Combinepdf

COVID-19 Vaccination
in Patients with Cancer:

Answers to The Most
Common Questions
Dr. Nabil Elhadi Omar

RPh, BSc Pharm, BCOP, PharmD, CBT-HMS, IPTeC
Date: March 16, 2021

Biography
● Graduated from College of pharmacy; Mansoura University, Egypt 2008.
● PharmD from College of pharmacy; Qatar University, 2016.
● American Board-Certified Oncology/Hematology Pharmacist (BCOP) 2013.
● One year Post graduate diploma in cancer biology and therapeutics from Harvard Medical School 2016-2017.
● Indiana Pharmacy Resident Teaching Certificate Program (IPTeC) from Purdue University and Butler University,
March 2020.
● Published 20 articles in highly ranked peer-reviewed journals.
● Presented 10 poster abstracts in international conferences.
● Presented more than 50 poster abstracts in national and regional conferences.
● Volunteered as peer reviewer for many international journals (Frontiers in immunology journal, cancer immunology
immunotherapy journal and cancer chemotherapy & pharmacology)
● Advanced Clinical Internship Preceptor, Doctor of Pharmacy Program, College of Pharmacy, Qatar University
● Currently working as clinical pharmacist specialized in oncology and palliative care at the National Center for
Cancer Care and Research, Hamad Medical Corporation, Qatar
Acknowledgment
● I would like to acknowledged Ph/ Rana Bassuni, PharmD candidate for her effort in the
preparation of this presentation
Disclosure
I have no conflicts of interest with the presented material in this presentation
Outline
1 Introduction
2 Review of vaccine development process
3 Summary of available COVID-19 Vaccines
Answers to the most common questions about the

4
use of the vaccine in cancer patients
5 Review of the guidelines
6 Summary and conclusion

01
Introduction
A Timeline
31 Dec. 2019 11 Mar. 2020
WHO was informed of cases of pneumonia of Rapid increase in the number of cases outside led
unknown cause in Wuhan City, China WHO to announce that the outbreak could be
characterized as a Pandemic
A novel coronavirus was identified as the cause by

Chinese authorities and was temporarily named
“2019-nCoV”
7 Jan. 2020
Current Knowledge
Definition:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the strain of coronavirus that causes
coronavirus disease 2019 (COVID-19), the respiratory illness responsible for the COVID-19 pandemic
Clinical Features:
● Incubation period: 14 days
● Recovery time: 2 weeks for mild infections and 3-6 weeks for severe disease
Clinical Presentation:
Current Knowledge
Severity of Illness Definition
Asymptomatic or Pre-  Test positive for SARS-CoV-2 using a virologic test

symptomatic × No symptoms that are consistent with COVID-19
Mild  have any of the various signs and symptoms of COVID-19

× Do not have shortness of breath, dyspnea, or abnormal chest imaging
Moderate  Show evidence of lower respiratory disease during clinical assessment or imaging
 Have saturation of oxygen (SpO2) ≥94% on room air
Severe  Have SpO2 <94% on room air respiratory frequency >30 breaths per minute, or lung
infiltrates >50%
Critical  Have respiratory failure, septic shock, and/or multiple organ dysfunction
Current Knowledge
Complications:
Several complications of COVID-19 have been described:
02
Review of Vaccine
Development Process
Back to The Timeline
December 2019 March 2020 October 2020
WHO was informed of cases of Rapid increase in the number of FDA issued guidance on
pneumonia of unknown cause in cases outside led WHO to Emergency Use Authorizations for
Wuhan City, China announce that the outbreak could Vaccines to Prevent COVID-19
be characterized as a Pandemic
A novel coronavirus was identified

as the cause by Chinese
authorities and was temporarily WHO and their partners launched
named “2019-nCoV” the ACT-Accelerator partnership
January 2020 April 2020

The Access to COVID-19 Tools (ACT) Accelerator
The goal of the ACT Accelerator is to end the COVID-19 pandemic as quickly as possible by reducing COVID-
19 mortality and severe disease through the accelerated development, equitable allocation, and scaled-up
delivery of vaccines, therapeutics and diagnostics to reduce mortality and severe disease. This will accelerate the
end of the health and economic crisis, restoring full societal and economic activity globally in the near term and
facilitating high-level control of COVID-19 disease in the medium term.
By the end of 2020, the Diagnostics, Therapeutics, Vaccine the Health Systems Connector pillars were
established. The vaccines pillar of the ACT-Accelerator is speeding up the search for an effective vaccine for all
countries
With a fast-moving pandemic, no one is safe, unless everyone is safe

December 2019 March 2020 October 2020
WHO was informed of cases of Rapid increase in the number of FDA issued guidance on
pneumonia of unknown cause in cases outside led WHO to Emergency Use Authorizations for
Wuhan City, China announce that the outbreak could Vaccines to Prevent COVID-19
be characterized as a Pandemic
A novel coronavirus was identified

as the cause by Chinese
authorities and was temporarily WHO and their partners launched
named “2019-nCoV” the ACT-Accelerator partnership
January 2020 April 2020

Emergency Use Authorizations (EUA)
An Emergency Use Authorization (EUA) is a mechanism to facilitate the availability and use of medical
countermeasures, including vaccines, during public health emergencies, such as the current COVID-19
pandemic. Under an EUA, FDA may allow the use of unapproved medical products, or unapproved uses of
approved medical products in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or
conditions when certain statutory criteria have been met, including that there are no adequate, approved, and
available alternatives.
Manufacturers are required to submit an EUA request to the FDA for review
Comparing the Process of Developing a Vaccine
Regular Vaccine Developing Vaccine at
Development Speed (COVID-19 Vaccine)
Comparing the Process of Developing Vaccines
03
Summary of available
COVID-19 Vaccines
December 2019 March 2020 October 2020 18 Dec. 2020
WHO was informed of Rapid increase in the FDA issued guidance on EUA allows the Moderna
cases of pneumonia of number of cases outside Emergency Use COVID-19 Vaccine to be
unknown cause in Wuhan led WHO to announce that Authorizations for distributed in the U.S.
City, China the outbreak could be Vaccines to Prevent
characterized as a COVID-19
Pandemic
A novel coronavirus was

identified as the cause by EUA allows the Pfizer-
Chinese authorities and WHO and their partners BioNTech COVID-19
was temporarily named launched he ACT- Vaccine to be distributed
“2019-nCoV” Accelerator partnership in the U.S.
January 2020 April 2020 11 Dec. 2020

