pain, clinicians may
initiate opioid therapy in addition to nonopioid anal- Impact of CYP2D6 Polymorphism
gesics when the pain is severe enough to warrant it.5 on Opioid Metabolism
The use of opioids in oncology patients should be Several common opioids—specifically, codeine, hydro-
closely monitored for efficacy (in order to avoid lack codone, methadone, oxycodone, and tramadol—are
of pain control) and safety.5 The many risks of opioid metabolized by the CYP2D6 enzyme (FIGURE 1).7
use, including sedation, constipation, dependence, CYP2D6 converts codeine and tramadol to their more
overdose, and death, should be discussed with the active metabolites, morphine and O-desmethyltrama-
patient.4 Opioid treatment should be continued only dol, respectively.8 Therefore, alterations in the metab-
after the patient’s improvements in pain and function olism of these drugs can have a profound impact on
have been observed to outweigh these significant their analgesic effect or risk of side effects. Oxycodone
risks.4 In addition, the CDC recommends that clini- and hydrocodone are also converted by CYP2D6 into
cians consider developing an exit strategy if treatment oxymorphone and hydromorphone, respectively.9
with opioids does not prove beneficial for the patient.4 Although oxymorphone and hydromorphone have
Meperidine is not recommended for the treatment higher morphine equivalents than their parent drugs,
of cancer pain because of the risk of toxicity, and both oxycodone and hydrocodone are active drugs, so
given variations in metabolism, codeine is not pre- alterations in their metabolism have a less profound
ferred unless pharmacogenomic results are available.5 clinical effect than codeine and tramadol. Methadone,
Pharmacologic nonopioid options include acetamin- although partially metabolized by CYP2D6, is pre-
ophen, nonsteroidal anti-inflammatory drugs dominantly metabolized by other enzymes.10
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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’ olizers showed a 45% higher median plasma mor-
Effect on Opioids and Clinical phine AUC and 50% higher plasma concentrations
Recommendations of morphine compared with normal metabolizers.12
Among the opioids, the impact of CYP2D6 polymor- Clinical outcomes such as severe adverse effects
phisms on codeine has been the best established. Poor (AEs) in ultrarapid metabolizers are limited to case
metabolizers have shown both pharmacokinetic and reports.14 Based on these studies, the CPIC concluded
clinical differences compared with normal metaboliz- definitively that when they take codeine, CYP2D6
ers. One study showed that patients with poor-metab- ultrarapid metabolizers have increased morphine
olizer genotypes who took codeine had 96% lower formation leading to increased AEs, and that they
mean serum morphine AUC and 95% lower mor- should avoid the use of codeine.3
phine serum peak concentrations compared with Similarly, patients who were CYP2D6 poor metab-
normal and intermediate metabolizers.11 This study olizers and took tramadol showed lower median
also showed no analgesia in poor metabolizers com- plasma concentrations of O-desmethyltramadol com-
pared with normal and intermediate metabolizers, pared with normal metabolizers.10 In several studies,
who demonstrated analgesic response.12 Another CYP2D6 poor metabolizers had less analgesia after
study found that patients with sickle cell disease who taking tramadol compared with normal metaboliz-
did not respond to codeine therapy for pain manage- ers.10,15,16 These studies led the CPIC to definitively
ment were more likely to have an activity score less conclude that CYP2D6 poor metabolizers have
than 1.5.13 The CPIC determined that the evidence decreased O-desmethyltramadol and less analgesia,
was sufficient to conclude that CYP2D6 poor metab- and that they should avoid the use of tramadol.3
olizers who take codeine have greatly reduced mor- Ultrarapid metabolizers have demonstrated both
phine formation, thus resulting in decreased analge- higher O-desmethyltramadol AUC and greater anal-
sia. Based on these clinical studies, the CPIC strongly gesia compared with normal metabolizers.17 Addi-
recommended that codeine be avoided in CPY2D6 tionally, case studies have reported the occurrence of
poor metabolizers.3 severe AEs in ultrarapid metabolizers, leading the
Alternatively, in pharmacokinetic studies, CPIC to definitively conclude that CYP2D6 metabo-
CYP2D6 ultrarapid metabolizers have been shown lizers should avoid the use of tramadol because of
to have higher morphine levels.12 Ultrarapid metab- the potential for toxicity caused by an increase in
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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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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 polymorphisms. For these reasons, the CPIC con-
effects of CYP2D6 polymorphisms on hydrocodone cluded that data are insufficient to make recommen-
safety and efficacy are limited. For this reason, the dations for oxycodone and methadone.
CPIC added an optional recommendation to switch Current CPIC recommendations for opioid use
analgesics only if a CYP2D6 poor metabolizer does based on CYP2D6 gene polymorphisms are summa-
not respond to label-based doses of hydrocodone.3 rized in TABLE 1.
Recommendations for oxycodone and methadone
in CYP2D6 gene polymorphisms are uncertain. Safer Alternatives and Other
Although in one study poor metabolizers taking oxy- Considerations
codone had oxymorphone levels that were 67% For patients who are not candidates for codeine, tra-
lower than in normal metabolizers, this did not madol, or hydrocodone based on their CYP2D6 poly-
necessitate an increase in oxycodone dose in poor morphisms, the CPIC recommends using opioids that
metabolizers.21 Additionally, ultrarapid metaboliz- are not metabolized by CYP2D6—namely, morphine,
ers showed no pharmacokinetic differences for oxy- fentanyl, tapentadol, buprenorphine, and meperidine.
morphone levels compared with normal metaboliz- When indicated, pharmacologic nonopioid options
ers.21,22 Prospective studies of clinical effectiveness may include acetaminophen, NSAIDs, SNRIs, TCAs,
are variable; some studies show analgesic and AE gabapentinoids, and topical analgesics. When decid-
differences between poor, normal, and ultrarapid ing on alternatives, clinicians should also consider
metabolizers with oxycodone use, whereas other other CYP interactions. For example, if genetic testing
studies demonstrate no difference, making evidence results are available for a patient, providers should
inconclusive.21-25 CYP2D6 metabolizes methadone be aware of alterations in the metabolism of CYP2C9
to an inactive metabolite to a minor extent, but AEs for NSAIDs and both CYP2D6 and CYP2C19 for
and analgesia do not seem to be affected by CYP2D6 TCAs.26
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Pharmacogenomic Considerations in Opioid Therapy

Pharmacogenomics-guided opioid therapy and opioid-dose requirements.3 Owing to the lack of


enables clinicians to determine the best options for strong evidence, the CPIC did not make any recom-
avoiding treatment failure and serious side effects. mendations regarding opioid dosing based on
However, clinicians should continue to personalize OPRM1 or COMT genetic polymorphism. However,
pain management by considering other factors as this likely will change as knowledge in this area
well (TABLE 2).2-4,26-34 For example, elderly patients expands.
are at higher risk for falls and fractures secondary
to oversedation.4 Therefore, opioid therapy in The Pharmacist’s Role
elderly patients should be initiated and titrated with Pharmacists play a critical role in the optimization
caution, and patients should be monitored more of pain medications and risk mitigation in patients
frequently for constipation, cognitive function, seda- receiving chronic opioid therapy. Titrating nonopi-
tion, and fall risk. oid analgesics to their optimal tolerated doses can
It should be noted that the risks of oversedation reduce the need to escalate opioid regimens or even
and respiratory depression are considerable if opioid to introduce them altogether. On a broader scale,
therapy is used in conjunction with additional CNS pharmacists can play a vital part in curbing the
depressants, such as muscle relaxants and benzodi- national opioid crisis by providing patient and fam-
azepines.4 Particular caution should be taken when ily education and either requesting a prescription
CYP2D6 substrates are used in the presence of sig- for or furnishing naloxone to patients at higher risk.
nificant drug-drug interactions, especially CYP2D6 By better understanding the pathways of opioid
inhibitors (e.g., bupropion, cinacalcet, fluoxetine, metabolism, pharmacists can identify patients who
paroxetine, quinidine) and inducers (e.g., dexameth- would be appropriate candidates for CYP pharma-
asone, oritavancin, rifampin); this is because inter- cogenomic testing and can help select the optimal
acting medications can potentially change the pharmacogenomic test that takes patients’ ethnicity
CYP2D6 phenotype (i.e., phenoconversion).35 An and other clinical factors into consideration.38 For
alternative opioid independent of CYP2D6 may be patients who undergo pharmacogenomic testing,
safer in patients with interacting medications. pharmacists can take the lead in accurately inter-
preting the results and making recommendations
Impact of COMT and OPRM1 for appropriate therapy. Using the test results, phar-
Polymorphism on Opioid Use macists may be able to identify patients with drug-
The recent CPIC opioid guideline introduces other seeking behavior related to uncontrolled pain and
genes that potentially may be associated with altered offer them alternatives. In patients without genetic
opioid efficacy and AEs—namely, OPRM1 (mu testing who are responding unconventionally to
receptor) and catechol-O-methyltransferase opioid treatment, genetic alterations may help
(COMT).3 Because OPRM1 is a gene that codes for explain treatment failure and point to alternative
mu receptors, alterations in OPRM1 can cause options.
reduced mu-receptor expression.36 COMT conjugates
methyl to catecholamines, such as dopamine, and can Conclusion
affect synaptic levels of catecholamines and, in turn, As medicine continues to become more personalized,
pain perception. COMT polymorphism can lessen prescribers must adjust to its advances. Opioids
the enzyme’s ability to methylate dopamine, resulting must be used safely and monitored closely. Pharma-
in higher pain levels and decreased opioid effective- cogenomics helps practitioners predict clinical
ness.37 Although polymorphisms in OPRM1 and responses to therapies. Understanding the principles
COMT have been reported, study results on clinical of genetic testing for opioids leads to therapy that
differences in patients with OPRM1 and COMT yields improved responses and fewer AEs. Pharma-
polymorphism are inconsistent. Some studies show a cogenomic tests can help pharmacists identify
slightly increased opioid requirement in patients with patients at higher risk for opioid-related side effects
at least one copy of the rs1799971 G allele of or treatment failure.
OPRM1.3 No data demonstrate increased opioid AEs References available online at www.uspharmacist.com.
in patients with rs4680, a COMT variant. Therefore, The content contained in this article is for informational purposes
insufficient evidence is currently available on the pres- only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is solely
ence of OPRM1 and COMT allelic polymorphisms at your own risk.

HS-12
U.S. Pharmacist • March 2022 • www.uspharmacist.com
INDUSTRYNEWS

FDA Fully Approves Spikevax, genic cancer chemotherapy, including high-dose


Moderna’s mRNA COVID-19 Vaccine cisplatin, and delayed nausea and vomiting asso-
Moderna, Inc. announced that the FDA approved ciated with initial and repeat courses of moder-
the Biologics License Application for Spikevax to ately emetogenic cancer chemotherapy. Fosapre-
prevent COVID-19 in individuals aged 18 years pitant for injection is available in 150-mg,
and older. The FDA based its decision on the single-dose vials.
totality of scientific evidence shared by the com-
pany in its submission package, which included FDA Approves Azurity
follow-up data from the phase III COVE study Pharmaceuticals’ Fleqsuvy
showing high efficacy and favorable safety Azurity Pharmaceuticals, Inc., announced the
approximately 6 months after the second dose. FDA approval of Fleqsuvy (baclofen oral sus-
Moderna’s COVID-19 vaccine was available pension), 25 mg per 5 mL (5 mg/mL), concen-
under Emergency Use Authorization in the trated formulation for the treatment of spastic-
United States since December 18, 2020. A ity from multiple sclerosis (MS) or in patients
booster dose of the Moderna COVID-19 vaccine with spinal cord injuries and other spinal cord
at the 50-µg dose level is authorized for emer- diseases.
gency use in the U.S. for adults aged 18 years Nearly 1 million people are living with MS in
and older. A third dose of the Moderna COVID- the U.S. Spasticity is a commonly reported
19 vaccine at the 100-µg dose level is authorized symptom in MS, with an estimated prevalence
for emergency use in immunocompromised indi- of spasticity of 67%. Due to the severity of
viduals aged 18 years or older in the U.S. who spasticity resulting from MS or from spinal cord
have undergone solid organ transplantation, or injuries and other spinal cord diseases, dosing
who are diagnosed with conditions that are con- becomes paramount to providing appropriate
sidered to have an equivalent level of immuno- relief. Dysphagia is commonly experienced,
compromise. affecting approximately 43% of MS patients
and 16% to 30% of patients with spinal cord
Camber Launches Generic Colcrys, injuries.
Fosaprepitant for Injection Fleqsuvy provides an option as a baclofen
Camber Pharmaceuticals announced the addi- oral liquid medication at an effective dose for
tion of Colchicine Tab- patients who have trouble swallowing pills or
lets (Colcrys; Takeda prefer a liquid formulation. As the most concen-
Pharmaceuticals) to its trated FDA-approved oral liquid baclofen for-
current portfolio. mulation, Fleqsuvy allows for the lowest volume
Colchicine Tablets to be prescribed for patients, which can be an
are an alkaloid indi- important consideration for those suffering from
cated for prophylaxis dysphagia.
and treatment of gout flares in adults and
familial Mediterranean fever in adults and chil- Agios Announces Approval of Pyrukynd
dren aged 4 years or older. Camber Colchicine Agios Pharmaceuticals, Inc., Cambridge, Massa-
0.6-mg Tablets are available in 30- and 100- chusetts, announced that the FDA approved
count bottles. Pyrukynd (mitapivat) in the U.S. for the treat-
Camber Pharmaceuticals also announced the ment of hemolytic anemia in adults with pyru-
addition of fosaprepitant for injection to its cur- vate kinase (PK) deficiency, a rare, debilitating,
rent portfolio. Fosaprepitant for injection is lifelong hemolytic anemia. Pyrukynd is a first-
indicated in adults for the prevention of acute in-class, oral PK activator and the first
and delayed nausea and vomiting associated approved disease-modifying therapy for this
with initial and repeat courses of highly emeto- condition.
13
U.S. Pharmacist • March 2022 • www.uspharmacist.com
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%

© gettyimages.com / JobsonHealthcare
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- 43%
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 vided temporary relief rather than a cure. The
from pain severe enough to interfere with their National Center for Complementary and Integra-
lives. The annual cost of health care—including tive Health supports, conducts, and funds pain
lost productivity due to pain—approximated $600 research, as do the Department of Defense and the
billion, with missed workdays costing $13 billion Department of Veterans Affairs, which have funded
and lost work hours costing $97 billion, according 4% and 5%, respectively, of research. In federally
to the NAS. funded research on pain mechanisms and treat-
ment, 20.4% of studies chiefly focused on neuro-
Nonpharmaceutical Research: This type of research logic/glial aspects, 7.3% examined nondrug
focuses on psychological and/or physical approaches, and 5.9% investigated biobehavioral
approaches to pain management. To obtain pain and psychosocial aspects. Although training for
relief, 3 million adults used acupuncture, 4.2 mil- pain management was included in only 7% of stud-
lion used yoga, 15.4 million used massage therapy, ies, all study protocols addressed basic (40%), clini-
and 29.7 million used meditation. Nontraditional cal (42%), and translational (18%) aspects of
methods were also used for pain management in research.
children and adolescents aged 4 to 17 years, includ-
ing massage (385,000 individuals), meditation (4 Research Themes: Overarching pain-research
million), and yoga (4.5 million). themes in 2011 included pain mechanisms (42%),
basic-to-clinical (11%), disparities (10%), training
Characteristics and Type of Research: A systematic and education (10%), tools and instruments (8%),
review by the Agency for Healthcare Research and and surveillance and human trials (5%). Among
Quality found increased evidence that nondrug the topics of studies related to disparities were
approaches such as acupuncture, hypnosis, mas- health and access to care (10%); sex and gender
sage, mindfulness meditation, spinal manipulation, (12%); women’s and minority health (14%); sub-
tai chi, and yoga may help manage some painful stance use and abuse/addiction (19%); and specific
conditions. In some instances, such approaches pro- patient populations, such as elderly, end-of-life, dis-
abled, and military (45%).
Somnath Pal, BS (Pharm), MBA, PhD
Professor of Pharmacy Administration The content in this article is for informational purposes only.
The content is not intended to be a substitute for professional
College of Pharmacy & Health Sciences, St. John’s University advice. Reliance on any information provided in this article is
Jamaica, New York 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 Rheumatoid Arthritis
immune system’s inability to differentiate true foreign Although the cause of autoimmune and inflammatory
invaders. Therefore, the immune system mistakes parts diseases remains unknown, there are more than 80
of the body as threats and releases autoantibodies to clinical diseases that originate from an autoimmune
destroy the healthy cells. Although the cause for these response.3 The variety of diseases stems from the fact
disease states remains a mystery, medications and new that autoimmune disorders can affect any tissue or
therapeutic guidelines have emerged over time to com- organ in the body. Hence, the range of symptoms
bat these conditions. between each disease state can differ, with some being
Rheumatoid arthritis (RA), for instance, is one of mild and manageable while others are debilitating and
the most prevalent autoimmune disorders in the U.S. life-threatening. An example of this is the common
Although there is currently no cure for this disease, the condition RA, an autoimmune and inflammatory dis-
goal is to achieve a state of remission in which symp- ease in which the immune system attacks healthy cells,
toms are less likely to occur. Adalimumab (Humira), causing inflammation mainly in the joints of the body.4
introduced in 2002, was one of the many common The synovium, the tissue around the joint that pro-
therapies used to reduce signs and symptoms of RA.2 duces fluid allowing for smooth movement, is espe-
Despite providing relief to a large number of patients cially damaged, and the inflamed area makes the joint
over the years, there were consistent barriers that pre- sore and painful, causing difficult movement.5,6 The
vented individuals from accessing appropriate care.
Amanda Ye, RPh, PharmD
The FDA recently approved the first interchange- Medical Director–Health Professional Digital Education
able biosimilar to adalimumab, creating a major 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 (Humira). TABLE 1 shows all of the available FDA-
hands, knees, and wrists, but in more severe cases, this approved DMARDs for the treatment of RA.6,8
form of arthritis can also affect other parts of the body,
such as the lungs, eyes, and heart.5,6 Internal organs Adalimumab
that are affected become subject to persistent tissue Adalimumab is a registered trademark of AbbVie Bio-
damage, and RA can cause chronic pain or severe technology Ltd.9 Adalimumab is a tumor necrosis fac-
deformities. tor (TNF) blocker indicated for an array of conditions,
In the U.S., approximately 1.3 million patients such as moderate-to-severe RA, juvenile idiopathic
suffer from RA.7 While the number of cases continues arthritis, psoriatic arthritis, ankylosing spondylitis,
to surge, the total healthcare costs increase as well.7 Crohn’s disease, ulcerative colitis, plaque psoriasis,
The objective of ensuring that all patients have afford- hidradenitis supprativa, and uveitis.2 Its mechanism of
able access to treatment that can relieve their symp- action revolves around TNF, a naturally occurring
toms and improve their quality of life remains unmet. cytokine involved in normal inflammatory and
In most cases, the treatment goal, at a minimum, is to immune responses.2 Elevated levels of TNF are seen in
reduce inflammation and swelling while improving many autoimmune and inflammatory diseases and play
joint function. However, the end result that clinicians a role in pathological inflammation and joint destruc-
hope for is to slow the progression of the disease and tion.2 Adalimumab binds to TNF-alpha and blocks its
reduce further damage to the affected areas.6 interaction with TNF receptors on the surface of p55
and p75 cells.2 Specifically, for RA, adalimumab works
Management of RA by inhibiting the progression of structural damage and
Currently, there are three main classes of therapeu- improving physical function in adult patients. It can be
tic options available to treat RA: nonsteroidal used alone or in combination with a nonbiologic
anti-inflammatory agents (NSAIDs), corticosteroids, DMARD.2 Adalimumab is administered as an SC
and disease-modifying antirheumatic drugs injection, and the dose varies depending on the patient’s
(DMARDs).5,6 NSAIDs and corticosteroids are used condition, weight, and age. The most common adverse
to relieve pain and help mitigate inflammation at effects associated with adalimumab are injection-site
the site of injury. Side effects most commonly seen reactions, infections, headache, and rash.2
with the use of NSAIDs are stomach and kidney
damage. For patients who have localized gastric Adalimumab-adbm
side-effect concerns, cyclooxygenase 2 (COX-2) On October 15, 2021, the FDA approved the first
anti-inflammatory agents are seen as an alternative. interchangeable biosimilar to adalimumab, called
These agents restrain COX-2 enzyme and decrease adalimumab-adbm (Cyltezo). A biosimilar is a bio-
the number of prostaglandins.5 In doing so, pros- logical product that carries no clinical difference from
taglandins that are protective of the stomach and the already-approved medication but includes similar
kidney remain, and inflammation is reduced. Mean- components.10 The idea behind creating interchange-
while, low-dose corticosteroids can be utilized to able biosimilars is to offer products that can be substi-
decrease the amount of inflammation and suppress tuted for the reference product without the worry of a
flares by regulating the autoimmune system.4 change in clinical efficacy. Adalimumab-adbm was
DMARDs are a major class of drugs that halt the originally approved in August 2017 for the treatment
progression of disease by altering the immune system. of multiple chronic inflammatory diseases.11 However,
There are two categories in this class: traditional in October 2021, the FDA granted its approval through
DMARDs and biologics. The severity of the ailment, the supplemental Biologics License Application to
side effects, and patient preferences all play a role in Boehringer Ingelheim.9 The new biosimilar falls within
medicine selection. While traditional DMARDs have its mission’s intention by providing an alternative ther-
been used extensively throughout treatment, biolog- apeutic option to help with many chronic inflammatory
ics are becoming increasingly popular. Biologics are conditions. Both products share the same clinical
produced using recombinant DNA and prevent or results, including expected boxed warnings. The
reduce inflammation in the damaged sites.8 They approval of these interchangeable biosimilars creates
attack more specific inflammation-causing cells and, increased access to treatment options for patients with
therefore, are considered more effective.8 One exam- serious medical conditions.4
ple of a biologic drug used for RA is adalimumab Adalimumab-adbm is also a TNF inhibitor and is
19
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Different. Bold.