Ccurrently Available Vaccines
Rolled out in Vaccine

Received EUA Included in clinical
countries across candidates in
from FDA trials
three platforms development
3 7 60 >200
Comparison Between Some of the Vaccines
Company Type Number of Time between Efficacy
doses doses
mRNA 21 days 95%

vaccine
mRNA 28 days 94.1%

vaccine
Viral vector 28 days 63.09%
Viral vector - 66%
Viral vector 21 days 91.6%
Subunit vaccine 21 days 95.6%

04
Answers to The Most Common
Questions About The Use of
The Vaccine in Cancer Patients
Q1 Shall cancer patients receive any vaccine?
A1 General Rule:
Yes, vaccines are important for patients with cancer as they are at increased of serious
infection. Many of these infections are vaccine preventable.
All indicated vaccines should be given to adult cancer patients before initiation of
chemotherapy, before therapy with other immunosuppressive drugs, and before radiation or
splenectomy, when feasible.
Indicated inactivated vaccines should be given ≥2 weeks prior to chemotherapy and

indicated live-virus vaccines should be given ≥4 weeks prior to chemotherapy.
Q1 Shall cancer patients receive any vaccine?
A1 Patients with cancer currently receiving chemotherapy or other immunosuppressive therapy

should not receive live-virus vaccines because of the risk of vaccine-derived infections.
Patients with cancer currently receiving chemotherapy or other immunosuppressive therapy

should not receive inactivated vaccines because they may not be effective
Q2 Are cancer patients eligible to receive COVID-19 vaccine?
A2 Yes, if they have no contraindications.
CDC: Immunocompromised individuals can receive COVID-19 vaccination if they have no

contraindications to vaccination. However, they should be counselled about the unknown
vaccine safety profile and effectiveness in immunocompromised populations, and the
potential for reduced immune responses and the need to continue to follow all current
guidance to protect themselves against COVID-19.
The JCVI: The committee’s advice is to offer vaccination to those aged 65 years and older
followed by those in clinical risk groups aged 16 years and older including cancer patients.
Contraindication to COVID-19 Vaccine
CDC considers a history of the following to be a contraindication to vaccination with
both the Pfizer-BioNTech and Moderna COVID-19 vaccines:
Severe allergic reaction (e.g., anaphylaxis) after a previous dose of an mRNA COVID-19 vaccine
or any of its components
Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any
of its components (including polyethylene glycol [PEG])
Immediate allergic reaction of any severity to polysorbate (due to potential cross-reactive

hypersensitivity with the vaccine ingredient PEG)
Q3 Do cancer patients need to be vaccinated?
A3 Yes, persons with immunocompromising conditions or who take immunosuppressive

medications or therapies might be at increased risk for severe COVID-19. Thus, they should
be prioritized to take the COVID-19 vaccine including those who are in remission.
The available evidence supports that patients with cancer, in particular with hematologic
malignancies, should be considered among the very high-risk groups for priority COVID-19
vaccination.
Q4 Have the vaccines been tested on cancer patients?
A4 Not yet, despite several vaccine candidates being in phase 2/3 clinical trials, no current
clinical trial of a COVID-19 vaccine has enrolled immunocompromised patients. Thus, the
efficacy and safety of a SARS-CoV-2 vaccine has not been established in the different
immunocompromised patient populations.
Q3.1 Are there any plans to do Phase 4 studies in immunocompromised patients?
A3.1 Yes, the FDA EUA recommends that immunocompromised individuals

and other subpopulations with specific comorbidities be studied in post-
authorization observational studies.
Q4 When should patients with cancer get the COVID-19 vaccine?
A4
Patients Cancer
undergoing Cancer patients
treatment survivors already had
COVID-19
Offer vaccination in
Offer vaccination as Wait 90 days post
between treatments
long as no infection to start the
when the patient is least
contraindications two injection vaccine
immunosuppressed
series
What are the expected side effects of the vaccines on cancer patients
Q5
and how to manage them?
A5
Common Serious
Side Side Effects Important for Side
Effects Cancer Patients Effects
Common
Side
The following side effects were more commonly reported in younger vaccine Effects
recipients and following the second shot of the 2-dose series:
 Pain or swelling at the injection site

 Fatigue
 Headache
 Fever
 Chills
 Muscle and joint pain
Common
Side
Effects
Side effects typically resolved after one to two days. Such side effects can be
managed by the following:
 To take pain relievers (like ibuprofen or acetaminophen) every 4–6

hours to manage headache or fever
 To drink plenty of fluids
 To rest throughout the day
 To soak in a bath to soothe aching muscles
 To use or exercise the arm
Serious
Side
Effects
 Anaphylaxis
It should be considered when signs or
symptoms are generalized (i.e., if there are
generalized hives or more than one body
system is involved) or are serious or life-
threatening in nature, even if they involve a
single body system (e.g., hypotension,
respiratory distress, or significant swelling of
the tongue or lips).
Serious
Side
Effects
If anaphylaxis is suspected, take the following steps:

1. Rapidly assess airway, breathing, circulation, and mentation (mental activity)
2. Call for emergency medical services (EMS)
3. Place the patient in a supine position with feet elevated, unless upper airway obstruction is present, or the
patient is vomiting.
4. Epinephrine is the first-line treatment for anaphylaxis and should be administered immediately.
• Epinephrine dose may be repeated approximately every 5-15 minutes if symptoms do not improve or if
they return while waiting for EMS. The number and timing of epinephrine doses should be recorded and
communicated to EMS.
Side Effects Important for
Cancer Patients
Axillary adenopathy (swollen/tender lymph nodes)
Some people have swelling or tenderness of the lymph nodes under the arm in which they got the injection. Axillary
adenopathy in women with an otherwise normal screening mammogram is a rare occurrence, reported in 0.02%-0.04% of
screening mammograms.
For patients receiving the Pfizer-BioNTech COVID-19 vaccine, lymphadenopathy was only reported as
an unsolicited adverse event with 58 more cases in the vaccine group than the placebo group (64 vs 6
respectively). Lymphadenopathy occurred in the arm and neck within 2-4 days of vaccination and
lasted for a mean of 10 days
For patients receiving the Moderna COVID-19 vaccine, axillary swelling or tenderness (i.e.,
lymphadenopathy) was a solicited adverse event reported in 11.6% of patients (vs 5.0% for
placebo) following dose 1 and 16.0% of patients (vs 4.3% for placebo) following dose 2
Side Effects Important for
Cancer Patients
Since the COVID-19 vaccine can cause swollen lymph nodes under the arm in which the
Caution injection was given, it is recommended that people with breast cancer or a history of
breast cancer get the injection in the unaffected arm.
 Consider a short term follow up exam in 4-12 weeks following the second vaccine
dose.
Management
 If axillary adenopathy persists after short term follow up, then consider lymph node
sampling to exclude breast and non-breast malignancy
05
Review of The
Guidelines
Guidelines To Be Reviewed
01
02
03
Guidelines To Be Reviewed
01
02
03
Therapy Specific
Disease Specific
Recommendations
Recommendations
Hematopoietic stem cell Rituximab