A first-in-class, oral fungicidal treatment for vulvovaginal


candidiasis (VVC), also known as vaginal yeast infection

BREXAFEMME, a non-azole,
works by inhibiting glucan synthase

1 day: 2 pills, 2 times

Proven to completely resolve the signs and


symptoms of VVC in most patients

Broad spectrum* antifungal activity against


all Candida species that cause VVC

*Based on in vitro studies. Clinical significance is unknown.

Indication
BREXAFEMME® is a triterpenoid antifungal indicated for the treatment of adult and postmenarchal
pediatric females with vulvovaginal candidiasis (VVC).

Important Safety Information


• BREXAFEMME is contraindicated during pregnancy and in patients with a history of hypersensitivity
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
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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 USE IN SPECIFIC POPULATIONS
BRIEF SUMMARY OF PRESCRIBING INFORMATION Pregnancy
This Brief Summary does not include all information needed to use BREXAFEMME Based on findings from animal studies, BREXAFEMME use is contraindicated
safely and effectively. Please visit www.BREXAFEMMEHCP.com for full prescribing in pregnancy because it may cause fetal harm. In pregnant rabbits, oral
information (PI). ibrexafungerp administered during organogenesis was associated with rare
malformations including absent forelimb(s), absent hindpaw, absent ear pinna,
INDICATIONS AND USAGE and thoracogastroschisis at dose exposures greater or equal to approximately
BREXAFEMME® is indicated for the treatment of adult and post-menarchal 5 times the human exposure at the RHD. Oral ibrexafungerp administered to
pediatric females with vulvovaginal candidiasis (VVC). pregnant rats during organogenesis was not associated with fetal toxicity or
Usage increased fetal malformations at a dose exposure approximately 5 times the
human exposure at the RHD. Available data on BREXAFEMME use in pregnant
If specimens for fungal culture are obtained prior to therapy, antifungal therapy women are insufficient to draw conclusions about any drug-associated risks of
may be instituted before the results of the cultures are known. However, once major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
these results become available, antifungal therapy should be adjusted accordingly.
There is a pregnancy safety study for BREXAFEMME. If BREXAFEMME is
DOSAGE AND ADMINISTRATION inadvertently administered during pregnancy or if pregnancy is detected within
Recommended Dosage 4 days after a patient receives BREXAFEMME, pregnant women exposed
to BREXAFEMME and healthcare providers should report pregnancies to
The recommended dosage of BREXAFEMME is 300 mg (two 150 mg tablets)
SCYNEXIS, Inc. at 1-888-982-SCYX (7299).
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). Lactation
BREXAFEMME may be taken with or without food. 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.
Dosage Modifications in Patients due to Concomitant Use of a Strong
Inhibitor of Cytochrome P450 Isoenzymes (CYP) 3A Females and Males of Reproductive Potential
With concomitant use of a strong CYP3A inhibitor, administer BREXAFEMME Based on animal data, BREXAFEMME may cause fetal harm when administered to
150 mg approximately 12 hours apart (i.e., in the morning and in the evening) for a pregnant female. Verify the pregnancy status in females of reproductive potential
one day. No dosage adjustment is warranted in patients with concomitant use of prior to initiating treatment with BREXAFEMME. Advise females of reproductive
a weak or moderate CYP3A inhibitor. potential to use effective contraception during treatment with BREXAFEMME and
for 4 days after the last dose.
Pregnancy Evaluation Prior to Initiating Treatment
Verify the pregnancy status in females of reproductive potential prior to initiating Pediatric Use
treatment with BREXAFEMME. The safety and effectiveness of BREXAFEMME for treatment of VVC have been
established in post-menarchal pediatric females. Use of BREXAFEMME in
CONTRAINDICATIONS post-menarchal pediatric patients is supported by evidence from adequate and
BREXAFEMME is contraindicated in pregnancy and in patients with hypersensitivity well-controlled studies of BREXAFEMME in adult non-pregnant women with
to ibrexafungerp. additional safety data from post-menarchal pediatric females.
WARNINGS AND PRECAUTIONS The safety and effectiveness of BREXAFEMME have not been established in
Based on findings from animal studies, BREXAFEMME use is contraindicated pre-menarchal pediatric females.
in pregnancy because it may cause fetal harm. In animal reproduction studies, Geriatric Use
ibrexafungerp administered orally to pregnant rabbits during organogenesis was Clinical studies with ibrexafungerp did not include sufficient numbers of
associated with fetal malformations including absent forelimb(s), absent hindpaw, subjects aged 65 and older to determine whether they respond differently from
absent ear pinna, and thoracogastroschisis at dose exposures greater or equal younger subjects. No clinically meaningful differences in the pharmacokinetics
to approximately 5 times the human exposure at the recommended human of ibrexafungerp were observed in geriatric patients compared to younger adults.
dose (RHD).
Prior to initiating treatment with BREXAFEMME, verify the pregnancy status in
Manufactured for:
females of reproductive potential. Advise females of reproductive potential to use
SCYNEXIS, Inc.
effective contraception during treatment with BREXAFEMME and for 4 days after
Jersey City, NJ 07302
the last dose.
BREXAFEMME® is a registered trademark of SCYNEXIS, Inc.
ADVERSE REACTIONS
Copyright © 2021
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).
Anticipating the First Adalimumab Biosimilar
Table 1

Available FDA-Approved DMARDs for the Treatment of RA (2021)


DMARD Classification FDA-Approved Medications

csDMARD Conventional synthetic Hydroxychloroquine


Leflunomide
Methotrexate
Sulfasalazine

tsDMARD Targeted synthetic Baricitinib


Tofacitinib
Upadacitinib

bDMARD Biologic Anti-TNF: Non-TNF:


Adalimumab Abatacept
Certolizumab pegol Rituximab
Etanercept Tocilizumab
Golimumab Sarliumab
Infliximab

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- able treatment options for complex, and often expen-
to-severe active RA, psoriatic arthritis, ankylosing sive, biologic reference products.”9
spondylitis, moderate-to-severe active Crohn’s disease,
moderate-to-severe active ulcerative colitis, moderate- VOLTAIRE-RA Trial
to-severe chronic plaque psoriasis, moderate-to-severe The VOLTAIRE-RA trial was completed in 2015,
active polyarticular juvenile idiopathic arthritis in with the objective to prove the clinical equivalence of
patients aged 2 years and older, and pediatric patients adalimumab-adbm and adalimumab. In a test group
aged 6 years and older with Crohn’s disease.10,12 The of 645 patients with clinically diagnosed active RA,
formulation is a single-dose, prefilled glass syringe with this study used a double-blind, randomized, parallel-
two available strengths: 40 mg/0.8 mL and 20 mg/0.4 group intervention approach.14 It was noted that the
mL.12 Adalimumab-adbm works in the same way as patients were stable on methotrexate and randomized
adalimumab; both bind specifically to TNF-alpha and to continue with either the biosimilar adalimumab-
block interactions with TNF receptors on the p55 and adbm or adalimumab within a 24-hour treatment
p75 cell surfaces and lyse in vitro–expressed surface time frame.14 The primary endpoint was illustrated
TNFs.12 Likewise, treatment can reduce the thickness through the percentage of patients achieving the
of the epidermis and cause infiltration of inflammatory American College of Rheumatology 20% response
cells.12 Infections, injection-site reactions, headache, criteria (ACR20) at Weeks 12 and 24.14 Efficacy,
and rash are all common side effects.11,12 safety, and immunogenicity were also observed up to
Adalimumab-adbm represents the first interchange- Week 58 of treatment.14
able monoclonal antibody. With its approval, the Results show that 67.0% (n = 324) of those who
FDA’s Purple Book, the official directory of all received adalimumab-adbm and 61.1% (n = 321) of
approved biosimilars and interchangeables, is those who received adalimumab achieved ACR20
updated.13 Adalimumab-adbm will not be available (90% CI 0.9-12.7).14 Meanwhile, at the 24th week,
until July 2023, but the therapeutic impact could be 69.0% and 64.5% (95% CI 3.4-12.5) were achieved,
staggering.9 Replacing benchmark products with bio- respectively.14 Changes in mean response rates for
similars could further ease the financial burden of ACR20 were similar when re-randomized at 24
patients. As the chairman of the Division of Dermatol- weeks.14 The significance of this evidence indicates a
ogy at Baylor University Medical Center exclaimed, positive outcome for the therapeutic equivalence of the
“As the first interchangeable biosimilar of adalim- two agents. Likewise, safety, tolerability, and immu-
umab, Cyltezo (adalimumab-adbm) represents an nogenicity were similar between the two treatment
important step toward bringing patients more afford- groups.
23
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Anticipating the First Adalimumab Biosimilar

VOLTAIRE-RAext Trial A double-blind, randomized, parallel intervention model


A phase IIIb VOLTAIRE-RAext trial, based on previ- was used in this study.17 There were 259 enrolled par-
ous studies, supported the basis of adalimumab-adbm ticipants between ages 18 and 80 years.17 The primary
and its indications for the treatment of RA. This study endpoint was demonstrated by the pharmacokinetics
was conducted for 48 weeks using an open, multicenter measurements of adalimumab over a dosing interval of
interventional approach.15 The sample size was 430 Weeks 30 to 32: area under the plasma concentration
adults with a diagnosis of moderate-to-severe RA who (AUC) and maximum observed concentration (Cmax).17
wished to continue treatment with adalimumab- Secondary endpoints were assessed through the effi-
adbm.15 These patients were extracted from their par- cacy, safety, and immunogenicity profiles, and other
ticipation in the VOLTAIRE-RA trial. The patients pharmacokinetic measurements, such as minimum
received a prefilled, 40-mg syringe of adalimumab- observed plasma concentration (Cmin) and time to
adbm and administered it every 2 weeks.15 The primary maximum observed plasma concentration (Tmax).17
endpoint was the number of patients with adverse drug The results supported the primary and secondary end-
reactions from the start of the trial to the end of the points. There were three endpoint-reporting groups:
10-week follow-up period.15 run-in period with adalimumab (loading dose on first
Results were divided into three groups: continuous day), treatment switching between adalimumab and
administration of adalimumab-adbm, conversion from adalimumab-adbm, and continued administration of
adalimumab reference product (RP) to adalimumab- adalimumab.17 Equivalence was estimated based on a
adbm, and continuous administration of adalimumab 90.2% CI.16 This interval corresponds to the AUC and
RP in the previous study.15 Among these groups, Cmax tests, and CI was calculated based on the ratio of
20.2% experienced ≥1 drug-related adverse effect, with switching treatments to continuous dosing.17 The results
a lower proportion of 17.6% in the group with the show that both the primary and secondary endpoints
switched therapy.15 Secondary endpoints were investi- were satisfied. Adalimumab-adbm was very similar to
gated to assess efficacy using disease activity score 28, adalimumab in terms of safety, efficacy, and immuno-
erythrocyte sedimentation rate, and achievement of the genicity. This study, along with previous studies, showed
ACR/European League Against Rheumatism that adalimumab-adbm is a biosimilar and adalimumab
response.15,16 Expansion of this study did not lead to is therapeutically equivalent.
significant new findings in terms of efficacy, safety, or The three trials elaborated here—VOLTAIRE-RA,
immunogenicity.15,16 VOLTAIRE-RAext, and VOLTAIRE-X—all demon-
strated supporting evidence for the efficacy and safety
profiles of adalimumab-adbm for RA patients. In addi-
The positive data from the VOLTAIRE-X tion, the clinical trials also attested to adalimumab-
phase III study demonstrated that adbm being an interchangeable biosimilar. However, it
is noted that there are other clinical trials reviewing
interchangeability was achieved: adalimumab-adbm’s role and effectiveness compared
Adalimumab-adbm was very similar to with adalimumab in other disease states, such as Crohn’s
(VOLTAIRE-CD).18
adalimumab in terms of safety,
efficacy, and immunogenicity. Conclusion
With positive evidence exhibited in various studies,
adalimumab-adbm is the first interchangeable mono-
VOLTAIRE-X Trial clonal antibody. This citrate-free adalimumab-adbm has
The positive data from the VOLTAIRE-X phase III study been proven to exude the same efficacy and safety as the
demonstrated that interchangeability was achieved. The original medication. The introduction of the first inter-
VOLTAIRE-X trial was designed to assess the pharma- changeable adalimumab biosimilar offers an alternative
cokinetic similarity between patients who regularly took and inexpensive option for many and could potentially
adalimumab and those who alternated between the bio- lead to other scientific breakthroughs.
similar adalimumab-adbm and adalimumab.11,16 The References available online at www.uspharmacist.com.
treatment groups were clinically diagnosed with moder- The content contained in this article is for informational purposes
ate-to-severe chronic plaque psoriasis and received 48 only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is
weeks of treatment with a 10-week follow-up period.17 solely at your own risk.