transplantation and cellular
therapy Immune
Hematologic Solid Tumors Steroids Intravenous Checkpoint
Malignancies Immunoglobulin Inhibitors
(IVIG) (ICIs)
Hematologic Malignancies
Disease Recommendation
CLL o Asymptomatic  Hold B-cell depleting therapy until one month after completion of vaccination
(special consideration of rituximab, o Small molecule therapy in symptomatic patients  hold vaccination until 1 month after completion of
venetoclax, ibrutinib)
treatment, once there is evidence of B-cell recovery
B- or T-ALL o Induction therapy for newly diagnosed disease should not be delayed for vaccination
(Induction/maintenance therapy) o Vaccine should be given during the maintenance phase at a time patient displays evidence of
hematopoietic count recovery. It can also be considered during induction with less intense regimens
DLBCL and other aggressive o Systemic induction therapy, including anti-CD20 antibodies, for newly diagnosed disease should in general
B-cell lymphoma not be delayed for vaccination.
o Vaccine should be given after completion of therapy, assuming patient is in remission and no further
treatment is planned, once there is evidence of B-cell recovery from anti-CD20 depletion
Indolent lymphomas o Asymptomatic  Hold B-cell depleting therapy until one month after completion of vaccination
o Systemic therapy needed treat with induction but without maintenance therapy, and vaccinating
following completion of therapy
T cell lymphomas o Therapy for newly diagnosed and progressive disease should not be delayed for vaccination purposes.
o Vaccine can be given during induction therapy, preferably following count recovery.
Lymphoma patients with o Systemic therapy with the potential for therapeutic benefit should not be delayed for vaccination purposes
relapsed or refractory
disease
Hematologic Malignancies
Disease Recommendation
Myeloma o With the exceptions of lymphodepleting therapy administration there are no specific disease or
treatment related contraindications for vaccination in patients with myeloma.
o Patients treated with lymphodepletion, vaccination can be attempted once lymphocyte recovery is
observed
AML o Induction therapy for newly diagnosed disease should not be delayed for vaccination purposes.
(induction/consolidation therapy) o Vaccine should not be given during the induction remission phase but should be considered during
consolidation therapy.
o Patients with relapsed disease may be considered for vaccination.
Myelodysplastic syndromes o Patients on observation or active therapy should be considered for vaccination
Myeloproliferative Neoplasm o Patients on observation or active therapy should be considered for vaccination
CML o Patients receiving TKIs (with or without remission) should be considered for vaccination.
Solid Tumors
Patients with solid tumors should receive the COVID-19 vaccine, as stratified by factors such as age. There are
no additional stratification recommendations related to cancer type or stage of disease at this time.
Patients planned for but not yet on Time first dose of vaccine to be given ≥ 2 weeks prior to initiation of
immunosuppressive cancer directed therapy therapy
Patients already on cytotoxic chemotherapy Time first dose of vaccine in between chemotherapy cycles, and away
from nadir period
Patients completing cytotoxic therapy Time first dose of vaccine to be given after therapy complete and
nadir period resolved
No specific timing is recommended relative to surgery from a vaccine

Patients undergoing cancer related surgery efficacy standpoint
Q Why might some hematology patients not respond to vaccines?
A In order to generate optimal protective immunity following vaccination,

intact host immunity is needed, particularly with respect to antigen
presentation, B and T cell activation, and plasma B cell antibody
generation. Therefore, hosts lacking functional adaptive immune cells
may be unable to generate a fully protective immune response to a
SARS-CoV-2 vaccine approved for use in the general population.
Therapy Specific Recommendations
Hematopoietic stem cell Rituximab

transplantation and cellular
therapy
Intravenous Immune
Steroids Checkpoint
Immunoglobulin
(IVIG) Inhibitors
(ICIs)
Hematopoietic stem cell transplantation
and cellular therapy
Treatment Timing of vaccine administration
Autologous HCT Vaccination may be initiated 2- 3 months after HCT
Conventional, no severe GVHD, no anti-CD20 Vaccination may be initiated as early as 3 months post HCT
antibodies
Ex-vivo T-cell depleted and post HCT Vaccination may be initiated around 6 months post HCT with
Allogeneic HCT confirmed presence of B cells (>50) and CD4+ T-cells (>100)
CART cell therapy and receipt of antiCD20 Vaccination may be initiated as early as 3 months if demonstrated
antibodies IVIG independence and B-Cell count ≥50
HSCT patients with GVHD So far, there is no data suggesting immune activation of
underlying conditions making the likelihood that COVID-19
vaccines will exacerbate GVHD low
Q When to postpone vaccination?
A • Severe, uncontrolled acute GVHD grades III – IV

• Recipients, who have received anti-CD20 antibodies during the last
six months and absolute B-cell count <50
• CAR T cell patients with B-cell aplasia (absolute B-cell count <50)
• Recent therapy with Anti-thymocyte globulin or alemtuzumab
IVIG
Steroids COVID-19 vaccines may be administered
Patients treated with corticosteroids as these are unlikely to substantially
should be vaccinated prior to therapy, impair development of protective antibody
if feasible responses.
Immune Checkpoint
Rituximab
It is recommended that patients Inhibitors (ICIs)
should be vaccinated prior to Patients on ICI therapy should receive
initiation of therapy when feasible the COVID-19 vaccine. Clinicians
should not pause ICI therapy for
vaccination (No specific timing is
recommended)
06
Summary and
Conclusion
Review of Questions and Answers
Yes,
if no
Shall cancer patients receive any vaccine? contraindic
ations
Yes,
Are cancer patients eligible to receive COVID-19 vaccine? if no
contraindic
ations
Do cancer patients need to be vaccinated? Yes

When should patients with cancer get the COVID vaccine?
Patients Cancer
undergoing Cancer patients
treatment survivors already had
COVID-19
offer vaccination in
offer vaccination as Wait 90 days post
between treatments
long as no infection to start the
when the patient is least
contraindications two injection vaccine
immunosuppressed
series.
What are the expected side effects of the vaccines on cancer patients?
Common Serious
Side Side Effects Important for Side
Effects Cancer Patients Effects
References
1. UpToDate [Internet]. UpToDate. 2021 [cited 24 February 2021]. Available from: https://www.uptodate.com/home
2. Coronavirus disease (COVID-19) – World Health Organization [Internet]. Who.int. 2021 [cited 24 February 2021]. Available from: https://www.who.int/emergencies/diseases/novel-
coronavirus-2019?gclid=EAIaIQobChMI2orf3oKD7wIVgh0rCh1bvQScEAAYASAAEgJtufD_BwE
3. How have Covid-19 vaccines been made quickly and safely? | News | Wellcome [Internet]. Wellcome. 2021 [cited 24 February 2021]. Available from: https://wellcome.org/news/quick-
safe-covid-vaccine-development
4. Collaboration and competition in the race for a COVID-19 vaccine [Internet]. lionbridge. 2021 [cited 24 February 2021]. Available from: https://www.lionbridge.com/blog/life-
sciences/collaboration-and-competition-in-the-race-for-a-covid-19-vaccine/
5. Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines | CDC [Internet]. Cdc.gov. 2021 [cited 24 February 2021]. Available from: https://www.cdc.gov/vaccines/covid-
19/info-by-product/clinical-considerations.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fvaccines%2Fcovid-19%2Finfo-by-product%2Fpfizer%2Fclinical-considerations.html
6. ASH-ASTCT COVID-19 and Vaccines: Frequently Asked Questions - Hematology.org [Internet]. Hematology.org. 2021 [cited 24 February 2021]. Available from:
https://www.hematology.org/covid-19/ash-astct-covid-19-and-vaccines
7. Vaccines FAQ [Internet]. Idsociety.org. 2021 [cited 24 February 2021]. Available from: https://www.idsociety.org/covid-19-real-time-learning-network/vaccines/vaccines-information--
faq/
8. Polack F, Thomas S, Kitchin N, Absalon J, Gurtman A, Lockhart S et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine.
2020;383(27):2603-2615.
9. Baden L, El Sahly H, Essink B, Kotloff K, Frey S, Novak R et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. New England Journal of Medicine. 2021;384(5):403-416.
10. Priority groups for coronavirus (COVID-19) vaccination: advice from the JCVI, 2 December 2020 [Internet]. GOV.UK. 2021 [cited 24 February 2021]. Available from:
https://www.gov.uk/government/publications/priority-groups-for-coronavirus-covid-19-vaccination-advice-from-the-jcvi-2-december-2020/priority-groups-for-coronavirus-covid-19-
vaccination-advice-from-the-jcvi-2-december-2020
References Cont.
11. Ribas A, Sengupta R, Locke T, Zaidi S, Campbell K, Carethers J et al. Priority COVID-19 Vaccination for Patients with Cancer while Vaccine Supply Is Limited. Cancer Discovery.
2020;11(2):233-236.
12. Shimabukuro T, Cole M, Su J. Reports of Anaphylaxis After Receipt of mRNA COVID-19 Vaccines in the US—December 14, 2020-January 18, 2021. JAMA. 2021;.
13. [Internet]. SBI Recommendations for the Management of Axillary Adenopathy in Patients with Recent COVID-19 Vaccination. 2021 [cited 24 February 2021]. Available from:
https://www.sbi-online.org/Portals/0/Position%20Statements/2021/SBI-recommendations-for-managing-axillary-adenopathy-post-COVID-vaccination.pdf
14. Side effects of the COVID-19 vaccine [Internet]. Geisinger.org. 2021 [cited 24 February 2021]. Available from: https://www.geisinger.org/health-and-wellness/wellness-
articles/2021/01/22/19/27/vaccine-side-effects
15. COVID-19 Vaccines in People with Cancer [Internet]. Cancer.org. 2021 [cited 24 February 2021]. Available from: https://www.cancer.org/treatment/treatments-and-side-
effects/physical-side-effects/low-blood-counts/infections/covid-19-vaccines-in-people-with-cancer.html
16. [Internet]. https://www.asco.org/sites/new-www.asco.org/files/content-files/2021-MSK_COVID19_VACCINE_GUIDELINES_final_V.2.pdf. 2021 [cited 24 February 2021]. Available

from: https://www.asco.org/sites/new-www.asco.org/files/content-files/2021-MSK_COVID19_VACCINE_GUIDELINES_final_V.2.pdf
17. COVID-19 Vaccine & Patients with Cancer [Internet]. ASCO. 2021 [cited 24 February 2021]. Available from: https://www.asco.org/asco-coronavirus-resources/covid-19-patient-care-
information/covid-19-vaccine-patients-cancer
18. Coronavirus Disease 2019 (COVID-19) Resources for the Cancer Care Community [Internet]. Nccn.org. 2021 [cited 24 February 2021]. Available from: https://www.nccn.org/covid-19/
19. [Internet]. Clinician Frequently Asked Questions (FAQs) and guidance on COVID19 vaccine for patients receiving Systemic Anti-Cancer Therapy. 2021 [cited 24 February 2021].
Available from: https://b-s-h.org.uk/media/19241/clinician-faqs-and-guidance-on-covid19-vaccine-for-patients-receiving-sa_.pdf
Thank you for listening
Questions?
Pain Management:
Non-Opioid Treatments
Learning Objectives
1. Recognize appropriate patient recommendations and explanations for non-prescription

treatment options including herbal, supplement, vitamin, antihistamine, topical, and stimulant.
2. Select appropriate patient recommendations and explanations for non-opioid prescription
treatment options including botulinum toxin, antihistamine, transdermal, and topical
medications.
3. Differentiate NSAIDs based on structural class, individual characteristics, unique side effects, and
anticipated drug-drug interactions.
Herbals & Supplements
Anti-inflammatory Properties
White Willow Bark

• Salicin
• Metabolized salicylic
Wintergreen acid
• Contains methyl
salicylate
Peppermint
• Menthol derived from
• Inhibits Sodium (Na)
channels
Caution: Drug Interactions

Herbals & Supplements
Anti-inflammatory Properties
Aquamin
Boswellia (Frankincense Extracted from)
Wild, Sweet, Winter, & Sour Cherries
Ginger
Ginseng (American, Panax/Asian, or Siberian)
Kava Kava
Valerian Root
St. John’s Wort
Devil’s Claw
Vitamin B & Vitamin D
o Low Vitamin B/D levels lead to increased pain & decreased immunity
Caution: Drug Interactions
L-methylfolate
Serotonin (5HT)
Folate (Natural)
Dihydrofolate Tetrahydrofolate L-methylfolate Norepinephrine
or Folic Acid MTHFR BBB
(DHF) (THF) (Bioactive) (NE) Dopamine
(Synthetic)
(DA)
L-Methylfolate Product ~ Pricing