24
U.S. Pharmacist • March 2022 • www.uspharmacist.com
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
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
detrimental and can be debilitating. Based on the of life, functioning, and comfort.
2019 National Health Interview Survey, about one in Over the past 3 decades, the approach to pain and
five adults in the U.S. experiences pain on most days its management has been a key focus area.5 In the
or every day.1 Appropriate pain management has been 1990s, the inadequate assessment and treatment of
a growing concern since the rise of the opioid epi- pain was recognized as a health emergency and even-
demic. When prescription pharmacologic agents do tually labeled as “the 5th vital sign.” In the effort to
not alleviate their pain or are not easily accessible, improve pain control and in the wake of new phar-
patients seek alternative therapies. In 2011, chronic maceutical formulations, liberal opioid prescribing
pain was reported to have an annual economic bur- eventually led to a national opioid crisis. In response,
den of $560 billion to $635 billion, of which direct research and guidelines have aimed to identify alter-
healthcare costs comprised only $261 billion to $300 native pain-management modalities.5,6 Most recent
billion.2 guidelines and best-practice reports have recom-
The International Association for the Study of Pain mended individualized, multimodal, and multidisci-
(IASP) defines pain as “an unpleasant sensory and plinary pain management encompassing medications,
emotional experience associated with, or resembling
Tara Smith, PharmD Candidate 2023
that associated with, actual or potential tissue dam-
age.”3 As the definition implies, pain is relative to the Brandon Morel, PharmD Candidate 2023

individual afflicted; the optimal treatment depends Elina Delgado, PharmD, BCPS
Assistant Professor of Pharmacy
on the pain classification. There are four common
William Carey University School of Pharmacy
pain-classification schemes based on the pathophysi- Department of Pharmacy Practice
ologic mechanism (nociceptive or neuropathic), dura- 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, ing methyl groups to the formation of myelin sheaths
behavioral-health approaches, and complementary around neurons. Animal models have exhibited sev-
and integrative medicine. One limitation of these eral mechanisms through which vitamin B12 is pro-
documents, however, is the lack of discussion of the posed to alleviate neuropathic pain in humans (TABLE
role that vitamins and minerals may play in pain man- 1). A recent systematic review of 325 articles found
agement. According to a survey conducted in 2002, that the strongest areas of research on the use of vita-
more than one-third of Americans use complementary min B12 in treating peripheral polyneuropathy are
and alternative medicine.7 Given that pharmacists are postherpetic neuralgia (PHN), diabetic neuropathy,
often the only healthcare professionals available to and alcohol-related neuropathy.9 This study found no
answer consumers’ questions about OTC medica- articles that disproved the utility of vitamin B12 for
tions, it is important to understand the possible role neuropathic pain.
of these agents in pain management.
Diabetic Neuropathy: Hyperglycemia (and hyperlip-
NEUROPATHIC PAIN idemia) cause the increased production of reactive
The IASP defines neuropathic pain as “pain caused oxygen species (ROS), advanced glycation end prod-
by a lesion or disease of the somatosensory nervous ucts, and insoluble sugars such as sorbitol.11 All of
system.”8 This condition encompasses a number of these end products induce cellular damage and a pro-
etiologies, including diabetes, cancer, chronic alcohol inflammatory environment, particularly affecting the
consumption, herpes zoster infection, traumatic nerve peripheral neurons. Although there is a positive trend
injury, drug toxicity, and central processes including in the use of vitamin B12 for diabetic neuropathy,
cerebrovascular accidents, spinal cord injuries, and evidence is insufficient because most of the research
multiple sclerosis.9 Broadly, current pharmacologic trials lacked adequate follow-up periods or sample
treatment strategies include serotonin-norepinephrine sizes and did not have a placebo arm for comparison.
reuptake inhibitors such as venlafaxine and dulox- Additionally, many of these studies focused on the
etine, tricyclic antidepressants, and the anticonvul- adjunctive use of vitamin B12 with gabapentinoids and
sants gabapentin and pregabalin as first-line thera- other B vitamins, thereby limiting the assessment of
pies. However, given the complex nature of vitamin B12 on its own.
neuropathic pain, its spectrum of symptoms, and its
prevalence in up to 10% of the population (according PHN: PHN is a lingering pain that persists beyond 4
to validated questionnaires), there is a growing months following a rash induced by herpes zoster.12
demand for new treatments.9 Research into vitamin Inflammation caused by the virus triggers fibrosis of
supplementation—with or without a preexisting defi- nerves and spontaneous activity capable of maintain-
ciency—has been gaining traction. ing pain in the absence of ongoing tissue damage. Five
randomized, controlled trials included in a systematic
Vitamin B12 review found that vitamin B12 was helpful—whether
In humans, vitamin B12 functions mainly as a cofactor as monotherapy or adjunctively—for PHN regardless
for the methyltransferase enzyme known as methio- of where the pain manifested.9
nine synthase.10 This allows for the formation of
methionine, which is later converted to S-adenosyl Alcohol-Related Neuropathy: Vitamin deficiencies
methionine (SAMe). SAMe is responsible for donat- resulting from chronic alcoholism lead to complica-
26
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Vitamins and Minerals for Pain Management

tions in the demyelination of peripheral neurons and neurotoxic chemotherapy found no difference in
to slow nerve conduction caused by alcohol-induced CIPN incidence regardless of whether vitamin E was
neurotoxicity.13 Symptoms are usually symmetrical administered.14 The researchers found a slight posi-
and distal, including paresthesia, cramps, weakness, tive effect on neuropathy duration in patients who
and pain. Vitamin supplementation in this case would took 400 mg of vitamin E twice daily; however, they
help reverse those complications. It has been found noted that the dose may have been too low to achieve
that the addition of vitamin B12 may provide a ben- a statistically significant benefit. A randomized trial
efit in pain improvement.9 that examined vitamin E supplementation versus pla-
cebo as an adjunct to standard pain management for
Zinc diabetic neuropathy concluded that vitamin E was
The pathogenesis of chemotherapy-induced periph- effective in reducing some pain, but no improvement
eral neuropathy (CIPN) is not well understood, but was seen in overall quality-of-life scores.19
the mechanism appears to involve axonal degradation
from chronic exposure to chemotherapeutic agents.14 CHRONIC PAIN
One possible cause may be an increase in ROS from According to the IASP, chronic pain is “pain that
the chemotherapeutic agents, so researchers are inves- persists or recurs for longer than 3 months.”20 The
tigating the use of antioxidants to treat or prevent principles informing the treatment of neuropathic
CIPN. The questionnaire-based Diet, Exercise, Life- pain and chronic pain are subject to overlapping, as
style, and Cancer Prognosis (DELCaP) study found a forms of neuropathic pain can become chronic afflic-
correlation between multivitamin use and reduced tions. The preferred first-line treatment options are
incidence of CIPN in stage I–III breast cancer patients nonpharmacologic therapies (diet, exercise, and
who received doxorubicin, cyclophosphamide, and behavioral) and nonopioid prescription medications;
paclitaxel, but there was no statistically significant however, given the nature of chronic pain, many of
risk reduction with individual supplement use.15 A the affected patients have been prescribed opioids.21
study in mouse models with paclitaxel-induced CIPN Because chronic pain is the leading cause of disability
demonstrated dose-dependent reduction of local allo- in U.S. adults, there has been a significant push for
dynia following intraplantar zinc administration for alternative treatments, including research into vita-
up to 4 days.16 This study found that exogenous zinc mins and minerals.22
inhibited TRPV1 (transient receptor potential cation
channel subfamily V member 1; a nonselective cation Vitamin C
transport protein), thereby preventing paclitaxel- Vitamin C deficiency (plasma concentrations <11
induced sensitization of peripheral nociceptors. The mcmol/L) manifests as scurvy-related myalgia and
Pathways study found that women who initiated zinc arthralgia in the knees, wrists, and ankles due to
and other antioxidants after diagnosis were two to bleeding within these areas.23 Deficiency of this vita-
three times more likely to report CIPN at 6-month min is rare in developed countries (<6% in the U.S.),
follow-up.17 Further research is needed on the use of but the populations primarily affected are hospital-
zinc for CIPN treatment before any changes to recom- ized elderly patients, cancer patients, and critically ill
mendations are made. patients. The use of vitamin C has been shown to be
effective in several aspects of pain management.
Vitamin E
Vitamin E, the primary fat-soluble antioxidant, is Complex Regional Pain Syndrome (CRPS): Many ran-
being studied relative to the role of ROS in neuro- domized, controlled trials have demonstrated that
pathic pain. A 2006 study using rat models concluded vitamin C supplementation reduced the incidence of
that vitamin E administration—as either a high-dose CRPS in wrist- and ankle-surgery patients, with the
single injection (0.1, 1, or 5 g/kg with no equivalent most efficacious dosage being 0.5 g or more per
human dose owing to variations in metabolic rates day.23,24 The same dosage was also administered pro-
between species) or repetitive daily low-dose injec- phylactically for osteoarthritis in joint-replacement
tions (50 or 100 mg/kg, equating to 3 g in a 60-kg patients, who were then found to have no incidence
human)—reduced behaviors associated with mechan- of CRPS.
ical allodynia.18 Similar to the results of the DELCaP
study, a phase III clinical trial in patients receiving Rheumatoid Arthritis and Osteoarthritis: It has been

27
U.S. Pharmacist • March 2022 • www.uspharmacist.com
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 No cases of active tuberculosis (TB) were reported in clinical trials


OPZELURA is indicated for the topical short-term and non-continuous with OPZELURA. Cases of active TB were reported in clinical trials of
chronic treatment of mild to moderate atopic dermatitis in oral Janus kinase inhibitors used to treat inflammatory conditions.
non-immunocompromised patients 12 years of age and older Consider evaluating patients for latent and active TB infection prior to
whose disease is not adequately controlled with topical prescription administration of OPZELURA. During OPZELURA use, monitor patients
therapies or when those therapies are not advisable. for the development of signs and symptoms of TB.
Limitation of Use: Viral reactivation, including cases of herpes virus reactivation (e.g.,
Use of OPZELURA in combination with therapeutic biologics, other herpes zoster), were reported in clinical trials with Janus kinase
JAK inhibitors or potent immunosuppressants such as azathioprine or inhibitors used to treat inflammatory conditions including OPZELURA.
cyclosporine is not recommended. If a patient develops herpes zoster, consider interrupting OPZELURA
treatment until the episode resolves.
IMPORTANT SAFETY INFORMATION
Hepatitis B viral load (HBV-DNA titer) increases, with or without
SERIOUS INFECTIONS associated elevations in alanine aminotransferase and aspartate
Patients treated with oral Janus kinase inhibitors for inflammatory aminotransferase, have been reported in patients with chronic
conditions are at risk for developing serious infections that may lead HBV infections taking oral ruxolitinib. OPZELURA initiation is not
to hospitalization or death. Reported infections include: recommended in patients with active hepatitis B or hepatitis C.
• Active tuberculosis, which may present with pulmonary or MORTALITY
extrapulmonary disease. Higher rate of all-cause mortality, including sudden cardiovascular
• Invasive fungal infections, including candidiasis and pneumocystosis. death, has been observed in patients treated with oral Janus kinase
• Bacterial, viral, and other infections due to opportunistic pathogens. inhibitors for inflammatory conditions.
Avoid use of OPZELURA in patients with anactive, serious infection, MALIGNANCIES
including localized infections. If a serious infection develops, interrupt Lymphoma and other malignancies have been observed in patients
OPZELURA until the infection is controlled. Carefully consider the treated with Janus kinase inhibitors for inflammatory conditions.
benefits and risks of treatment prior to initiating OPZELURA in Patients who are current or past smokers are at additional increased risk.
patients with chronic or recurrent infection. Closely monitor patients Non-melanoma skin cancers, including basal cell and squamous cell
for the development of signs and symptoms of infection during and carcinoma, have occurred in patients treated with OPZELURA. Perform
after treatment with OPZELURA. 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™ .
Eligible
Eligible
patients
patients
with with
commercial
commercial
insurance
insurance
may may Eligibility
† †
Eligibility
required.required.
IndividualIndividual
savings limited
savingstolimited to
$2,076.50/tube,
$2,076.50/tube,
$10,000 per$10,000
year. For
peruse
year.
only
Forwith
use only with
PAYPAY
AS LITTLE
AS LITTLE
AS AS commercial commercial
insurance. insurance.
The card may
The card
not be
may not be

1010
used if patient
used ifispatient
enrolledisin
enrolled
a government-funded
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.
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no clear no clear relationship exposed to
wasrelationship exposed
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and healthcareand healthcare
providers should
providers should
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and thrombotic
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events. events. report OPZELURA
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calling 855-4MEDINFO
by calling 855-4MEDINFO
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should be should
used be withused
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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
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ar Thrombocytopenia,
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and neutropenia
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for OPZELURA™
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risk. BSA, body
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l Reference:
Reference:
OPZELURA™
OPZELURA™
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cream. Prescribing
cream. Prescribing
Information.
Information.
Incyte Corporation,
Incyte Corporation,
2021. 2021.
m
ng
OPZELURAOPZELURA
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© 2021, Incyte
© 2021, Corporation.
Incyte Corporation.
MAT-ONA-00177
MAT-ONA-00177
09/21 09/21
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
OPZELURA™ (ruxolitinib) cream, for topical use (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
Brief Summary of FULL PRESCRIBING INFORMATION zoster, consider interrupting OPZELURA treatment until the episode resolves.
INDICATIONS AND USAGE: OPZELURA is indicated for the topical short-term Hepatitis B and C: The impact of Janus kinase inhibitors used to treat inflammatory
and non-continuous chronic treatment of mild to moderate atopic dermatitis in conditions including OPZELURA on chronic viral hepatitis reactivation is unknown.
non-immunocompromised patients 12 years of age and older whose disease is Patients with a history of hepatitis B or C infection were excluded from clinical trials.
not adequately controlled with topical prescription therapies or when those therapies
are not advisable. Hepatitis B viral load (HBV-DNA titer) increases, with or without associated
elevations in alanine aminotransferase and aspartate aminotransferase, have been
Limitation of Use: Use of OPZELURA in combination with therapeutic biologics, other reported in patients with chronic HBV infections taking oral ruxolitinib. OPZELURA
JAK inhibitors or potent immunosuppressants such as azathioprine or cyclosporine initiation is not recommended in patients with active hepatitis B or hepatitis C.
is not recommended.
Mortality: A higher rate of all-cause mortality, including sudden cardiovascular
WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR death was observed in clinical trials of oral Janus kinase inhibitors used to treat
ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS inflammatory conditions. Consider the benefits and risks for the individual patient
prior to initiating or continuing therapy with OPZELURA.
SERIOUS INFECTIONS
Patients treated with oral Janus kinase inhibitors for inflammatory conditions Malignancy and Lymphoproliferative Disorders: Malignancies, including
are at risk for developing serious infections that may lead to hospitalization or lymphomas, were observed in clinical trials of oral Janus kinase inhibitors used to
death [see Warnings and Precautions and Adverse Reactions]. treat inflammatory conditions. Patients who are current or past smokers are at
additional increased risk. Consider the benefits and risks for the individual patient
Reported infections include: prior to initiating or continuing therapy with OPZELURA, particularly in patients with
• Active tuberculosis, which may present with pulmonary or a known malignancy (other than successfully treated non-melanoma skin cancers),
extrapulmonary disease. patients who develop a malignancy, and patients who are current or past smokers.
• Invasive fungal infections, including candidiasis and pneumocystosis. Non-melanoma Skin Cancers: Non-melanoma skin cancers including basal cell and
• Bacterial, viral, and other infections due to opportunistic pathogens. squamous cell carcinoma have occurred in patients treated with OPZELURA. Perform
Avoid use of OPZELURA in patients with an active, serious infection, periodic skin examinations during OPZELURA treatment and following treatment
including localized infections. If a serious infection develops, interrupt as appropriate.
OPZELURA until the infection is controlled. Major Adverse Cardiovascular Events (MACE): Major adverse cardiovascular
The risks and benefits of treatment with OPZELURA should be carefully events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI),
considered prior to initiating therapy in patients with chronic or and non-fatal stroke were observed in clinical trials of Janus kinase inhibitors used
recurrent infection. to treat inflammatory conditions. Consider the benefits and risks for the individual
patient prior to initiating or continuing therapy with OPZELURA particularly in
Patients should be closely monitored for the development of signs and patients who are current or past smokers and patients with other cardiovascular risk
symptoms of infection during and after treatment with OPZELURA [see factors. Patients should be informed about the symptoms of serious cardiovascular
Warnings and Precautions]. events and the steps to take if these symptoms occur.
MORTALITY Thrombosis: Thrombosis, including deep venous thrombosis (DVT), pulmonary
Higher rate of all-cause mortality, including sudden cardiovascular death embolism (PE) and arterial thrombosis, has been observed at an increased incidence
have been observed in patients treated with oral Janus kinase inhibitors in patients treated with oral Janus kinase inhibitors for inflammatory conditions
for inflammatory conditions [see Warnings and Precautions]. compared to patients treated with placebo. Many of these adverse reactions were
MALIGNANCIES serious and some resulted in death. Thromboembolic events were observed in
Lymphoma and other malignancies have been observed in patients treated clinical trials with OPZELURA. There was no clear relationship between platelet
with Janus kinase inhibitors for inflammatory conditions [see Warnings count elevations and thrombotic events. OPZELURA should be used with caution in
and Precautions]. patients who may be at increased risk of thrombosis.

MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) Thrombocytopenia, Anemia and Neutropenia: Thrombocytopenia, anemia and
Higher rate of MACE (including cardiovascular death, myocardial infarction, neutropenia were reported in the clinical trials with OPZELURA. Consider the
and stroke) has been observed in patients treated with Janus kinase benefits and risks for individual patients who have a known history of these events
inhibitors for inflammatory conditions [see Warnings and Precautions]. prior to initiating therapy with OPZELURA. Perform CBC monitoring as clinically
indicated. If signs and/or symptoms of clinically significant thrombocytopenia,
THROMBOSIS anemia, and neutropenia occur, patients should discontinue OPZELURA.
Thrombosis, including deep venous thrombosis, pulmonary embolism, and
arterial thrombosis has been observed at an increased incidence in patients Lipid Elevations: Treatment with oral ruxolitinib has been associated with increases
treated with oral Janus kinase inhibitors for inflammatory conditions in lipid parameters including total cholesterol, low-density lipoprotein (LDL)
compared to placebo. Many of these adverse reactions were serious and cholesterol, and triglycerides.
some resulted in death. Patients with symptoms of thrombosis should be ADVERSE REACTIONS
promptly evaluated [see Warnings and Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying
WARNINGS AND PRECAUTIONS 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
Serious Infections: Serious and sometimes fatal infections due to bacterial, rates observed in practice. In two double-blind, vehicle-controlled clinical trials (Trials 1
mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been and 2), 499 subjects 12 years of age and older with atopic dermatitis were treated with
reported in patients receiving oral janus kinase inhibitors. Serious lower respiratory OPZELURA twice daily for 8 weeks. In the OPZELURA group, 62% of subjects were
tract infections were reported in the clinical development program with topical females, and 71% of subjects were White, 23% were Black, and 4% were Asian. The
ruxolitinib. Avoid use of OPZELURA in patients with an active, serious infection, adverse reactions reported by ≥ 1% of OPZELURA-treated subjects and at a greater
including localized infections. Consider the risks and benefits of treatment prior to incidence than in the vehicle arm through week 8 are as follows for OPZELURA
initiating OPZELURA in patients: with chronic or recurrent infection; with a history of (N=499) vs Vehicle (N=250), respectively: Subjects with any treatment emergent
a serious or an opportunistic infection; who have been exposed to tuberculosis; who adverse event (TEAE) 132 (27%) vs 83 (33%), Nasopharyngitis 13 (3%) vs 2 (1%),
have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or Bronchitis 4 (1%) vs 0 (0%), Ear infection 4 (1%) vs 0 (0%), Eosinophil count increased
with underlying conditions that may predispose them to infection. Closely monitor 4 (1%) vs 0 (0%), Urticaria 4 (1%) vs 0 (0%), Diarrhea 3 (1%) vs 1 (<1%), Folliculitis
patients for the development of signs and symptoms of infection during and after 3 (1%) vs 0 (0%), Tonsillitis 3 (1%) vs 0 (0%), and Rhinorrhea 3 (1%) vs 1 (<1%).
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.
Adverse reactions that occurred in Trials 1 and 2 in < 1% of subjects in the OPZELURA and other bone measures [e.g., bone mineral content, peripheral quantitative
group and none in the vehicle group were: neutropenia, allergic conjunctivitis, pyrexia, computed tomography, and x-ray analysis] occurred at doses ≥ 5 mg/kg/day. When
seasonal allergy, herpes zoster, otitis externa, Staphylococcal infection, and administered starting at postnatal day 21 (the equivalent of a human 2-3 years of
acneiform dermatitis. 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
DRUG INTERACTIONS
more severely affected than females in all age groups, and effects were generally
Drug interaction studies with OPZELURA have not been conducted. Ruxolitinib is more severe when administration was initiated earlier in the postnatal period. These
known to be a substrate for cytochrome P450 3A4 (CYP3A4). Inhibitors of CYP3A4 findings were observed at systemic exposures that are at least 40% the MRHD
may increase ruxolitinib systemic concentrations whereas inducers of CYP3A4 may clinical systemic exposure.
decrease ruxolitinib systemic concentrations.
Geriatric Use: Of the 1249 total subjects with atopic dermatitis in clinical trials with
Strong Inhibitors of CYP3A4: Avoid concomitant use of OPZELURA with strong OPZELURA, 115 were 65 years of age and older. No clinically meaningful differences
inhibitors of CYP3A4 as there is a potential to increase the systemic exposure of in safety or effectiveness were observed between patients less than 65 years and
ruxolitinib and could increase the risk of OPZELURA adverse reactions. patients 65 years and older.
USE IN SPECIFIC POPULATIONS PATIENT COUNSELING INFORMATION
Pregnancy Advise the patient or caregivers to read the FDA-approved patient labeling
Pregnancy Exposure Registry: There will be a pregnancy registry that monitors (Medication Guide).
pregnancy outcomes in pregnant persons exposed to OPZELURA during pregnancy. Infections: Inform patients that they may be at increased risk for developing
Pregnant persons exposed to OPZELURA and healthcare providers should report infections, including serious infections, when taking Janus kinase inhibitors. Instruct
OPZELURA exposure by calling 1-855-463-3463. patients to tell their healthcare provider if they develop any signs or symptoms of an
Risk Summary: Available data from pregnancies reported in clinical trials with infection. Advise patients that Janus kinase inhibitors increase the risk of herpes
OPZELURA are not sufficient to evaluate a drug-associated risk for major birth zoster, and some cases can be serious.
defects, miscarriage, or other adverse maternal or fetal outcomes. In animal Malignancies and Lymphoproliferative Disorders: Inform patients that Janus kinase
reproduction studies, oral administration of ruxolitinib to pregnant rats and rabbits inhibitors may increase the risk for developing lymphomas and other malignancies
during the period of organogenesis resulted in adverse developmental outcomes at including skin cancer. Instruct patients to inform their health care provider if they
doses associated with maternal toxicity. have ever had any type of cancer. Inform patients that periodic skin examinations
The background risks of major birth defects and miscarriage for the indicated should be performed while using OPZELURA.
populations are unknown. All pregnancies carry some risk of birth defects, loss, or Major Adverse Cardiovascular Events: Advise patients that events of major adverse
other adverse outcomes. The background risk in the U.S. general population of major cardiovascular events (MACE) including non-fatal myocardial infarction, non-fatal
birth defects and miscarriage is 2-4% and 15-20%, respectively. stroke, and cardiovascular death, have been reported in clinical studies with Janus
Data kinase inhibitors used to treat inflammatory conditions. Instruct all patients,
especially current or past smokers or patients with other cardiovascular risk factors,
Animal Data: Ruxolitinib was administered orally to pregnant rats or rabbits during
to be alert for the development of signs and symptoms of cardiovascular events.
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 Thrombosis: Advise patients that events of DVT and PE have been reported in clinical
dose. A decrease in fetal weight of approximately 9% was noted in rats at the studies with Janus kinase inhibitors used to treat inflammatory conditions. Instruct
highest and maternally toxic dose of 60 mg/kg/day. This dose resulted in systemic patients to tell their healthcare provider if they develop any signs or symptoms of
exposure approximately 22 times the clinical systemic exposure at the maximum a DVT or PE.
recommended human dose (MRHD); the clinical systemic exposure from ruxolitinib
Thrombocytopenia, Anemia and Neutropenia: Advise patients of the risk of
cream, 1.5% applied twice daily to 25-40% body surface area is used for calculation
thrombocytopenia, anemia, and neutropenia with OPZELURA. Instruct patients to tell
of multiples of human exposure. In rabbits, lower fetal weights of approximately 8%
their healthcare provider if they develop any signs or symptoms of thrombocytopenia,
and increased late resorptions were noted at the highest and maternally toxic dose
anemia or neutropenia [see Warnings and Precautions].
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, Administration Instructions: Advise patients or caregivers that OPZELURA is for
pregnant animals were dosed with ruxolitinib from implantation through lactation topical use only [see Dosage and Administration].
at doses up to 30 mg/kg/day. There were no drug-related adverse effects on
Advise patients to limit treatment to 60 grams per week.
embryofetal survival, postnatal growth, development parameters or offspring
reproductive function at the highest dose evaluated (3.1 times the MRHD clinical Pregnancy: Inform patients to report their pregnancy to Incyte Corporation
systemic exposure). at 1-855-463-3463 [see Use in Specific Populations].
Lactation Lactation: Advise a patient not to breastfeed during treatment with OPZELURA
and for four weeks after the last dose [see Use in Specific Populations].
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
Manufactured for:
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 Incyte Corporation
neutropenia, advise women not to breastfeed during treatment with OPZELURA 1801 Augustine Cut-off
and for approximately four weeks after the last dose (approximately 5 elimination Wilmington, DE 19803
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 OPZELURA is a trademark of Incyte. All rights reserved.
collected for up to 24 hours. The AUC for total radioactivity in milk was approximately U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481;
13 times the maternal plasma AUC. Additional analysis showed the presence of 9079912; 9974790; 10639310; 10610530; 10758543; 10869870
ruxolitinib and several of its metabolites in milk, all at levels higher than those in © 2021 Incyte Corporation. All rights reserved
maternal plasma. Issued: September 2021 PLR-ONA-00004
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
Vitamins and Minerals for Pain Management

noted that patients with rheumatoid arthritis present musculoskeletal and orthopedic pain. In these condi-
with average vitamin C levels less than half the level tions, higher reported levels of pain and opioid use
in healthy controls.23 One study reported a total occurred in patients with deficient circulating levels
reduction of pain in a single rheumatoid arthritis of vitamin D.25,26 In addition to its bone-regulation
patient following twice-weekly infusions of high-dose and hormonal effects, vitamin D regulates the inflam-
vitamin C, and a study in osteoarthritis patients given matory responses mediated by the adaptive immune
1 g of oral calcium ascorbate per day found that the system.26 Similar to vitamin C supplementation,
reduction in pain was less than half of that reported administration of vitamin D in these cases prevents
for nonsteroidal anti-inflammatory drugs.23 These pain associated with a deficiency of the vitamin (<30
data may also suggest more efficacy with parenteral nmol/L) and has little effect in patients with adequate
versus oral administration in patients with arthritis. levels. Current evidence is insufficient to change rec-
ommendations regarding vitamin D supplementation,
Orthopedic Pain: Vitamin C exhibits regulatory effects and more research should be conducted.
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 Deficiency of vitamin C is rare
vitamin C per day for 2 weeks. However, the pain
reduction was not greater than that observed with
in developed countries, but
typical calcitonin treatment for the disease. the populations primarily affected
PHN: Serum levels of vitamin C are much lower in
are hospitalized elderly patients,
shingles patients than in healthy persons, and this has cancer patients, and critically
been found to increase the risk of PHN.23 Random-
ized, controlled trials have shown a reduced incidence ill patients.
of PHN and decreased long-term pain following par-
enteral vitamin C administration. Magnesium
Magnesium is an antagonist of N-methyl-d-aspartate
Cancer Pain: Cancer patients typically have increased voltage-gated receptors that exhibits antinociceptive
vitamin C requirements and lower circulating levels effects by preventing and attenuating hypersensitivity
than healthy individuals.23 Questionnaire-based stud- to pain.27,28 It is also known to reduce neuromuscular
ies examining quality of life showed significant excitability by antagonizing the effects of calcium on
improvements (>30%) due to decreased pain follow- acetylcholine release.21 Further research must be con-
ing vitamin C administered orally or parenterally. ducted before changes to recommendations should
be considered, but promising trends have been noted
Decreased Opioid Requirements: Patients receiving in the use of magnesium for the following conditions.
opioids have been found to exhibit decreased with-
drawal symptoms with coadministration of vitamin Perioperative Pain: In a systematic review of 27 ran-
C.23 Several studies have also observed that these domized, controlled trials, data trends suggested that
patients required fewer morphine equivalents of opi- systemic administration of magnesium during general
oids compared with patients who did not receive vita- anesthesia may lessen postoperative pain without
min C coadministration. increasing the risk of adverse effects.27 The usual
regimen is a loading dose of 30 mg/kg to 50 mg/kg
Vitamin D followed by a maintenance dose of 6 mg/kg to 20 mg/
Vitamin D deficiency is associated with several eti- kg per hour. Magnesium has also been associated with
ologies of chronic pain, including type 1 diabetes, increased hemodynamic stability during surgery as
hypertension, metabolic syndrome, ischemic heart well as reduced anesthetic and opioid use. It has been
disease, falls, broken bones, depression, and cancer.25 found to be largely ineffective for attenuating pain
More recent studies have also linked vitamin D defi- associated with cesarean delivery, hysterectomy,
ciency to sickle cell disease, aromatase inhibitor– inguinal hernia repair, and varicose vein surgery;
induced arthralgia, headache, PHN, pain in patients however, it is worth noting that the studies reporting
taking high doses of opioids, and various types of these results used a single dose rather than a loading
32
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Vitamins and Minerals for Pain Management

dose plus continuous infusion.28 CIPN: A 2004 study reported that infusions of cal-
cium and magnesium (Ca2+/Mg2+) before and after
Migraine: Hypomagnesemia has been observed in administration of oxaliplatin could prevent the
patients who develop migraines, but the etiology of development of CIPN.27,28 Metanalyses and system-
this condition is not fully understood.27 Magnesium atic reviews have yielded inconsistent results, and
supplementation has yielded inconsistent results in although their effectiveness remains inconclusive,
preventing and treating migraines. This may be due these infusions have been adopted into clinical prac-
to differences in magnesium formulation, dosing, and tice anyway.
administration as well as migraine subtype.
CONCLUSION
Fibromyalgia: Patients with fibromyalgia have been Pain is a complex and multifaceted health condition
found to have lower magnesium levels and magne- that has variable effects on different individuals.
sium intake.27 Magnesium supplementation has been Although a number of pharmacologic therapies are
suggested to be beneficial because it reduces levels of available to help manage pain, no uniform regimen
substance P, which correlates to a decrease in fibro- works for all patients. Vitamins and minerals may
myalgia pain. be an alternative option for pain relief, particularly
for neuropathic and chronic pain. Although evi-
PHN: IV magnesium sulfate administered at 30 mg/kg dence supporting the use of vitamins and minerals
over 30 minutes was shown to lessen or completely is limited, pharmacists are well positioned to help
resolve pain in patients with PHN.28 Studies have patients make educated decisions on the use of these
suggested that it is as effective as ketamine for reduc- nutrients.
ing pain associated with PHN, but more research The content contained in this article is for informational purposes
should be conducted before it is recommended as a only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is
treatment option.27 solely at your own risk.

REFERENCES 15. Zirpoli GR, McCann SE, Sucheston-Campbell LE, et al. Supple-
1. Yong RJ, Mullins PM, Bhattacharyya N. Prevalence of chronic pain ment use and chemotherapy-induced peripheral neuropathy in a coop-
among adults in the United States. Pain. 2022;163(2):e328-e332. erative group trial (S0221): the DELCaP study. J Natl Cancer Inst.
2. Smith TJ, Hillner BE. The cost of pain. JAMA Netw Open. 2017;109(12):djx098.
2019;2(4):e191532. 16. Luo J, Bavencoffe A, Yang P, et al. Zinc inhibits TRPV1 to allevi-
3. International Association for the Study of Pain. Definition of pain. ate chemotherapy-induced neuropathic pain. J Neurosci.
www.iasp-pain.org/resources/terminology/#pain. Accessed January 2, 2018;38(2):474-483.
2022. 17. Greenlee H, Hershman DL, Shi Z, et al. BMI, lifestyle factors and
4. Abd-Elsayed A, Deer TR. Different types of pain. In: Abd-Elsayed taxane-induced neuropathy in breast cancer patients: the Pathways
A, ed. Pain: A Review Guide. Cham, Switzerland: Springer Nature Study. J Natl Cancer Inst. 2016;109(2):djw206.
Switzerland; 2019:15-16. 18. Kim HK, Kim JH, Gao X, et al. Analgesic effect of vitamin E is
5. HHS.gov/Opioids. Pain Management Best Practices Inter-Agency mediated by reducing central sensitization in neuropathic pain. Pain.
Task Force report. www.hhs.gov/sites/default/files/pain-mgmt-best- 2006;122(1-2):53-62.
practices-draft-final-report-05062019.pdf. Accessed January 2, 2022. 19. Rajanandh MG, Kosey S, Prathiksha G. Assessment of antioxi-
6. Institute for Clinical Systems Improvement. Pain: assessment, non- dant supplementation on the neuropathic pain score and quality of
opioid treatment approaches and opioid management care for adults. life in diabetic neuropathy patients—a randomized controlled study.
www.icsi.org/wp-content/uploads/2021/11/Pain-Interactive-7th- Pharmacol Rep. 2014;66(1):44-48.
V2-Ed-8.17.pdf. Accessed January 2, 2022. 20. Treede RD, Rief W, Barke A, et al. Chronic pain as a symptom or
7. Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complemen- a disease: the IASP Classification of Chronic Pain for the International
tary and alternative medicine use among adults: United States, 2002. Classification of Diseases (ICD-11). Pain. 2019;160(1):19-27.
Adv Data. 2004;(343):1-19. 21. CDC. About CDC’s opioid prescribing guideline. www.cdc.gov/
8. Murnion BP. Neuropathic pain: current definition and review of opioids/providers/prescribing/guideline.html. Accessed January 2,
drug treatment. Aust Prescr. 2018;41(3):60-63. 2022.
9. Julian T, Syeed R, Glascow N, et al. B12 as a treatment for periph- 22. Zelaya CE, Dahlhamer JM, Lucas JW, Connor EM. Chronic pain
eral neuropathic pain: a systematic review. Nutrients. and high-impact chronic pain among U.S. adults, 2019. NCHS Data
2020;12(8):2221. Brief. 2020;(390):1-8.
10. Buesing S, Costa M, Schilling JM, Moeller-Bertram T. Vitamin 23. Carr AC, McCall C. The role of vitamin C in the treatment of
B12 as a treatment for pain. Pain Physician. 2019;22:e45-e52. pain: new insights. J Transl Med. 2017;15(1):77.
11. Feldman EL. Pathogenesis of diabetic neuropathy. UpToDate. 24. Zollinger PE, Tuinebreijer WE, Breederveld RS, Kreis RW. Can
Waltham, MA: UpToDate Inc. www.uptodate.com. Accessed January vitamin C prevent complex regional pain syndrome in patients with
2, 2022. wrist fractures? J Bone Joint Surg Am. 2007;89(7):1424-1431.
12. Ortega E. Postherpetic neuralgia. UpToDate. Waltham, MA: 25. Nadolski CE. Vitamin D and chronic pain: promising correlates.
UpToDate Inc. www.uptodate.com. Accessed January 2, 2022. US Pharm. 2012;37(7):42-44.
13. Charness ME. Overview of the chronic neurologic complications 26. Helde-Frankling M, Björkhem-Bergman L. Vitamin D in pain
of alcohol. UpToDate. Waltham, MA: UpToDate Inc. www.uptodate. management. Int J Mol Sci. 2017;18(10):2170.
com. Accessed January 2, 2022. 27. Shin HJ, Na HS, Do SH. Magnesium and pain. Nutrients.
14. Kottschade LA, Sloan JA, Mazurczak MA, et al. The use of vita- 2020;12(8):2184.
min E for the prevention of chemotherapy-induced peripheral neurop- 28. Na HS, Ryu JH, Do SH. The role of magnesium in pain. In: Vink
athy: results of a randomized phase III clinical trial. Support Care R, Nechifor M, eds. Magnesium in the Central Nervous System. Ade-
Cancer. 2011;19(11):1769-1777. laide, Australia: University of Adelaide Press; 2011.