(90)
Rx 15mg (Deplin®, etc.) $200-$500
Rx 7.5mg (Deplin®, etc.) $100-$500
Rx 3mg (Metanx®, etc.) $75-$225
Non-FDA Approved Supplements 1-5mg $12-$60

Emu Products
Observed Uses (MOAs)
 Arthritis (Omega-3, Omega-6, & Omega-9)
• Hypocholesterolemic Effect (Omega-3, Omega-6, & Omega-9)
• Mucositis (Omega-3, Omega-6, & Omega-9)
• Irritable Bowel Disease (Omega-3, Omega-6, & Omega-9)
• Cancer Chemotherapy Induced Bone Loss (TNF-alpha, RANK, etc.)
• Hair Loss (Omega-3, Omega-6, & Omega-9)
• Mosquito Repellant (Effective for ~30 Minutes)
Antihistamines
• Histamine promotes pain “transmission”
• Antihistamines have very little evidence of analgesia or

dose-sparing effects
o Commonly used for analgesia of bone pain

associated with chemo-induced neutropenia
o Promethazine commonly used as an adjunct to

opioids post-operatively
Stimulants
Amphetamine Products
• Controversial, Overstimulation of D/NE
• Similar MOA in ADHD treatment
Stimulants
Caffeine
Product Caffeine
• 1980’s Studies showed 40% Efficacy of APAP (~mg)
12oz. Starbucks® Cup of Joe 250
• Other studies showed adjunctive Cup of Decaf Joe 5
enhanced/prolonged effect with other analgesics Espresso (shot) 40

8oz. Black Tea 50
• Possible MOAs: 8oz. Green Tea 25
12oz. Can of Soda 40-50

(FDA Max 71)
• Block Adenosine Receptors?
8oz. Red Bull® 80
1.5oz Dark Chocolate 30
• COX-2 Inhibition? 1.5oz Milk Chocolate 10
Hot Cocoa 10
• or simply by affecting one’s mood

Botulinum Toxins
• Botulinum toxin is a neurotoxin which is produced by the Gram-positive anaerobic bacteria

Clostridium botulinum which causes Botulism, a disease that is characterized by potentially
life-threatening neuroparalysis
• There are seven distinct serotypes of Botulinum toxin : A, B, C1, D, E, F, and G
• Human botulism is caused mainly by types A, B, E, and (rarely) F
• 1989: FDA approves BOTOX® for strabismus (crossed eyes) & blepharospasm (twitching
eyelids)
• 2000: FDA approves BOTOX® for head & neck spasms
Al-Ghamdi AS, et al. Botulinum Toxin: Non Cosmetic & Off-Label Dermatological Uses. J Derm & Derm Surg 19 (2015) 1-8.
Botulinum Toxins
Products
o ONAbotulinumtoxinA (Botox®)
 100 Unit & 200 Unit Vials
o ABObotulinumtoxinA (Dysport®)
o INCObotulinumtoxinA (Xeomin®)
o RIMAbotulinumtoxinB (Myobloc®)
 2,500 U/mL, 5,000 U/mL, & 10,000 U/mL Vials
Typical Treatments
• Muscle Stiffness (Neck, elbow, wrist, & fingers)
• Headaches
Lidocaine
Transdermal Treatments
Lidocaine Mechanism of Action (MOA): Decreases frequency (not duration) of Na Channel opening
Prescription (Rx)
 Lidocaine 5% Patch (Lidoderm®)
o Up to 3 patches, 12 hours on & 12 hours off
o 40% Released in 1st Hour, then will release for almost 5 days
Over-The-Counter (OTC)
 Lidocaine 4% Patches
o Icy/Hot® (+ Menthol): Apply 1 patch up to every 12 hours
Lidocaine
Transdermal Treatments
o 0.5% to 5.0%
o Dentinox, Jogel, Doxiproct, etc …
Prescription (Rx)
o Lidocaine 5% Ointment
o Eutectic Mixture of Local Anesthetics (EMLA® Rx Cream)
 Lidocaine 2.5% & prilocaine 2.5% (25mg each per 1g)
 Apply with occlusion for 1-2 hours, remove, then pain relief lasts 1-2 hours
Topical Treatments
Counterirritants
o MOA: Flood pain/touch sensory channels (TRP-V1/PA1/M8)
o Examples: Menthol, methyl salicylate, eucalyptus oil, turpentine oil, & camphor
o Products: Icy/Hot®
Capsaicin
o Found in hot chili peppers & depletes Substance P (pain transmission)
o OTC 0.025% & 0.075% Creams & Patches
Topical Treatments
Topical NSAIDs
Patch Diclofenac epolamine 1.3%
Solution Diclofenac Sodium 1.5%
Gel Diclofenac Sodium 1% (Voltaren®)

Diclofenac sodium 5% (Diclac®)
Clinical Pharmacology Online Database. 2018.

Topical Treatments
NSAIDs
Voltaren® Gel
• FDA Approved for osteoarthritis pain relief in joints (knees and hands)
• Dosing
o 2 g for each elbow, wrist, or hand
o 4 g for each knee, ankle, or foot
 Max Dose Per Day is 32g
• Penetration Enhancers
o Isopropyl alcohol, propylene glycol, and water
Novartis. 2009. Voltaren Gel Prescribing Information. http://www.voltarengel.com/common/pdf/Voltaren-PI-10-19.pdf

NSAID Mechanisms of Action
Major Side Effects of NSAIDs & COX-2 Selective Inhibitors. March 2017. http://tmedweb.tulane.edu/pharmwiki/doku.php/nsaid_side_effects
Major Side Effects of NSAIDs & COX-2 Selective Inhibitors. March 2017. http://tmedweb.tulane.edu/pharmwiki/doku.php/nsaid_side_effects
NSAIDs
Non-Steroidal Anti-Inflammatory Drugs
NSAIDs inhibit prostaglandin biosynthesis by preventing arachidonic acid binding to
• Cyclooxygenase (COX) Enzymes 1 & 2
o Also known as Prostaglandin Endoperoxide Synthase 1 & 2
o Also known as prostaglandin G/H synthase 1 & 2
Cox-1
COX-1
• Expressed in nearly all cells but mainly functioning in the GI tract, kidneys, & platelets
• Produces thromboxane & prostacyclin in equal amounts, maintaining a balance
COX-2
• Expressed in the brain, kidneys, & blood vessels (i.e. the areas most susceptible to Cox-2
thrombotic events)
• Expression of COX-2 can be induced by cytokine release due to injury or inflammation
COX-1 Inhibitors COX-2 Inhibitors

Pros Pros
• Inhibits production of thromboxane • More specific to prostaglandins
➢Less Cardio issues (MI/stroke) ➢Less GI issues (Less ulcers & bleeds)
Cons Cons
• Affects GI mucosa • Inhibits production of prostacyclin
➢Peptic ulcers/GI bleeding ➢More Cardio concerns (MI/Stroke)
Feldman M & McMahon A. Do Cyclooxygenase-2 Inhibitors Provide Benefits Similar to Those of Traditional Nonsteroidal Anti-Inflammatory Drugs, with Less Gastrointestinal Toxicity? Ann Intern Med. 2000;132:134-143.
COX-1 Selective COX-2 Selective
Feldman M & McMahon A. Do Cyclooxygenase-2 Inhibitors Provide Benefits Similar to Those of Traditional Nonsteroidal Anti-Inflammatory Drugs, with Less Gastrointestinal Toxicity?
Ann Intern Med. 2000;132:134-143.
The 4 A’s of Cox Inhibition
1. Anti-inflammatory (reduces inflammation)

2. Antipyretic effect (reduces fever)
3. Antithrombotic effect (reduces platelet
stroke risk)
4. Analgesic effects (reduces pain)
Pain Management:
Non-Opioid Treatments (Part II)
Learning Objectives
1. Recognize appropriate patient recommendations and explanations for non-prescription

treatment options including herbal, supplement, vitamin, antihistamine, topical, stimulant, and
electrical treatments.
2. Select appropriate patient recommendations and explanations for non-opioid prescription
treatment options including botulinum toxin, antihistamine, transdermal, and topical
medications.
3. Identify appropriate patient explanations for interventional pain management therapies
including nerve blocks and injections, radio-frequency ablations, neurostimulation, pain pumps,
and also surgical treatment options.
4. Differentiate NSAIDs based on structural class, individual characteristics, unique side effects, and
anticipated drug-drug interactions.
Over-The-Counter (OTC) NSAIDs
OTC NSAID OTC Amount OTC Dosage OTC Daily Max
ibuprofen 200mg 1 tab q 4 to 6 h 6 tablets
naproxen 220mg 1 tab q 8 to 12 h 3 tablets
aspirin (Low Dose) 81mg 4 or 8 tab q 4 h 48 tablets
aspirin (Regular Strength) 325mg 1 or 2 tabs q 4 h 12 tablets

3 tabs q 6 h
aspirin (Extra Strength) 500mg 1 or 2 tabs q 4 to 6 h 8 tablets
https://www.getreliefresponsiblyprofessional.com/sites/getreliefresponsiblyhcp_us/files/PDF/GRRAdultDosingChart.pdf
NSAID Structural Classes
Acetic Acids Fenamates Oxicams Proprionic Diarylheterocycles (Naphthyl) Salicylates
(Anthranilic Acids) (Enolic Acids) Acids (COX-2 Selective) Alkanones
Indole/Indene meclofenamate meloxicam fenoprofen celecoxib nabumetone Acetylated
etodolac mefenamic Acid piroxicam flurbiprofen aspirin
indomethacin ibuprofen Non-Acetylated
sulindac ketoprofen choline salicylate
Heteroaryl naproxen magnesium

salicylate
tetrahydrate
diclofenac oxaprozin choline magnesium
trisalicylate
ketorolac diflunisal
tolmetin salsalate
Antman EM, et al. Use of Nonsteroidal Anti-Inflammatory Drugs. Circulation. 2007;115:1634-1642.

NSAIDs
Acetic Acids
NSAIDs
Acetic Acids (Indole/Indene)
Etodolac
• 2-{1,8-diEThyl-1H,3H,4H,9H-pyranO[3,4-b]inDOL-1-yl}ACetic acid
• Approved in 1991 for OA and RA

• Notable ADE: GI (dyspepsia 10%)
• Products
o Brand Name
 Lodine® 400mg tablets
o Generics
 400mg/500mg tablets
 200mg/300mg capsules
 400mg/500mg/600mg ER tablets
NSAIDs
Indomethacin
• 2-[1-(4-chlorobenzoyl)-5-METHoxy-2-METHyl-1H-INDOl-3-yl]ACetic acid
1964: Synthesized as a potent anti-inflammatory
1965: 1st FDA Approved non-aspirin NSAID

 Same relative gastrointestinal (GI) upset to
aspirin, but reduced “pill burden” and acid
load, thus increasing tolerability
NSAIDs
Indomethacin
• Preterm Labor
• Tocolytic: inhibits cytokines that may trigger labor (Constricts ductus arteriosus)
• American Geriatric Society (AGS) & Beers’ List

• Avoid long term use in elderly (GI & Cardiovascular Risks)
• Notable ADEs
• GI Upset, Edema, Hyperkalemia, Hypernatremia, & Hypertension
• Metabolism
• CYP-2C9 Substrate
NSAIDs
Indomethacin
• Products
o Generic 75mg SR capsules (FDA Approved 1982)
o Generic 25 & 50mg capsules (FDA Approved in 1965)
o Tivorbex® 20mg & 40mg capsules (FDA Approved 2014)
o Indocin® 50mg rectal suppository (also available generic)
o Indocin® 25mg/5mL suspension
o Generic 1mg powder for injection

NSAIDs
Sulindac
• 2-[(1Z)-5-fluoro-1-[(4-methaneSULfinylphenyl)methylidene]-2-methyl-1H-
INDen-3-yl]ACetic acid
• Prodrug with less relative NSAID induced GI Upset
• Products: Generic tablets 150mg and 200mg
• Currently being studied for Alzheimer’s Disease

NSAIDs
Acetic Acids (Heteroaryl)
Diclofenac
• 2-(2,6-DIChLOranilino)-PHENylacetic Acid
o Synthesized by Alfred Sallmann and Rudolf Pfister

o Ciba-Geigy introduced diclofenac in 1973
o CYP-2C9 Substrate
• Notable ADEs
o Edema (33%)
o >Relative NSAID Liver Toxicity
Available Diclofenac Products
Formulation Brand Generic 1988: Voltaren® 25/50/75mg EC Tablets