33
U.S. Pharmacist • March 2022 • www.uspharmacist.com
SPECIAL SECTION: SPECIALTY PHARMACY

Specialty Pharmacy News Digest


Could One Autoimmune Disease The researchers found that a human polyomavi-
Lead to Another? rus (HPyV9) was associated with the deaths of three
Researchers at the University of Colorado Anschutz solid-organ transplant recipients who developed a
Medical Campus have discovered that having one severe skin rash and then died about a year later
kind of autoimmune disease can lead to another. The from pulmonary and multiorgan failure.
scientists serendipitously found that mice with anti- The study, published in JAMA Dermatology, was
body-induced rheumatoid arthritis in their joints led by Stephanie Gallitano, MD, assistant professor
went on to develop spinal lesions similar to those in of dermatology at Columbia University Vagelos Col-
axial spondyloarthritis (AxSpA), which causes fusion lege of Physicians and Surgeons, and Nischay
of the vertebrate and curvature, or bending, of the Mishra, PhD, assistant professor of epidemiology at
backbone. The study was published in the journal Columbia’s Mailman School of Public Health and
Immune Network. Center for Infection and Immunity.
“This interesting disease association may be due The deaths of the organ-transplant recipients were
to the binding of anti-collagen autoantibodies to the initially a mystery. Some viruses can cause life-threat-
spine, or to some alteration of the immune system ening diseases in transplant recipients and other
that requires further investigation,” said the study’s immunocompromised people, but none of these were
lead author, Nirmal Banda, PhD, professor in the found in the three patients.
division of rheumatology at the University of Colo- To identify a culprit, the researchers turned to Vir-
rado School of Medicine. CapSeq-VERT, a technique developed by researchers
These same anticollagen antibodies are also pres- in the Center for Infection and Immunity, that detects
ent in humans with arthritis. They directly attack all known vertebrate viruses. Using these techniques,
joint cartilage, resulting in inflammation and pain. the researchers detected HPyV9 and found that the
Dr. Banda noted that every mouse injected with col- virus was present in the skin, blood, and lungs of the
lagen antibody–induced arthritis developed arthritis three patients. Additional tests showed that the virus
and then curvature of the spine consistent with was not just present in the patients but was actively
AxSpA. replicating, causing the initial skin rash and damaging
“I began to notice the proliferation of bone in the the lungs.
spine and fusing of the vertebrate,” he said. “The Because of the newly identified risk, the research-
normal spaces between the spine vertebrate in certain ers say organ-transplant recipients and other immu-
locations were disappearing. This is similar to what nocompromised patients should be routinely tested
happens to humans with AxSpA.” for HPyV9 infection. (VirCapSeq-VERT recently
The connection, he said, has not been made in any received approval for clinical use from the New York
other study he has seen. But exactly how one autoim- State Department of Health.)
mune disease could trigger another remains a mystery, Although HPyV9 has been found in the blood of
one that Dr. Banda hopes to investigate. “I want to transplant recipients and may be present in up to
know what the mechanism is,” he said. In the mean- 30% of the general population, it has not been previ-
time, he suggested that those with an autoimmune dis- ously linked to a human disease. “Since HPyV9 is
ease be vigilant in case they develop another. not routinely tested in clinical settings, we may find it
is more common than we realize,” says Dr. Mishra.
Common Virus May Pose Serious Threat “And as we begin to use VirCapSeq-VERT in clinical
to Transplant Patients microbiology, we can anticipate finding other patho-
A common virus that causes no harm in most people genic viruses that we cannot otherwise predict.”
may be a danger to organ-transplant recipients and Earlier detection with the new technique may
other immunocompromised people, say researchers improve clinical outcomes. A fourth patient with
at Columbia University Irving Medical Center. HPyV9 identified by the researchers is currently
34
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Specialty Pharmacy News Digest

being screened for viral load to monitor disease pro- approach coaxes the dormant virus to reveal itself in
gression and is receiving treatment. infected cells, so it can then be targeted and killed. In
“Our study is the first to describe immunosup- the earlier study, the researchers gave antiretroviral
pressed transplant recipients infected with HPyV9, drugs to mice whose immune systems had been
so the risk of developing HPyV9 infection is still altered to mimic those of humans and then infected
unknown,” Dr. Gallitano says. “As we learn more with HIV. They then administered a synthetic com-
about the pathogenesis of this disease, targeted novel pound called SUW133, which was developed at
forms of antiviral therapy and/or modification of Stanford University, to activate the mice’s dormant
immunosuppressive drug regimens may improve HIV. Up to 25% of the previously dormant cells that
patient outcomes.” began expressing HIV died within 24 hours.
But a more effective way to kill those cells was
“Kick and Kill” Strategy Aims to needed. In the new study, while the mice were receiv-
Eliminate HIV-Infected Cells ing antiretrovirals, the researchers used SUW133 to
In a study using mice, a UCLA-led team of research- flush HIV infected cells out of hiding. They then
ers have improved upon a method they developed in injected healthy natural killer cells into the mice’s
2017 that was designed to kill HIV-infected cells. blood to kill the infected cells. The combination of
The advance could move scientists a step closer to SUW133 and injections of healthy natural killer
being able to reduce the amount of virus, or even immune cells completely cleared the HIV in 40% of
eliminate it, from infected people who are dependent the HIV-infected mice.
on lifesaving medications to keep the virus from mul- The researchers also analyzed the mice’s spleens
tiplying and illness at bay. because the spleen harbors immune cells and is a
The strategy, described in Nature Communica- favorable place to look for latent HIV-infected cells.
tions, uses cells that are naturally produced by the They did not detect the virus there, suggesting that
immune system to kill infected cells that hide in the cells harboring HIV were eliminated. In addition, the
body, potentially eradicating them, said Dr. Jocelyn combination approach performed better than either
Kim, an assistant professor of medicine in the divi- the administration of the latency reversing agent
sion of infectious diseases at the David Geffen School alone or the natural killer cells alone.
of Medicine at UCLA. Dr. Kim said the researchers’ next objective is to fur-
“These findings show proof-of-concept for a ther- ther refine the approach to eliminate HIV in 100% of
apeutic strategy to potentially eliminate HIV from the mice they test in future experiments. “We will also
the body, a task that had been nearly insurmountable be moving this research toward preclinical studies in
for many years,” said Dr. Kim, the study’s lead nonhuman primates with the ultimate goal of testing
author. “The study opens a new paradigm for a pos- the same approach in humans,” she said.
sible HIV cure in the future.”
Worldwide, there are currently 38 million people Researchers Find Protein Trove That
living with HIV, and an estimated 36 million have May Influence Cystic Fibrosis
died of HIV-related diseases in the decades since HIV Researchers at the University of Toronto (U of T)
began circulating, according to UNAIDS. have identified hundreds of new proteins that could
Patients with HIV take antiretroviral medication play a role in cystic fibrosis and which may shed light
to keep the virus at bay. But HIV has the ability to on why some patients respond better than others to
elude antiretrovirals by lying dormant in cells called current therapies.
CD4+ T cells, which signal another type of T cell, the Many of these proteins, part of a group of drugga-
CD8, to destroy HIV-infected cells. When a person ble molecules called membrane proteins, interact
with HIV stops treatment, the virus emerges from with the CFTR protein, which when missing or
those reservoirs and replicates in the body, weaken- faulty leads to the buildup of mucos in the lungs and
ing the immune system and raising the likelihood of other organs that is often fatal in cystic fibrosis.
opportunistic infections or cancers that can lead to “We identified more than 400 proteins associated
illness or death. with either healthy or mutant CFTR and have shown
The UCLA-led study continues research on a that some of them could predict the variability seen
strategy called “kick and kill,” which many of the in patient symptoms and treatment responses,” said
same scientists first described in a 2017 paper. The Igor Stagljar, principal investigator on the study and
35
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Specialty Pharmacy News Digest

a professor in the Donnelly Centre for Cellular and the factors that cause its intestinal inflammation.
Biomolecular Research at U of T’s Temerty Faculty Crohn’s disease can lead to chronic inflammation
of Medicine. of the entire digestive tract. Symptoms include diar-
“With a more comprehensive view of the CFTR rhea, pain and cramping, fatigue, weight loss, and
protein interaction network, we can identify novel more. There is no cure for Crohn’s disease, but
drug targets that should enable more patient-specific patients can alleviate symptoms with current treat-
therapies,” Dr. Stagljar said. The journal Molecular ment options, and new treatment options for
Systems Biology published the findings. Crohn’s disease patients may be on the horizon
To help identify protein-protein interactions thanks to the research linking a common fungal
involving CFTR, the researchers developed a new pathogen to inflammatory bowel disease.
technology based on a platform they designed in The study recently appeared in Cellular and
2014. The approach is a high-throughput version of Molecular Gastroenterology and Hepatology. This
their Mammalian Membrane Two-Hybrid system new research from the Case Western Reserve School
that allows for screening of many more membrane of Medicine focuses on the role of the fungus Can-
proteins associated with a specific protein. dida tropicalis in triggering chronic inflammation
“The earlier design was array-based, and we within the gut microbiome. The gut microbiome is a
could only screen about 200 proteins at a time,” said complex ecosystem of fungus and bacteria found
Dr. Stagljar, who is also a professor of biochemistry within the digestive tract.
and molecular genetics at U of T. “With this new Researchers introduced the fungi into animal
technology, we’ve introduced several changes that models and induced colitis (inflammation of only the
allow us to screen thousands of protein targets simul- large intestine) through a chemical compound. The
taneously, in a pooled manner.” models infected with C tropicalis showed severe
Dr. Stagljar and his laboratory used the technol- inflammation and significant imbalance of the gut
ogy to find several overlooked proteins, including microbiome with changes in bacteria levels.
many membrane proteins that may play a role in Researchers say the findings show that this imbal-
CFTR function and cystic fibrosis. Membrane pro- ance of fungi and bacteria can create a predisposi-
teins account for roughly one-third of all proteins in tion to inflammatory bowel disease. Past studies
cells and about 65% of all drug therapy targets. have shown that people with Crohn’s disease have
One especially promising candidate the team found higher levels of C tropicalis compared with healthy
is the fibrinogen-like 2 protein, thought to play a role individuals.
in hepatitis, liver disease, and immune function. Understanding the impact of C tropicalis on a per-
Downregulation of this protein, the team showed, son’s health, therefore, will play a role in developing
leads to increased expression of CFTR in organoids, treatments for Crohn’s disease.
3D in vitro models that show how cells interact in an
organ, in this case with patient-derived gut tissues. Researchers Restore Function in Liver
“We think fibrinogen-like 2 protein is a valuable Cancer–Suppressing Gene
drug target for cystic fibrosis, and we’re now work- A team of researchers from Massachusetts General
ing with our collaborators to validate other proteins Hospital (MGH) and Brigham and Women’s Hospital
that turned up in this study and in genome-wide (BWH) has reprogrammed the tumor microenviron-
association studies,” Dr. Stagljar said. ment of liver cancer by using mRNA nanoparticles.
Cystic fibrosis affects over 90,000 people globally. This technology, similar to the one used in COVID-19
The disease can arise when children inherit two vaccines, restored the function of the p53 master
mutated CFTR genes, one from each parent, result- regulator gene, a tumor suppressor mutated in not
ing in defective CFTR proteins on the surface of cells just liver but also other types of cancer. When used in
in the lungs and other organs. combination with immune checkpoint blockade
(ICB), the p53 mRNA nanoparticle approach not
Study Links Gut Fungi to Crohn’s only induced suppression of tumor growth but also
Inflammation significantly increased antitumor immune responses
Results of a new study by researchers at Case West- in hepatocellular carcinoma (HCC) laboratory mod-
ern Reserve University represent a step toward els. The results of the study were published in Nature
improving our understanding of Crohn’s disease and Communications.
36
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Specialty Pharmacy News Digest

“The reprogramming of the cellular and molecular tumor microenvironment and tumor response by
components of the tumor microenvironment could be restoring p53 expression.”
a transformative approach for treating HCC and other
cancers,” said cosenior author Jinjun Shi, PhD, with How Exercise Could Help People
the Center for Nanomedicine at BWH, who developed With Asthma
the platform with MGH liver cancer biologist and Interventions aimed at promoting physical activity in
cosenior author Dan G. Duda, DMD, PhD. “By using people with asthma could improve their symptoms
this new approach, we’re targeting specific pathways and quality of life, according to new research from
in tumor cells with mRNA nanoparticles. These tiny the University of East Anglia (UEA).
particles provide the cells with the instructions to build Researchers looked at whether interventions such
proteins, which, in the case of HCC, delayed tumor as aerobic and strength or resistance training had
growth and rendered the tumor more responsive to helped participants with asthma. Although they
treatment with immunotherapy.” found that these interventions worked, patients with
HCC is the most prevalent form of liver cancer, asthma may have had difficulty undertaking them
characterized by a high mortality rate and dismal because of their challenge of travel to fitness groups
prognosis. Immune checkpoint blockers, a revolu- or because the interventions were not suitable for
tionary new class of drugs that enable the body’s people with additional health conditions.
immune system to recognize and attack cancer cells, But the team say that digital interventions—such
have shown efficacy in treating HCC, but most as video appointments, smartwatches, and mobile
patients do not benefit. To overcome this resistance, apps—could remove some of these barriers and
multiple strategies are being developed to improve enable patients to carry out home-based programs.
ICBs by combining them with other existing thera- Dr. Andrew Wilson, from UEA’s Norwich Medi-
pies, such as anti-VEGF drugs and radiotherapy. cal School, said, “Being physically active is widely
However, even these approaches are expected to ben- recommended for people with asthma. Doing more
efit only a small number of patients, creating an than 150 minutes a week of moderate to vigorous
urgent need for new combination therapies. physical activity has extensive benefits including
Encouraged by the success of mRNA in COVID- improved lung function and asthma control. But
19 vaccines, Dr. Shi decided to apply the technology research has shown that people living with asthma
(with certain modifications) to targeting cancer cells. engage in less physical activity and are more seden-
He teamed up with Dr. Duda, whose MGH labora- tary than people without asthma.”
tory had already created sophisticated animal models The team studied interventions that were designed
to analyze the microenvironment of liver tumors in to promote physical activity in adults with asthma.
response to immunotherapy. They developed and They looked at 25 separate studies from around the
optimized an mRNA nanoparticle strategy to restore world involving 1,849 participants with asthma to
loss of function of p53, a tumor-suppressor gene see whether their symptoms and quality of life were
whose function is lost in more than one-third of changed thanks to the interventions.
HCC cases. In doing so, they uncovered evidence Postgraduate researcher Leanne Tyson, also from
that p53 regulates the tumor microenvironment by UEA’s Norwich Medical School, said, “We found
modulating the interaction of cancer cells with that interventions that promote physical activity
immune cells as part of ICB therapy. had significant benefits in terms of increasing physi-
“In our previous work we had developed cal activity, decreasing time spent sedentary,
nanoparticles to target CXCR4—a chemokine recep- improving quality of life, and decreasing asthma
tor expressed by liver cancer cells—and selectively symptoms.
codeliver drugs such as kinase inhibitors,” explained “This is really important because helping patients
Dr. Duda. “We’ve now adapted this platform to use make significant behavior changes could really
CXCR4 as a kind of ZIP code to selectively target improve their outcomes in the long term. Our review
the tumor with nanoparticles encapsulating thera- also highlights the potential use of digital interven-
peutic mRNAs. When we combined this nanomedi- tions, which were notably absent.”
cine with anti–programmed death receptor 1 (PD-1) The content contained in this article is for informational purposes
antibodies, a standard immunotherapy for HCC only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is solely
patients, it induced global reprogramming of the at your own risk.

37
U.S. Pharmacist • March 2022 • www.uspharmacist.com
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-
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
tion, and up to 13% of these individuals may be undi- loads to nondetectable levels.3 The focus of this article
agnosed.1 Occurrences are highest in men who have sex will be to discuss who is a candidate for PrEP, available
with men (MSM), Black, and Hispanic patients.1 At this treatment options, recommended monitoring, and pipe-
time, there is no vaccine available to prevent HIV trans- line therapies.
mission. Nonpharmacologic and pharmacologic inter- The use and consistent adherence of PrEP have been
ventions are needed to successfully reduce HIV acquisi- estimated to reduce the occurrence of HIV by 99% for
tion. Nonpharmacologic methods include, but are not MSM, 90% or more for women, and 74% among indi-
limited to, counseling regarding safe sex practices, access viduals who inject drugs.5,6 Currently, there are two
to harm-reduction strategies such as syringe service pro- FDA-approved, once-daily oral tablet PrEP therapies
grams to decrease sharing syringes, and circumcision in available to prevent HIV infection in adolescents and
some situations.2 Pharmacologic methods for HIV pre- adults weighing at least 35 kilograms: emtricitabine-
vention focus on postexposure prophylaxis (PEP), pre- tenofovir disoproxil fumarate (FTC/TDF) and emtric-
exposure prophylaxis (PrEP), and treatment as preven- itabine-tenofovir alafenamide (FTC/TAF).5,7,8 FTC/TDF
tion (TasP).3 PEP is starting antiretroviral therapy (ART) is recommended to prevent HIV infection in all indi-
within 72 hours of potential exposure to HIV.3,4 PrEP is viduals at risk through injection drug use or sex.7 In
utilizing ART to prevent HIV infection in HIV-negative 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