Topical Patch Flector® X o Dosing: 50 mg BID-TID or 75mg BID
Topical Gel Solaraze® & Voltaren® Available 1996: Voltaren® 100mg XR Tablets
Topical Powder Rexaphenac® X o Dosing: QD
Topical Solution Pennsaid® Available
2009: Zipsor® 25mg Capsules
Capsule / Capsule (liquid filled) Zorvolex / Zipsor
® ® X
o Dosing: QID
Tablet IR/ER/XR Voltaren® (XR) Available
Powder for Oral Solution Cambia® X 2015: Zorvolex® 18mg & 35mg
Ophthalmic Solution X Available o Solu-matrix Capsules
Solution for Injection Dyloject® X o Dosing: Up to TID

NSAIDs
Ketorolac
• 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-caRbOxyLic ACid
• Structurally related to indomethacin, yet with internal KETO group
Keto
• Products
• Sprix® nasal spray
• Acular® ophthalmic solution (generic available)
• Generic tablets
• Generic solution for injection
 DO NOT USE FOR MORE THAN 5 DAYS (GI/Heart/Kidneys)

Ketorolac (Toradol®)
NSAIDs
Tolmetin
• 2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic acid
• Notable ADE
o Nervousness (up to 3%)
• Generic Products
o 400mg capsule
o 200mg & 600mg tablet


salicylate
tetrahydrate
diclofenac oxaprozin choline
magnesium
trisalicylate
tolmetin salsalate

NSAIDs
Fenamates (Anthranilic Acids)
Meclofenamate
• 2-[(2,6-diCHLOro-3-MEthylPHENyl)AMINo]benzoic acid
• FDA approved in 1980 for joint & muscle pain
 Inhibits PGs & Leukotrienes, thus possibly better in Asthma
• Products
• Generic 50mg & 100mg capsules (solely by Mylan Pharmaceuticals)
NSAIDs
Fenamates (Anthranilic Acids)
Mefenamic Acid
• 2-[(2,3-diMEthylPHENyl)AMino]benzoIC acid
o Discovered and marketed by Parke-Davis in 1960’s

o Indicated for mild to moderate pain (menstrual)
o CYP-2C9 Substrate
• Notable ADE
o Premature closure of the ductus arteriosus
 Package Insert updated in 2008 to include
• Products
o Ponstel® 250mg capsule (generic available)



salicylate
tetrahydrate
trisalicylate
tolmetin salsalate

NSAIDs
Oxicams (Enolic Acids)
Meloxicam
• 4-hydroxy-2-methyl-N-(5-MEthyl-1,3-thiazoL-2-yl)-1,1-diOXo-2H-1λ⁶,2-benzothiazine-3
CArboxaMide
• Developed by Boehringer-Ingelheim as a derivative of enolic acid
• Used often in Veterinary medicine
• Products
o Mobic® 7.5mg/15mg tablet (FDA Approved 2000, generic available)
o Vivlodex® 5mg/10mg capsule (FDA Approved 2015)
o Generic 7.5mg/5mL suspension
NSAIDs
Oxicams (Enolic Acids)
Piroxicam
• 4-hydroxy-2-methyl-1,1-diOXo-N-(PYRidin-2-yl)-2H-1λ⁶,2-benzothiazine-3-CArboxaMide
• Launched in 1980 by Pfizer

• Dosing: Once daily
• Max therapeutic effect seen in >/= 2 weeks
• Notable ADE
• Skin reactions (more than others)
• Products
• Feldene® 10mg & 20mg capsules (generic available)
Fenamates Oxicams Proprionic Diarylheterocycles (Naphthyl)

Acetic Acids Salicylates

salicylate
tetrahydrate

magnesium
trisalicylate
tolmetin salsalate
NSAIDs
Proprionic Acids
Al-Ghamdi AS, et al. Botulinum Toxin: Non Cosmetic & Off-Label Dermatological Uses. J Derm & Derm Surg 19 (2015) 1-8.
NSAIDs
Proprionic Acids
Fenoprofen
• 2-(3-PHENOxyPHENyl)-PROpanoic acid
• Typical Uses
o Acute & Post-operative Pain
o Dysmenorrhea
• Products
o Nalfron® 200mg & 400mg capsules (only generic 400mg available)
o ProFeno® 600mg tablet (generic available)
NSAIDs
Proprionic Acids
Flurbiprofen
• 2-(3-FLUORO-4-PHENylphenyl)-PROpanoic acid
• Pharmacia & Upjohn developed in the US in 1988 (Boots UK in 1960s)
• Clinical Pearls
o Initial Dose 100mg q 12h
o Taking with food decreases absorption & GI ADEs
o CYP-2C9 Substrate
• Products
o Ansaid® 100mg tablet
o Flurbiprofen 50mg & 100mg tablets
o Ocufen® 0.03% ophthalmic solution (generic available)
NSAIDs
Proprionic Acids
Ibuprofen
• 2-(4-IsoBUtylPHENyl)-PROpionic acid, or
• 2-[4-(2-methylPROpyl)PHENyl]propanoic acid
• History
• 1961: Discovered by Dr. Stewart Adams & John Nicholson) of UK Boot Rx
• 1969: Available in the UK market
• 1974: Rx formulation available in the USA market
• 1984: OTC formulation available in USA market
NSAIDs
Proprionic Acids
Ibuprofen
• 1996: Children’s liquid available in USA market (*For those > 6 Months of Age)
o Fever < 102.5 F̊ (39 c) → 5mg/kg
o Fever >/= 102.5 F̊ (39 c) → 10mg/kg
 Most references generally recommend: ~8mg/kg
 Notable (but rare) ADE: Aseptic Meningitis

o Most frequent cause of drug-induced aseptic meningitis
 CYP-2C9 Substrate
 Being studied in Parkinson’s and Alzheimer’s

NSAIDs
Proprionic Acids
Ibuprofen
• Exists as a racemate (racemic mixture)
• ~60% of R-ibuprofen is converted to S-

ibuprofen
• Higher S-ibuprofen concentrations led to

greater inhibition of Cox-1 & Cox-2
• S-ibuprofen is metabolized via CYP2C9 to

inactive metabolites
NSAIDs
Proprionic Acids
Ibuprofen Products
OTC junior ibuprofen 100mg
OTC ibuprofen 200mg
OTC concentrated infant drops 50mg/1.25mL
OTC children’s suspension 100mg/5mL
Prescription ibuprofen 400mg, 600mg, & 800mg