(which usually resolves after a few weeks).7,8 Clinicians
HIV antibody/ At baseline, every 3 months, and
may consider prescribing supportive therapy, such as
antigen after discontinuation of therapy
antiemetics, to help with adverse effects. Changes in
Creatinine At baseline, 3 months, then every 6 bone mineral density and renal function are associated
clearance months with FTC/TDF and are usually reversible after a certain
Pregnancy At baseline, every 3 months, and time period following discontinuation.7 FTC/TDF is
testing after discontinuation of therapy appropriate for patients with renal function >60 mL/min
while FTC/TAF is approved for ≥30 mL/min based on
HBV screening At baseline
Vaccinate and/or continue to the Cockcroft-Gault equation.7,8 In patients who have
monitor if individual is not immune difficulty swallowing larger tablets, FTC/TAF may be
preferred given its smaller size than FTC/TDF. Prescrib-
Hepatitis C At baseline, then annually
antibody ers and clinicians can consult the National Clinician
Consultation Center PrEP Line at 1-855-448-7737 for
STI screening At baseline, then every 3-6 months additional prescribing information.5
as deemed appropriate
PrEP: preexposure prophylaxis; STI: sexually transmitted Alternative Dosing Strategy
infection. Source: References 13, 15.
On-Demand Oral PrEP: The only FDA-approved, oral
once-daily therapies are FTC/TDF and FTC/TAF. On-
The CDC determined that more than 1.2 million demand oral PrEP is another strategy prescribers are
individuals met eligibility criteria for PrEP in 2015.12,13 utilizing against the adherence barrier prevalent in many
TABLE 1 provides indications for PrEP for patients at high individuals’ PrEP therapy. Although on-demand PrEP—
risk of acquiring HIV.13 The U.S. Preventive Services also known as “nondaily PrEP,” “event-driven PrEP,” or
Task Force has given PrEP a “grade A recommendation” “2-1-1 PrEP”—is not FDA-approved or CDC-recom-
that prescribers offer PrEP to patients at high risk of mended, it has been studied and is currently being utilized
acquiring HIV.14 A specialization in infectious diseases in clinics worldwide.16 This approach replaces daily oral
or HIV medicine is not required for prescribing, which PrEP therapy with PrEP therapy at times of a sexual
39
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Current and Evolving Treatments for HIV PrEP

encounter. This means that a patient would take two function is recommended, and if hepatotoxicity occurs,
tablets of oral PrEP 2 to 24 hours prior to sex, followed to discontinue use.19
by a third tablet 24 hours after the initial double dose, CAB-LA was studied in two randomized, double-
and then a fourth tablet 48 hours after the initial double blind, controlled, multinational trials: HIV Prevention
dose.15,16 In a multisex scenario, the patient would con- Trials Network (HPTN) 083 and HPTN 084. HPTN
tinue to take one tablet every 24 hours until 48 hours 083 compared CAB-LA to FTC/TDF. The primary out-
after the last sexual encounter.15,16 If there are fewer than come was the prevalence of HIV transmission in high-
7 days between sexual episodes, the patient would need risk men who have sex with men and transgender
to take one tablet to restart the cycle. If there are more women. Individuals were to be followed for 153 weeks
than 7 days between sexual episodes, the patient would and were randomly assigned to either CAB-LA or FTC/
need to start again with the two-PrEP-tablet cycle.15,16 TDF. The study was stopped early due to the HIV infec-
The IPERGAY trial compared on-demand PrEP with tion rate being significantly lower in the CAB-LA group.
placebo and found an 86% reduction rate of HIV infec- In total, 52 of the 4,566 participants contracted HIV—
tion in the on-demand PrEP group.17 Study limitations 39 participants in the FTC/TDF group and 13 in the
included the low participant population and the median CAB-LA group. This study was the first to show great
number of doses (15 tablets per month); this is very close promise for the use of an injection as an alternative to
to the four tablets per week that has been known to daily PrEP therapy.20
produce high levels of protection during attempted daily Furthermore, the HPTN 084 trial compared CAB-LA
dosing.17 This brings to light the question of whether the to FTC/TDF in adult women in sub-Saharan South
high rate of dosing was a main contributor to the HIV- Africa who were at high risk of being infected with HIV.
acquisition reduction rate.17 Current guidelines for on- This trial was also stopped early due to the HIV infection
demand PrEP are conflicting, and more data will be rate being significantly lower in the CAB-LA group.
needed before we have a clear understanding of the impli- Thirty-eight of the 3,223 participants contracted HIV—
cations of on-demand dosing in PrEP therapy. 34 participants in FTC/TDF group and four in the CAB-
LA group.20 Primary analysis showed an 88% reduction
Recent FDA Approval in the risk of acquiring HIV-1 infection with CAB-LA.19
Cabotegravir Long-Acting Injectable (CAB-LA): CAB-LA The availability of a long-acting injectable PrEP
was recently approved by the FDA in December 2021 option will be an effective tool against current usage and
for PrEP in at-risk adults and adolescents weighing at adherence barriers in at-risk populations. Adjustments
least 35 kilograms to reduce the risk of sexually acquired will need to be made in pharmacies and provider offices
HIV.18 Prior to initiation and each subsequent injection, to establish workflow processes that are safe and efficient
individuals must produce a negative HIV-1 test result.19 in billing and provide monthly and bi-monthly PrEP
Shared decision-making with healthcare provider and injections.
patient should occur to determine the use of oral cabo-
tegravir 30 mg once-daily lead-in for a month prior to PrEP Therapies in the Pipeline
administration of CAB-LA or to start CAB-LA without The protective effects of FTC/TDF and FTC/TAF rely on
an oral lead-in.19 optimal adherence, which can be a barrier for at-risk
CAB-LA is a 600-mg injection given 1 month apart patient populations. To combat this, clinical trials are in
for 2 consecutive months and subsequent injections every progress exploring alternative treatment options to daily
2 months thereafter administered by a healthcare pro- oral PrEP therapy.
vider via gluteal intramuscular injection. If an oral lead-
in of cabotegravir is used, initiation injections should be Islatravir (ISL) Once-Monthly Oral Tablet: Impower-022
administered on the last day or within 3 days of oral and Impower-024 are both phase III trials comparing ISL
cabotegravir. CAB-LA can be administered 7 days before with FTC/TDF and FTC/TAF in different patient popu-
or after the scheduled date to receive the injection.19 If lations. The primary end point will be the incidence of
individuals miss subsequent injections, discussions with HIV infections. Both are estimated to be completed in
their healthcare provider are warranted to explore addi- 2024.22,23
tional options. The most common adverse reactions with
CAB-LA include injection site reactions, diarrhea, head- Dapavirine Long-ActingVaginal Ring (DPR-VR): DPR-VR
ache, fatigue, and pyrexia.19 Hepatoxicity has been is a long-acting vaginal ring system dosed once-monthly
reported with CAB-LA; regular monitoring of hepatic that is in clinical trials to offer PrEP therapy for women
40
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Current and Evolving Treatments for HIV PrEP

in developing countries who are at substantial risk of and educate patients to notify prescribing clinicians when
acquiring HIV. starting a new medication—whether it is an herbal sup-
Two separate phase III clinical trials showed that plement, OTC medication, or prescription therapy—to
DPR-VR significantly reduced the risk of HIV transmis- avoid potential interactions. Pharmacists can also pro-
sion compared with placebo. The Ring Study showed a vide counseling on PrEP therapy to discuss potential
risk reduction of 31%, and the ASPIRE trial showed a adverse effects, as well as management, importance of
risk reduction of 27%.24,25 optimal adherence, and need for routine follow-up for
DPR-VR received positive scientific opinion from the monitoring. Pharmacists may be able to identify repeat
European Medicines Agency in 2020 for use in adult PrEP patients as candidates for PrEP therapy and recom-
women in developing countries, recommendations from mend follow-up with a prescriber. Additionally, pharma-
the World Health Organization (WHO) in 2021, and cists may be able to assist with resources available to
approval in Zimbabwe in July 2021.26,27 DPR-VR also make PrEP therapy more affordable, including co-pay
has regulatory reviews pending in additional countries cards and patient-assistance programs.
in Africa and is currently under review by the FDA.26
Although these results are promising and trials are Impact of COVID-19
still in process, approval of DPR-VR in developing coun- COVID-19 has impacted healthcare and individuals’
tries would need to act as a supplement to existing HIV- access to PrEP. Some offices may have been able to
prevention practices. The ring could be another expan- expand telehealth services to patients, while other offices
sion in our “PrEP toolbox” to fight the global rate of may have reduced their hours or closed. The CDC con-
HIV infection. tinues to recommend quarterly HIV testing for patient
Other delivery systems in the pipeline include addi- safety and prefers laboratory-only visits for assessment.29
tional topical products, implants, and transdermal However, if laboratory-only visits are not available, there
devices. The goal of these new delivery systems is to 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
U.S. Pharmacist • March 2022 • www.uspharmacist.com USP Quarter-page Horizontal.indd 1 12/8/21 1:28 PM
Current and Evolving Treatments for HIV PrEP

are two options: home specimen collection kits for HIV 191% increase in PrEP refill lapses and a 72.1%
and STI infection to test urine or blood, where the patient decrease in new PrEP starts. Continued emerging data
mails the kit back to the laboratory and test results are will show the impact of COVID-19 on PrEP therapy,
provided to the prescribing provider, or self-testing via and additional research is needed to assess the full
an oral swab–based test. The latter is used if other impact of COVID-19 and PrEP therapy.32
options are not available, given its lower sensitivity to
detect recent HIV infection.30 Once HIV-negative status Conclusion
is confirmed, the prescriber could consider writing PrEP is effective at reducing HIV transmission when used
90-day prescriptions instead of 30-day prescriptions. If consistently. Pharmacists can provide education to
a clinic is changing services or closing, it should provide patients to help continue therapy. There are new thera-
individuals with other services or clinics for continuity pies in development that may further prevent HIV.
of care and access to PrEP.30 COVID-19 continues to impact healthcare, and addi-
Some clinics may have created flexible care plans to tional research will be needed to be conclude the impact
extend laboratory work and utilized telemedicine when on PrEP usage.
in-person visits were not possible. One study showed The content contained in this article is for informational purposes
a 44% reduction in new PrEP starts and a 0% decrease only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is solely
in follow-up visits for PrEP.31 Another study showed a at your own risk.

REFERENCES
1. CDC. HIV Surveillance Report. www.cdc.gov/hiv/statistics/over- exposure-prevention. Accessed February 19, 2022.
view/index.html. Accessed November 1, 2021. 19. Apretude (cabotegravir extended-release injectable suspension)
2. CDC. HIV: Protect yourself if you inject drugs. www.cdc.gov/hiv/ package insert. Research Triangle Park, NC: GlaxoSmithKline.
basics/hiv-prevention/inject-drugs.html. Accessed November 3, 2021. Published December 2021.
3. Heendeniya A, Bogoch I. Antiretroviral medications for the 20. Landovitz RJ, Donnell D, Clement M, et al. Cabotegravir for
prevention of HIV infection: a clinical approach to preexposure HIV prevention in cisgender men and transgender women. N Engl
prophylaxis, postexposure prophylaxis, and treatment as prevention. J Med. 2021;385:595-608.
Infect Dis Clin North Am. 2019;33(3):629-646. 21. World Health Organization. Trial results reveal that long-acting
4. CDC. HIV: About PEP. www.cdc.gov/hiv/basics/pep/about-pep. injectable cabotegravir as PrEP is highly effective in preventing HIV
html. Accessed November 3, 2021. acquisition in women. www.who.int/news/item/09-11-2020-trial-
5. CDC. HIV: Pre-exposure prophylaxis (PrEP) www.cdc.gov/hiv/ results-reveal-that-long-acting-injectable-cabotegravir-as-prep-is-
clinicians/prevention/prep.html. Accessed November 1, 2021. highly-effective-in-preventing-hiv-acquisition-in-women. Accessed
6. Beymer M, Holloway I, Pulsipher C, et al. Current and future November 28, 2021.
PrEP medications and modalities: on demand, injectables, and 22. Clinicaltrials.gov. Oral islatravir (MK-8591) once-monthly as
topicals. Curr HIV/AIDS Rep. 2019;16(4):349-358. preexposure prophylaxis (PrEP) in men and transgender women who
7. Truvada (emtricitabine and tenofovir disoproxil fumarate) pack- have sex with men and are at high risk for HIV-1 infection (MK-
age insert. Foster City, CA: Gilead Sciences, Inc; Revised June 2020. 8591-024) (Impower-024). www.clinicaltrials.gov/ct2/show/
8. Descovy (emtricitabine and tenofovir alafenamide) package insert. NCT04652700. Accessed November 27, 2021.
Foster City, CA: Gilead Sciences, Inc; Revised March 2021. 23. Clinicaltrials.gov. Oral ISL QM as PrEP in cisgender women at
9. Grand RM, Lama JR, Anderson PL, et al. Preexposure chemo- high risk for HIV-1 infection (MK-8591-022) (Impower-022). www.
prophylaxis for HIV prevention in men who have sex with men. N clinicaltrials.gov/ct2/show/NCT04644029. Accessed November 27,
Engl J Med. 2010;363(27):2587-2599. 2021.
10. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophy- 24. Nel A, van Niekerk N, van Baelen B, et al. Safety, adherence,
laxis for HIV infection among African women. N Engl J Med. and HIV-1 seroconversion among women using the dapivirine
2012;367(5):411-422. vaginal ring (DREAM): an open-label, extension study. Lancet HIV.
11. Hare C, Coll J, Ruane P, et al. The phase 3 DISCOVER study: 2021;8(2):e77-e86.
daily F/TAF or F/TDF for HIV pre-exposure prophylaxis. Presented 25. Baeten J, Palanee-Phillips T, Brown E, et al. Use of a vaginal
at the Conference on Retroviruses and Opportunistic Infections, ring containing dapivirine for HIV-1 prevention in women. N Engl
Seattle, WA. March 2019. J Med. 2016;375:2121-2132.
12. Smith DK, Van Handel M, Wolitski RJ, et al. Vital signs: esti- 26. International Partnership for Microbicides. A long-acting ring
mated percentages and numbers of adults with indications for for women’s HIV prevention. www.ipmglobal.org/content/ring-
preexposure prophylaxis to prevent HIV acquisition–United States, backgrounder-0. Accessed November 28, 2021.
2015. MMWR Morb Mortal Wkly Rep. 2015;65(46):1291-1295. 27. World Health Organization. Consolidated guidelines on HIV
13. CDC. Preexposure prophylaxis for the prevention of HIV infec- prevention, testing, treatment, service delivery and monitoring:
tion in the United States–2017 update: a clinical practice guideline. recommendations for a public health approach. www.who.int/
www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf. publications/i/item/9789240031593. Accessed November 28, 2021.
Accessed November 5, 2021. 28. Coelho L, Torres T, Veloso V, et al. Preexposure prophylaxis
14. U.S. Preventive Services Task Force. Preexposure prophylaxis 2.0: new drugs and technologies in the pipeline. Lancet HIV.
for the prevention of HIV infection: US Preventive Services Task 2019;6:e788-e799.
Force Recommendation Statement. JAMA. 2019;321(22):2203-2213. 29. CDC. HIV: Paying for PrEP. www.cdc.gov/hiv/basics/prep/paying-
15. Baker J, Rolls J. Update on HIV prevention and preexposure for-prep/index.html. Accessed November 21, 2021.
prophylaxis. JAAPA. 2020;33(6):12-17. 30. CDC. PrEP during COVID-19. 2020. www.cdc.gov/nchhstp/
16. Saberi P, Scott H. On-demand oral pre-exposure prophylaxis dear_colleague/2020/dcl-051520-PrEP-during-COVID-19.html.
with tenofovir/emtricitabine: what every clinician needs to know. J Accessed December 1, 2021.
Gen Intern Med. 2020;35(4):1285-1288. 31. Rogers B, Tao J, Maynard M, et al. Characterizing the impact
17. Beymer M, Holloway I, Pulsipher C, Landovitz RJ. Current and of COVID-19 on pre-exposure prophylaxis (PrEP) care. AIDS Behav.
future PrEP medications and modalities: on demand, injectables, 2021;25:3754-3757.
and topicals. Curr HIV/AIDS Rep. 2019;16(4):349-358. 32. Krakower DS, Solleveld P, Levine K, et al. Impact of COVID-19
18. FDA. FDA approves first injectable treatment for HIV preex- on HIV preexposure prophylaxis care at a Boston community health
posure prevention. December 20, 2021. www.fda.gov/news-events/ center. NATAP. 2020. www.natap.org/2020/IAC/IAC_75.htm. Accessed
press-announcements/fda-approves-first-injectable-treatment-hiv-pre- December 1, 2021.

42
U.S. Pharmacist • March 2022 • www.uspharmacist.com
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
increasing genetic distance. In first-degree rela-
Risk Factors for MS tives, MS risk is 2.77%. This risk drops to
Environmental • Epstein-Barr virus infection 1.02% in second-degree relatives and to 0.88%
• Geographical latitude in third-degree relatives. The risk in monozygotic
twins is 25% to 30% compared with 3% to 5%
Genetics • First-degree relative in dizygotic twins. More than 200 genetic risk
• Polymorphisms on HLA-
DRB1*15:01 allele
variants have been identified for MS, with the
human leukocyte antigen (HLA) region represent-
Modifiable Factors • Tobacco exposure ing the strongest MS susceptibility locus; the
• Obesity presence of the HLA-DRB1*15:01 allele
• Sodium intake increases MS risk threefold.1,3,9,10
• Low sun exposure
• Night work
Many environmental and lifestyle factors have
• Low vitamin D levels been identified that may increase an individual’s
risk for MS development. The timing of expo-
HLA: human leukocyte antigen; MS: multiple sclerosis. sure to these risk factors may be important;
Source: References 1, 3, 10.
migration studies have shown that key environ-
mental exposures associated with adult-onset MS
MS (PPMS), and progressive relapsing MS occur before age 15 years. Environmental expo-
(PRMS). The most common form of MS at dis- sure and MS risk may also depend on the
ease onset is RRMS, composing almost 90% of genetic background of the individual. The most
cases. This disease pattern is characterized by well-established environmental risk factors
periods of symptom flareups, or relapses, fol- include Epstein-Barr virus (EBV), tobacco expo-
lowed by periods of partial or complete remis- sure, low sun exposure, low vitamin D levels,
sion. There is no evidence of disease progression and adolescent obesity.3,9-12
between attacks. For some patients, relapses Exposure to the EBV, including infectious
decrease in frequency over time and sometimes mononucleosis, especially in adolescence, has
completely disappear. However, in most patients, been associated with an increased risk of MS.
neuronal damage becomes clinically evident, and Almost 100% of patients with MS are positive
usually within 10 to 20 years after disease onset, for EBV antibodies. Smoking has consistently
patients progress to SPMS. A steady worsening been shown to increase the risk of MS. The risk
of neurologic deficits occurs. Periods of relapses is dose-dependent, with both a higher amount of
typically lead to further progression. About 10% smoking and cumulative smoking associated with
of patients will present with PPMS at disease an increased risk. The age at which a person
onset; symptoms continue to worsen from the starts smoking does not seem to affect risk, but
beginning. Patients do not experience periods of smoking cessation regardless of the cumulative
relapses or remissions but may experience occa- dose has been correlated with a gradual decline
sional plateaus. The mean age of onset is about in risk, with the risk approaching zero after 10
40 years, and it seems to more frequently affect years of quitting. Passive exposure to smoking
men. PRMS is rare, affecting fewer than 5% of has been associated with an increased risk as
patients. It is progressive from the beginning and well. Smoking has also been linked to a faster
is characterized by a continual decline in neuro- disease severity progression, increasing the risk
logic functioning with occurrences of superim- of conversion from RRMS to SPMS and disabil-
posed relapses.3,5,9,10 ity progression. MS appears to be more prevalent
in geographical regions that are further from the
Risk Factors equator. Sun exposure, which decreases with
The exact cause of MS is still unknown, but epi- increasing latitude, has been inversely correlated
demiologic data suggest environmental and to MS risk. Sun exposure is also a major deter-
genetic factors both play a role (see TABLE 1). minant of vitamin D levels; low levels of vitamin
Genetics seem to play a role in the development D have been shown to increase the risk of MS
of MS. The recurrence rate of MS in families is and disease activity. Vitamin D supplementation
about 13% to 20%, but the risk decreases with may lower the risk of MS in susceptible individu-
44
U.S. Pharmacist • March 2022 • www.uspharmacist.com
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- avoided in patients with cardiac complications.
sive and immunomodulatory effects targeting By completing a comprehensive medication
lymphocyte number, proliferation, trafficking, review for all patients, pharmacists can help
and cytokine production, reducing central ner- identify such conditions that may worsen with
vous system inflammation, and preventing dis- the addition of specific DMTs. A comprehen-
ease progression. They have all been found to sive review also provides the pharmacist an
be effective in RRMS only, except for ocreli- opportunity to speak with the patient one-on-
zumab, which is the only agent indicated for one about MS, the importance of early treat-
the management of PPMS as well. They are cat- ment, and adhering to their regimen. Once
egorized as moderately effective or highly effec- therapy has been initiated, pharmacists play an
tive based on their impact on relapses. The important role in counseling the patient on the
selection of the most appropriate DMT for a appropriate use and adverse effects of the
patient can be challenging and is based on a medication. 19,20
multitude of factors, including clinical symp- Pharmacists may also help the healthcare team
toms, MRI activity, agent efficacy, side-effect understand more about the patient’s needs, assess
profile, and patient considerations, which potential drug interactions, and identify potential
include convenience, cost, and preference. Cur- barriers to adherence. One factor that can affect
rently, the dominant treatment strategy used is treatment adherence is cost. MS therapies are very
the escalation regimen. Therapy is started with costly, with annual expenses anywhere from
a less-effective agent and is switched to another $90,000 to $195,000. Many insurance providers
lower efficacy agent if the patient experiences require prior authorizations for these products,
intolerable side effects and to a higher-efficacy which can delay treatment start. Most manufac-
DMT when disease activity worsens. Common turers provide financial assistance through copay
management of MS symptoms, including spas- assistance programs to help with out-of-pocket
ticity, pain, fatigue, cognitive impairment, walk- expenses but require submission of documenta-
ing impairment, and bladder and bowel issues, tion. Pharmacists are in a unique position to help
should include a combination of pharmacologic patients navigate this very confusing process by
and nonpharmacologic agents. The management assisting them in selecting the most cost-effective
of these symptoms is important to improving option based on the patient’s insurance coverage
the quality of life in MS patients and requires a and financial needs and serving as an advocate for
multidisciplinary approach. 5,10,13-18 patients to obtain their medications promptly.19-21

Role of the Pharmacist Conclusion


An important role of the pharmacist in the MS is a chronic progressive disease with no cure.
management of MS is medication safety, iden- Management is focused on delaying the disease
tifying any contraindications to therapy and process. The use of DMTs is the cornerstone of
adverse event risks, and providing patient edu- treatment, and pharmacists can be an invaluable
cation about MS and its management. Many resource to both the patient and the interdisci-
agents will require complete blood counts and plinary healthcare team. Pharmacists can help
liver function tests. Other agents will require patients manage their disease state more effec-
yearly skin exams to detect malignancies, such tively by providing education about their therapy,
as melanoma. Many monitoring parameters are help patients and their caregivers understand the
outlined by regulatory agencies, and pharma- risks and benefits of DMTs and the possible
cists can ensure that the recommended and adverse effects, and assist patients in navigating
required monitoring parameters are completed the confusing landscape of insurance prior autho-
at baseline and before refill authorizations. rizations and copay assistance programs to
Before initiating a DMT, a patient’s comorbid obtain their medications in a timely manner.
conditions should be taken into consideration. References available online at www.uspharmacist.com.
For example, interferons should be avoided in The content contained in this article is for informational pur-
patients with a history of depression, and fin- poses only. The content is not intended to be a substitute for pro-
fessional advice. Reliance on any information provided in this
golimod should be used with caution or article is solely at your own risk.

47
U.S. Pharmacist • March 2022 • www.uspharmacist.com

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? as muscle spasms, urinary problems, pain,
This condition can cause many symptoms, depression, and constipation, medicines that are
depending on where the nerve damage is. Symp- normally taken to help with these conditions are
toms may differ greatly from person to person. utilized.
Common symptoms include numbness, tingling, The main class of medicines used works at
and feeling of pins and needles; muscle weak- slowing down the disease process. This class of
ness or spasms; vision problems such as double medications is known as disease-modifying ther-
vision, blurriness, partial color blindness, and apies. If you have MS, you want to start these
eye pain; fatigue; trouble with coordination and medications as soon as possible to prevent fur-
balance; trouble walking or speaking; trouble ther progression and help prevent disability.
thinking clearly; sensitivity to heat; trouble con- Many of these medications have significant
trolling your bowels or bladder; vaginal dryness health risks associated with their use. It is very
in women and erectile dysfunction in men; and important that you speak with your healthcare
electric shock sensations when you move your team, including your pharmacist, about the
head a certain way. associated risks, adverse effects, and monitoring
needs.
What Causes MS?
We do not know the exact cause of MS, but it is Where Can I Go for More Information?
likely due to genetic and environmental factors. You can contact the following organizations for
Women are more likely to be affected than men. additional support and resources:
If one of your parents or siblings has MS, you Multiple Sclerosis Foundation (MSF):
may be at greater risk. Certain viral infections, https://msfocus.org/ or 888-MSFOCUS.
such as Epstein-Barr, can trigger the condition. National Multiple Sclerosis Society (NMSS):
MS is more common in areas that are farther https://www.nationalmssociety.org/ or
away from the equator. Having low levels of 800-344-4867.
vitamin D and low exposure to sunlight can Multiple Sclerosis Association of America
increase your risk. Smokers are also at higher (MSAA): https://mymsaa.org/ or 800-532-7667.
risk for MS than nonsmokers.
PHARMACY STAMP
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

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

49
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Managing Chronic, Noncancer Pain With Opioids

pain may have depression, which can exacerbate pain


Table 1

Five-Point Opioid Strategy and worsen physical symptoms; pain may also ben-
• Improve access to prevention, treatment, and efit from antidepressant medication use.1 If opioid
recovery support services. therapy is warranted, it is recommended to combine
• Target the availability and distribution of overdose- it with nonpharmacologic therapy and nonopioid
reversing drugs. pharmacologic therapy and the lowest necessary dose
• Strengthen public health data reporting and
for the shortest duration.1,4 Immediate-release opi-
collection.
• Support cutting-edge research on addiction and pain. oids are preferred over extended-release/long-acting
• Advance the practice of pain management. formulations.1
References: 2, 3.
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
Table 2

Nonopioid Pharmacologic Therapy for daily function and pain, potential risk
Various Diagnoses of addiction before starting opioids, or
abuse potential while on long-term opi-
Type of Pain Nonopioid Pharmacologic Therapy
oids (TABLE 3). The validated assess-
Back pain Acetaminophen, NSAIDs, muscle relaxers, pain ment tools in TABLE 3 are not all inclu-
injections, and surgery sive, and more tools are available that
can be utilized in practice.4 It is recom-
Migraines Preventive: antihypertensive Abortive: triptans,
mended that this process, which sets
(propranolol, verapamil, oral CGRPs,
losartan), antidepressant MAOIs, Reyvow standards for opioid prescribing,
(amitriptyline, duloxetine), should be the same for all patients,
anticonvulsant (topiramate, regardless of abuse history.8 The pro-
gabapentin, carbamazepine, vider should be aware of legal require-
oxcarbazepine, lamotrigine), ments that are necessary to satify prior
injectable CGRPs (Nurtec, Boto)
to prescribing opioids. An example
would be the state of Michigan, where
Fibromyalgia Duloxetine, TCAs (amitriptyline, nortriptyline),
gabapentin, pregabalin, topiramate providers are required to have a con-
versation with the patient about risks
CGRPs: calcitonin gene–related peptides; MAOI: monoamine oxidase versus benefits of opioids prior to pre-
inhibitors; NSAIDs: nonsteroidal anti-inflammatory drugs; TCAs: tricyclic
antidepressants. References: 1, 4, 5. scribing them to establish a patient-
provider relationship. Part of this pro-
cess includes the review of the
from completely eliminating pain to minimizing the Prescription Drug Monitoring Program (PDMP) to
impact of pain on quality of life.6 assess history of opioid use and urine drug-screen
In 2016, A Compact to Fight Opioid Addiction monitoring. Community pharmacists can help in the
focused on reducing inappropriate prescribing of monitoring process by checking in with the patient
opioids, and many states have enacted opioid-limit- when dispensing opioids and with monitoring
ing legislation.7 (adhering to the PDMP). Pharmacists can notify
Given that pain is multifactorial, nonpharmaco- prescribing providers if there is a question of abuse
logic therapies for pain include cognitive behavioral or drug interactions.30
therapy, such as mindfulness or relaxation techniques Tools that can be used to determine if the opioid
and physical therapy. If pharmacologic therapy is is improving function and pain are the Pain, Enjoy-
appropriate, TABLE 2 shows some nonopioid phar- ment of Life and General Activity (PEG) scale and
macologic therapy options for some causes of pain. the Two-Item Graded Chronic Pain Scale.4 Both
For instance, acetaminophen is first-line therapy for scales help assess a patient’s pain and functionality
osteoarthritis.1 Neuropathic pain first- and second- and should be assessed at each visit.
line medications include anticonvulsants, tricyclic The PEG was developed based on the Brief Pain
antidepressants, and serotonin and norepinephrine Inventory (BPI) scale to make it easier to use in the
reuptake inhibitors (SNRIs).1 Patients with chronic primary care setting. The BPI scale for assessing pain
50
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Managing Chronic, Noncancer Pain With Opioids

intensity/functional impairment and pain-related hierarchy. It is a 24-question, self-administered tool


interference in daily activity and the healthcare famil- with a sensitivity of 81% and a specificity of 68%.13
iarity with a 0 to 10 scale were used to create the The maximum score is 96. A score of 18 or greater
PEG.9 The PEG is comparable to the BPI in assessing means the patient is at higher risk for abuse of opi-
patients’ pain, and the resulting three-question PEG oids.8 This tool should be used with clinical assess-
tool allows clinicians to quickly assess function and ments to help guide the clinician’s treatment pro-
pain while checking for other conditions.9 gram. When comparing ORT and SOAPP for
The Two-Item Graded Chronic Pain Scale was predicting risk of abuse in patients taking opioids for
created from a longer graded chronic scale. The chronic pain, SOAPP with clinical assessment was
original scale was a six-item question that asked more sensitive.14
patients about their pain and interference in activity When meeting with patients on long-term opioids,
for multiple time periods, which made scoring com- providers should determine if opioid tapering is rec-
plicated and more time-consuming. It was simplified ommended and use the clinical assessment tools that
to just two questions to help determine pain intensity have been discussed previously.15 The guidelines rec-
and interference, proving to be an effective tool dur- ommend discontinuation of opioids if there is no
ing a primary care visit.10 clinically meaningful improvement in pain and func-
Clinicians should not continue to prescribe opi- tion, treatment resulted in a severe adverse event, or
oids if there is not a clinically meaningful improve- the patient has a history or current substance-use
ment in function or pain interference during the acute disorder, excluding tobacco.4 In patients who are not
pain phase.1,4 Each state has its own PDMP, which showing abuse behavior or there is a concern for
should be checked to verify that a patient’s controlled harm to the patient, tapering may not be appropriate.
substance history is consistent with prescribing.1 Two There is concern for providers being pressured,
tools that can be used to assess for abuse potential whether by insurance companies or guidelines stating
are the Opioid Risk Tool (ORT) and the Screener and that patients are at increased risk of overdose if they
Opioid Assessment for Patients with Pain (SOAPP- are over a certain morphine equivalent. Other con-
R). The ORT is a five-item clinician self-administered siderations for tapering of opioids are patients con-
tool that can be used to help predict abuse-related currently treated with a benzodiazepine and a hyp-
behaviors in patients with chronic pain.4 It focuses notic, which puts them at increased risk of
on family/personal history of substance/alcohol/pre- overdose.1,14
scription abuse and mental disorders. The original Patients should be made aware of the long-term
assessment was a 10-item questionnaire that was complications of opioids, as shown in TABLE 4. These
developed by Dr. Lynn Webster to serve as another complications include constipation, nausea, somno-
tool to help with opioid-use assessments. Preadoles- lence, memory loss, increase risk of falls, respiratory
cent sexual abuse is only weighted for females since depression, effects on hormones that can lead to
when reviewed, researchers did not observe any dif- infertility, sexual dysfunction, osteoporosis, depres-
ference in the response when weighted in men. Scores sion, hyperalgesia, and mortality.1,16
greater than 8 indicate a high risk for potential abuse, Providers should enter the conversation with no
4 to 7 means moderate risk, and scores 3 or less indi- bias. A study showed that patients who have a sub-
cate low risk.11 The ORT was condensed to five ques- stance use disorder feel they are not treated the same
tions.12 In the study, the revised version was found as others and desire the same respect that is extended
to be 85.4% sensitive, with 85.1% specificity.12 One to other patients.30 The conversation should be gen-
benefit of the ORT is that it is part of MDCalc.8 The eralized and without emotions.8 The following com-
ORT may not absolutely predict potential abuse by ponents were found to be helpful when discussing
itself, but it can help guide clinicians in their deci- the tapering process with patients.17
sions concerning appropriate treatment for the
patient.8 Rationale for Tapering
The SOAPP-R was developed to help screen Explaining the reasoning for tapering to the patient
patients who are at risk for long-term opioid abuse. makes it individualized.17 The Canadian National
This tool was developed with the help of an expert Pain Centre at McMasters has a good, patient-
panel of pain and addiction specialists, identifying friendly document that discusses points for tapering.
the characteristics of opioid abuse and rating their Patients may feel they were being punished when told

51
U.S. Pharmacist • March 2022 • www.uspharmacist.com
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- withdrawal and treatment options available for
ications as prescribed.17 Most of the studies and com- symptom management.1,4,5 The last set of assessment
mentary reports making the conversation specific to tools that can be beneficial when tapering down
the patient. Clinicians should explain to the patient patients on their opioid dose are the Clinical Opiate
the tools and assessments used to determine why Withdrawal Scale (COWS) and the Clinical Institute
there was a need for tapering. A common theme also Narcotic Assessment (CINA). Both are 11-item scales
was to not tell the patient the tapering is the result of that assess questions based on patients’ behaviors
the opioid crisis; to them, this means nothing. Using and observation by clinician to tell how severe with-
either the ORT or SOAPP-R to start the conversa- drawal is. The CINA scores range from 0 to 31, and
tion, the provider can then assess for patients who the higher the score, the more severe withdrawal is.
are at increased risk of abuse. The use of these tools Scores using the COWS range from 0 to 47, and 5 to
does not predict abuse; rather, they indicate that 12 are considered mild, 13 to 24 are moderate, 25 to
these patients have risk factors that can make them 36 are moderately severe, and >36 is considered
more sensitive to abuse issues, whether environmen- severe withdrawal.18 There is potential for bias since
tal or genetic.13 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
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Managing Chronic, Noncancer Pain With Opioids
Table 5

Symptoms of Withdrawal and Treatment Strategies


Symptoms of
Withdrawal Treatment Options Comments

Diarrhea/cramping • Start loperamide 4 mg then • Loperamide has abuse potential


2 mg by mouth 4X a day prn • Dicyclomine can also be used for abdominal cramping
Dicyclomine 10-20 mg by mouth
4X a day prn

Myalgias • Ibuprofen 400 mg-600 mg by • Take ibuprofen with food and monitor renal function
mouth 4X a day prn • Acetaminophen (if liver impairment, do not exceed 2,000 mg)
• Acetaminophen 1,000 mg by
mouth every 8 hours prn

Anxiety/agitation Clonidine 0.1 mg daily to Monitor blood pressure for clonidine and propranolol
2X a day If patient ends up using clonidine more than prn, consider
Hydroxyzine 25 mg by mouth weaning off of it once withdrawal is over
3X a day prn Consider gabapentin if appropriate; may not be appropriate
Propranolol 10-20 mg by mouth in patients with a substance-abuse history
3X a day prn
Buspirone 5-15 mg by mouth
3X a day prn

Insomnia Trazodone 50-100 mg by mouth Propranolol and buspirone can also be used to help
prn for sleep transition the patient to sleep
Melatonin 5-10 mg by mouth Other agents to consider: mirtazapine or tricyclic
at night antidepressants
Hydroxyzine can also be used

Nausea Ondansetron 8 mg by mouth 2X Monitor QTC interval


a day prn

Tremors Propranolol 10-20 mg by mouth


3X a day prn

Diaphoresis Clonidine 0.1 mg daily to 2X a Monitor blood pressure


day prn

Source: References 1, 16.

the patient has a substance use disorder.4 A slow symptoms.1,3 Acute opioid withdrawal in ambula-
taper can start with less than 10% of the original tory patients is not considered lethal, but the symp-
dose per week with regular monitoring. Another toms can be bothersome.1
strategy is an understanding that an opioid Patients who do not tolerate the tapering process
decrease is made with the agreement between the may be designated for a slower taper. Patients can
provider and patient. In this strategy, the patient feel some side effects from tapering even after they
would be informed that once the decrease is made are off opioids up to 6 months post discontinuation,
an increase from that dose will not occur.4 Other so a slow taper may be beneficial.4 Buprenorphine
taper strategies include reduction of doses by 5% may have a role in patients unable to tolerate the
to 10% every 1 to 2 months, depending on how wean. It is a partial mu-receptor agonist that has an
the patient tolerates it.1,4,5,16 Use the PEG to assess advantage over other opioids in that the risk of
how patients are at each reduction and the COWS respiratory depression plateaus as the dose
scale to assess for withdrawal. If withdrawal symp- increases.14 Buprenorphine can be a good option for
toms are present, mitigating them will help with patients with poor pain control. 14 The patch is
the wean. TABLE 5 shows treatment options for approved for the treatment of pain. Providers need
54
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Managing Chronic, Noncancer Pain With Opioids

specialized training and a waiver from the DEA to Impact of COVID-19


prescribe other forms of buprenorphine (a waiver The coronavirus disease 2019 (COVID-19) pandemic,
is not required for the patch formulation).14 which was declared by the WHO on March 11, 2020,
After discussing the plan and what the patient has impacted the medical care provided to patients.
can expect, the provider can bring in other disci- Mental health concerns and substance use–related
plines to help manage the process. The pharmacist harms have risen amid the global pandemic due to a
can help the provider check in with the patient, variety of factors, including stay-at-home orders, social
answer questions regarding the taper, and make distancing, fear of sickness and death, loss of employ-
interventions as appropriate. One study showed ment, economic stress, and loss of family and friends
that a pharmacist can be the communicator due to illness.24 In April 2020, one in seven adults in the
between the patient and provider. The pharmacist U.S. reported serious psychological distress.25
met with the patient, and if an intervention was Another study showed that 13.3% of adults had
identified, the provider was contacted to discuss started or increased substance use to cope with stress
the intervention. Furthermore, the pharmacist con- or emotions related to the pandemic, while 30.9%
tacted the patient to make the intervention after had symptoms of anxiety or depressive disorders and
discussion with the provider.21 Local community 10.7% had considered suicide in the past month.25
pharmacists may also help in this process. They can People with opioid use disorder may be at higher risk
educate and ask questions when the patients pick of complications from COVID-19 given the immu-
up their medications. They can help review drug nosuppressive nature of opioids.26,27
interactions for patients who have multiple provid- In March 2020, the Office for Civil Rights at the
ers prescribing medications. Also, community phar- HHS allowed the use of nonpublic-facing audio or
macists can dispense naloxone in many states, if video communication products. Medicare now allows
needed.30 reimbursement for telehealth services. Since COVID-
Tapering requires a lot of communication, fre- 19, a face-to-face visit for controlled substances is no
quent assessment, and frequent follow-up appoint- longer required, and telemedicine is allowed to pre-
ments. Some concerns with the role of the pharma- scribe these medications. The opportunity to use tele-
cist in this process have been identified. Pharmacists medicine has the potential to manage more people and
are thought of as accessible; however, one study expand access to care.28 The federal Substance Abuse
looking at patients’ perspectives revealed that phar- and Mental Health Services Administration allowed
macists are sometimes thought of as too busy, so stable patients with opioid use disorder in opioid-
patients may not seek advice. Additionally, patients treatment programs to take home a 28-day supply of
may not be aware of the clinical role a pharmacist is medication or a 14-day supply for less stable patients.26
able to perform, including drug knowledge and One study showed a reduction in prescriptions for
counseling.31 Some patients feel that community opioid analgesics, and buprenorphine use for opioid
pharmacists may not have enough time to provide use disorder decreased among new patients during the
effective education.31 pandemic (but not among existing patients receiving
therapy).28 The ORT and SOAPP-R assessment tools
Naloxone can be conducted through telemedicine. An in-person
Naloxone is a highly competitive, mu-opioid recep- visit is recommended if a patient scores greater than 18
tor antagonist that reverses the central and periph- on the SOAPP-R and greater than 8 on the ORT.29
eral effects of exogenous and endogenous opioids Patients who use chronic opioids and are hospi-
within 2 to 5 minutes of administration. Naloxone talized for COVID-19 and who need to be intubated
can be administered through several different may require prolonged time on mechanical ventila-
routes, including IM, SC, and intranasal.22,23 The tors, and this may make extubating a greater chal-
CDC provides guidance in offering naloxone and lenge due to decreased respiration. Patients using
overdose-prevention education for patients and chronic opioids require opioids during hospitaliza-
their household for patients who are taking at least tion to prevent opioid-withdrawal syndrome, and
50 morphine milligram equivalents a day.1 There there is an increased risk of opioid-induced respira-
has been a decreased risk of death by opioid over- tory depression. Additionally, patients needing opi-
dose since community-based programs have distrib- oids have potential interactions with other necessary
uted naloxone.1 medications, including certain antibiotics or other
55
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Managing Chronic, Noncancer Pain With Opioids

drugs, which may be associated with prolongation cians provide pain relief in noncancer pain. Provid-
of the QT c and require closer monitoring during ers are not required to assess pain as a chronic
hospitalization. Clinicians may want to consider disease. When seeing patients, they should reassess
providing studied nonopioid alternatives and non- the need for the pain medication and, if appropri-
drug approaches for pain management in light of the ate, use validated tools to taper therapy. Commu-
COVID-19 pandemic in patients with opioid use nication plays a large part in establishing trust and
disorder. Additional research is needed to assess the a partnership with the patient, resulting in a more
impact of COVID-19 on long-term opioid use.27 successful taper. Pharmacists have a role in this
process.
Conclusion The content contained in this article is for informational purposes
The opioid epidemic has caused a shift in the pre- only. The content is not intended to be a substitute for professional
advice. Reliance on any information provided in this article is solely
scribing of opioids. It has changed the way clini- at your own risk.

REFERENCES
1. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing February 18, 2022.
opioids for chronic pain–United States, 2016. MMWR Recomm Rep. 17. Matthias MS, Johnson NL, Shields CG, et al. “I’m not gonna
2016;65(1):1-49. Erratum in: MMWR Recomm Rep. pull the rug out from under you”: patient-provider communication
2016;65(11):295. about opioid tapering. J Pain. 2017;18(11):1365-1373.
2. U.S. Department of Health and Human Services. What is the U.S. 18. Nuamah J, Sasangohar F, Erraguntla M, Mehta RK. The past,
opioid epidemic? www.hhs.gov/opioids/about-the-epidemic/index. present and future of opioid withdrawal assessment: a scoping review
html. Accessed December 1, 2021. of scales and technologies. BMC Med Inform Decis Mak. 2019;
3. U.S. Department of Health & Human Services. HHS Acting Secre- 19:113.
tary declares public health emergency to address national opioid cri- 19. Clinicians resources and Tools. My Top Care. www.mytopcare.
sis. www.hhs.gov/about/news/2017/10/26/hhs-acting-secretary- org/. Accessed December 21, 2021.
declares-public-health-emergency-address-national-opioid-crisis.html. 20. Hah JM, Trafton JA, Narasimhan B, et al. Efficacy of motiva-
Accessed December 4, 2021. tional-interviewing and guided opioid tapering support for patients
4. Washington State Agency Medical Directors’ Group (AMDG). undergoing orthopedic surgery (MI-Opioid Taper): a prospective,
Interagency guideline on prescribing opioids for pain. 2015. https:// assessor-blind, randomized controlled pilot trial. EClinicalMedicine.
agencymeddirectors.wa.govFiles/2015AMDGOpioid 2020;28:100596.
Guideline.pdf. Accessed November 23, 2021. 21. Lagisetty P, Smith A, Antoku D, et al. A physician-pharmacist
5. Busse JW, Craigie S, Juurlink DN, et al. Guideline for opioid ther- collaborative care model to prevent opioid misuse. Am J Health Syst
apy and chronic noncancer pain. CMAJ. 2017;189:E659-E666. Pharm. 2020;7(10):771-780.
6. Wenger S, Drott J, Fillipo R, et al. Reducing opioid use for 22. Kim HK, Nelson LS. Reducing the harm of opioid overdose with
patients with chronic pain: an evidence-based perspective. Phys Ther. the safe use of naloxone: a pharmacologic review. Expert Opin Drug
2018;98(5):424-433. Saf. 2015;14(7):1137-1146.
7. Austin RC, Fusco CW, Fagan EB, et al. Teaching opioid tapering 23. Rzasa Lynn R, Galinkin JL. Naloxone dosage for opioid reversal:
through guided instruction. Fam Med. 2019;51(5):434-437. current evidence and clinical implications. Ther Adv Drug Saf.
8. Ducharme J, Moore S. Opioid use disorder assessment tools and 2018;9(1):63-88.
drug screening. Mo Med. 2019;116(4):318-324. 24. Marroquin B, Vine V, Morgan R. Mental health during the
9. Krebs EE, Lorenz KA, Bair MJ, et al. Development and initial val- COVID-19 pandemic: effects of stay-at-home policies, social distanc-
idation of the PEG, a three-item scale assessing pain intensity and ing behavior, and social resources. Psychiatry Res. 2020;293:113419.
interference. J Gen Intern Med. 2009;24(6):733-738. 25. Czeisler ME, Lane RI, Petrosky E, et al. Mental health, substance
10. Von Korff M, DeBar LL, Krebs EE, et al. Graded chronic pain use, and suicidal ideation during the COVID-19 pandemic–United
scale revised: mild, bothersome, and high-impact chronic pain. Pain. States, June 24-30, 2020. MMWR Morb Mortal Wkly Rep.
2020;161(3):651-661. 2020;69(32):1049-1057.
11. Brott NR, Peterson E, Cascella M. Opioid Risk Tool. [Updated 26. Mitchell M, Shee K, Champlin K, et al. Opioid use disorder and
2021 May 19]. In: StatPearls [Internet]. Treasure Island, FL: Stat- COVID-19: implications for policy and practice. JAAPA.
Pearls Publishing; 2022. 2021;34(6):1-4.
12. Cheatle MD, Compton PA, Dhingra L, et al. Development of the 27. Shah R, Kuo YF, Baillargeon J, Raji MA. The impact of long-
revised opioid risk tool to predict opioid use disorder in patients term opioid use on the risk and severity of COVID-19. J Opioid
with chronic nonmalignant pain. J Pain. 2019;20(7):842-851. Manag. 2020;16(6):401-404.
13. Butler SF, Fernandez K, Benoit C, et al. Validation of the revised 28. Currie JM, Schnell MK, Schwandt H, Zhang J. Prescribing of
Screener and Opioid Assessment for Patients with Pain (SOAPP-R). J opioid analgesics and buprenorphine for opioid use disorder during
Pain. 2008;9(4):360-372. the COVID-19 pandemic. JAMA Netw Open. 2021;4(4):e216147.
14. Moore TM, Jones T, Browder JH, et al. A comparison of com- 29. Ogilvie CB, Jotwani R, Joshi J, et al. Review of opioid risk
mon screening methods for predicting aberrant drug-related behavior assessment tools with the growing need for telemedicine. Pain
among patients receiving opioids for chronic pain management. Pain Manag. 2021;11(2):97-100.
Med. 2009;10(8):1426-1433. 30. Murphy L, Ng K, Isaac P, et al. The role of the pharmacist in the
15. Covington EC, Argoff CE, Ballantyne JC, et al. Ensuring patient care of the patients with chronic pain. Integr Pharm Res Pract.
protections when tapering opioids: Consensus Panel Recommenda- 2021;10:33-41.
tions. Mayo Clin Proc. 2020;95(10):2155-2171. 31. Fatani S, Blake D, D’Eon M, El-Aneed A. Qualitative assessment
16. Oxford Pain Management Centre. Guidance for opioid of patients’ perspectives and needs from the community pharmacists
reduction in primary care. 2017. www.ouh.nhs.uk/services/refer- in substance use disorder management. Subst Abuse Treat Prev Pol-
rals/pain/documents/gp-guidance-opioid-reduction.pdf. Accessed icy. 2021;16(1):38.

56
U.S. Pharmacist • March 2022 • www.uspharmacist.com
Managing Chronic, Noncancer Pain With Opioids

Disclosure Statements:
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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
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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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Managing Chronic, Noncancer Pain 1. A B C D
Please print clearly and retain a copy for your records.
With Opioids 2. A B C D
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Lesson 122502 Type of Activity: Knowledge 0430-0000-22-025-H08-P

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U.S. Pharmacist • April 2021
U.S. Pharmacist • February 2022 • www.uspharmacist.com
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 Morphine Sulfate 5 mg/0.1 mL Nasal Solution
for the total amount to be prepared. Rx Ingredient Quantity
Accurately weigh or measure each (for 100 Morphine sulfate 5g
ingredient. Dissolve all of the ingre- mL): Benzalkonium chloride 10 mg
dients in sufficient purified water to Sodium chloride 200 mg
final volume and mix well. Package Purified water qs 100 mL
in a calibrated nasal-spray container
that delivers 0.1 mL per squeeze
(i.e., activation). MW 758.83) is a phenanthrene-derivative opiate
agonist used in the treatment of severe acute pain
Use: This preparation is used in the treatment of or moderate-to-severe chronic pain. It is odorless
moderate-to-severe pain. The dose is easily and occurs as white, feathery, silky crystals; cubi-
adjusted depending on the number of activations, cal masses of crystals; or a white, crystalline pow-
or squeezes, administered. der. Morphine sulfate gradually loses water of
hydration when exposed to air, and it darkens on
Packaging: Package in tight, light-resistant prolonged exposure to light. Morphine sulfate is
containers. soluble in water, freely soluble in hot water, and
slightly soluble in alcohol. It is available as injec-
Labeling: Keep out of reach of children. Discard tions, solutions, suppositories, and tablets, and as
after ____ [time period]. extended-release oral capsules and tablets.1
Benzalkonium chloride is a bactericidal antimi-
Stability: A beyond-use date of up to 30 days crobial agent commonly used as a preservative in
may be used for this formulation as a topical many ophthalmic, otic, nasal, and parenteral for-
preparation.1 mulations. It occurs as a white or yellowish-
white amorphous powder, a thick gel, or gelati-
Quality Control: Quality-control assessment can nous pieces/flakes with a characteristic mild
include weight/volume, pH, specific gravity, active aromatic odor, soapy touch, and very bitter taste.
drug assay, color, clarity, rheologic properties/ Benzalkonium chloride is highly soluble in water,
pourability, physical observation, physical stability alcohol, and acetone. It is hygroscopic, and a
(discoloration, foreign materials, gas formation, 10% w/v aqueous solution has a pH in the range
mold growth), and preservative-effectiveness of 5 to 8. Benzalkonium chloride is composed of
test.2,3 a mixture of straight-chain homologues that pos-
sess different physical, chemical, and microbio-
Discussion: Morphine sulfate has been used for logic properties. The proportions of these homo-
decades to treat moderate-to-severe pain. The logues in the mixture determine its effectiveness
advantage of this dosage form is that the dose to as a preservative and disinfectant. As a preserva-
be administered can be easily changed based on tive in ophthalmics, benzalkonium chloride is
the number of squeezes of the calibrated nasal- used in concentrations from 0.004% to 0.02%,
spray container. with the 0.01% concentration being common.1,4
Morphine sulfate ((C17H19NO3)2·H2SO4·5H2O, Sodium chloride (NaCl, MW 58.44) is avail-
able as a white, crystalline powder and colorless
Loyd V. Allen, Jr., PhD, RPh
Professor Emeritus, College of Pharmacy crystals with a saline taste. It is used in a variety
University of Oklahoma, Oklahoma City of parenteral and nonparenteral pharmaceutical
59
U.S. Pharmacist • March 2022 • www.uspharmacist.com
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- Hancock BC, Moss GP, Goldfarb DJ, eds. Handbook of Pharma-
ville, MD: U.S. Pharmacopeial Convention, Inc; February 2022. ceutical Excipients. 9th ed. London, England: Pharmaceutical Press;
2. Allen LV Jr. Summary of quality-control testing for sterile and 2020:132-135.
nonsterile compounded preparations, part 1: physical and chemical 5. Watters M. Sodium chloride. In: Sheskey PJ, Hancock BC, Moss
testing. IJPC. 2019;23(3):211-216. GP, Goldfarb DJ, eds. Handbook of Pharmaceutical Excipients. 9th
3. Allen LV Jr. Summary of quality-control testing for sterile and ed. London, England: Pharmaceutical Press; 2020:945-949.
nonsterile compounded preparations, part 2: microbiological test- 6. Dubash D, Shah U. Water. In: Sheskey PJ, Hancock BC, Moss
ing. IJPC. 2019;23(4):299-303. GP, Goldfarb DJ, eds. Handbook of Pharmaceutical Excipients. 9th
4. Kibbe AH, Quinn ME. Benzalkonium chloride. In: Sheskey PJ, ed. London, England: Pharmaceutical Press; 2020:1111-1115.

December 2021
Focus on: Gastroenterologic Diseases

Call for Specialty Pharmacy,


2 CE Credits

Pharmacist Review of
Loperamide Abuse
Probiotic Use in
Gastrointestinal
Oncology/Hematology Papers

I
Disorders
Special Section: Cold & Flu

n the majority of cases, articles are peer-reviewed


Comparing Oral Antivirals for
Seasonal Flu
Influenza in the Age of
COVID-19

and an honorarium is offered. As a general guideline,


Health Systems
we would like the articles to be approximately 2,500
Edition
Digesting the Updated
C difficile Guidelines
words. Prospective authors are urged to review the
Submitting a Manuscript information on the U.S.
Diabetes-Related
GI Emergencies

Pharmacist website at www.uspharmacist.com/


00_Dec_Cover_11_30.indd 1 12/2/21 2:10 PM

U.S. Pharmacist is
manuscript.
seeking articles on There is no guarantee that an article will appear in
specialty pharmacy, the Specialty Pharmacy/Oncology Focus Sections;
oncology, and however, there may be additional opportunities for these
hematology topics articles to appear in the National or Health Systems
for the Specialty Edition of U.S. Pharmacist.
Pharmacy/Oncology Interested authors should contact Robert Davidson,
Editor-in-Chief, at rdavidson@uspharmacist.com with
Focus Sections.
the specialty pharmacy or oncology/hematology topic(s)
they would like to cover. All articles must be original
and exclusive to U.S. Pharmacist.
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