NSAIDs
Proprionic Acids
Ketoprofen
• 2-(3-BENZOYLphenyl)-PROpanoic acid
• Marketed in 1973
• Was OTC as coated tablets, but classification changed to Rx
• Commonly utilized in horse veterinary care
• Products
o Generic 50mg & 75mg capsule
o Generic 200mg ER capsule
o Compounding 5% kit
NSAIDs
Proprionic Acids
Naproxen
• (2S)-2-(6-methOXyNAPhthalEN-2-yl)-PROpanoic acid
• First marketed in 1976 by Syntex for OA and RA
• Commonly utilized in horse veterinary care
 OTC → Approved for Age > 12 years
 Rx → Approved for Age > 2 Years
• Products
o Aleve® 220 mg capsule & caplet (generics available)
o Naprosyn® 250 mg, 375 mg, 500 mg IR & EC (generics available)
o Naprosyn® 125mg/5mL solution (generic available)
o Naprelan® ER 375 mg, 500 mg, & 700 mg (generics available)
NSAIDs
Proprionic Acids
Oxaprozin
• 3-(diphenyl-1,3-OXAzol-2-yl)-PROpanoic acid
• Clinical Pearls
• Initiation of Acute therapy can include a three (600mg) tablet loading dose
• Products
o Oxaprozin 600mg tablet


salicylate
tetrahydrate
magnesium
trisalicylate
tolmetin salsalate

NSAIDs
Diarylheterocycles (COX-2 Selective or Coxibs)
Celecoxib
• 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-1-sulfonamide
• Clinical Pearls
• All other coxibs have H3CO2S chains whereas celecoxib has a H2NO2S chain
• Also FDA approved for treatment of familial adenomatous polyposis
o An autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the
epithelium of the large intestine, which if left untreated can become malignant
• Being studied for treatment in breast cancer
• Products
o Generic Capsules: 50mg, 100mg, 200mg, & 400mg


Heteroaryl magnesium
naproxen
salicylate
tetrahydrate
trisalicylate
tolmetin salsalate

NSAIDs
(Naphthyl) Alkanones
Nabumetone
• 4-(6-METhoxy-2-NAphthyl)-2-ButanONE
• Clinical Pearls
 Typically less GI ADEs
o Prodrug, active 1st past metabolite 6-methoxy-2-naphthylacetic acid (6MNA)
o 6MNA metabolite does not undergo enterohepatic recirculation
o 6MNA metabolite is more Cox-2 selective (but not a clear selectivity)
o Is a ketone, thus only non-acid NSA
 Once Daily Dosing (with or without food)
• Products
o Generic only 500mg & 750mg tablets


naproxen
salicylate
tetrahydrate
trisalicylate
tolmetin salsalate

NSAIDs
Salicylates (Acetylated)
Aspirin
Acetyl-Salicylic Acid (ASA)
Aspirin → Acetyl SPIRIN (Spiraea ulmaria plant, Meadowsweet))
1897
• Dreser authored early study, & Eichengrun directed Hoffmann to synthesize
1899
• Bayer introduced for medical use
1970’s
• John Vane determined ASA Mechanism of Action
o PG Inhibition (Irreversible COX Inhibition)
NSAIDs
Salicylates (Acetylated)
Aspirin
MOA: Inhibit COX-1 & COX-2 (Slightly more Cox-1 Selective)
o Irreversibly blocks platelets for their 7 day duration lifespan
o Complete COX-1 blockade achieved with 75-150mg
Notable (but rare) ADE: Reye’s Syndrome Metabolism: Hepatic de-
acetylation to salicylic acid
Products
o Aspirin 81mg chewable tablet (generic available)
o Aspirin 81mg, 325mg, 500mg, 650mg tablet (generics available)
o Aspirin 300mg & 600mg rectal suppository (generics available)
o Aspirin EC 81mg, 325mg, 500mg (generics available)
o Aspergum® 227mg chewing gum !!! NOT for use in Children !!!
o Durlaza® 162.5mg extended-release (ER) capsule

Reyes Syndrome
• 1st description of Reye syndrome published in The Lancet in 1963 by Dr. Douglas Reye
• Children are most commonly affected, with less than one in a million a year
• Acute non-inflammatory encephalopathy and fatty degenerative liver failure
• “Syndrome” rather than a disease as the clinical features are quite broad
• Typically occurs after a viral illness (i.e. Upper respiratory tract infection, influenza, varicella,
or gastroenteritis) and is associated with the use of aspirin during the illness
Reyes Syndrome
• Early symptoms include diarrhea, rapid breathing, vomiting, and severe fatigue
 Serious Symptoms such as confusion, seizures, and loss of consciousness
• All children with Reye syndrome symptoms should be tested for IEMs
o Inborn Errors of Metabolism (IEMs)
o Large group of rare genetic diseases that result from a defect in an enzyme or
transport protein involved in a metabolic pathway
• There's no specific treatment for Reye's syndrome beyond supportive care and
aggressive monitoring for complications
NSAIDs
Salicylates (Non-Acetylated)
No inhibition of Thromboxane (better for use if patient has bleeding risk)

No affect on GI Prostaglandins (better for use if patient has risk of GI bleeding and ulcers)
NSAIDs
• Choline Salicylate
o Choline salt isolated from ox & pig bile in 1862 by Adolph Strecker
o OTC for cold combinations, numbing topicals, ear wax removal, etc.
o Oral Gel 15 GM
o Choline Salicylates +Glycerin Ear drops 10ml solution
NSAIDs
• Diflunisal
• Unique utilization: Reduce progression of Familial Amyloid Polyneuropathy (FAP)
o Rare group of autosomal dominant diseases wherein the autonomic nervous system is
compromised by protein aggregation and/or amyloid fibril formation
o Heart enlargement and irregular heartbeats are the leading causes of death
o Other symptoms: numbness, tingling, and swelling in your hands and feet
• Generic 250-500mg tablet available
• Salsalate
• Prodrug for Salicylic Acid (Hepatic metabolism to salicylic acid)
• Products: 500mg & 750mg tablet (generics available)


naproxen
salicylate
tetrahydrate
trisalicylate
tolmetin salsalate

NSAID and COX 1 / COX 2 selectivity
COX-2 : COX-1
Herndon, C. et al. Management of Chronic Nonmalignant Pain with Nonsteroidal Anti-inflammatory Drugs. Pharmacotherapy. 2008; 28 (6): 788-805.
FDA 2015 Statement
NSAID Cardiovascular Risk
 Risk of heart attack or stroke as early as the first weeks of use, and may increase with continued use
 Insufficient information to determine that the risk varies amongst individual NSAIDs
 Numerous studies show the increased risk of heart attack or stroke in patients with or without heart
disease or risk factors for heart disease
o However, patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke
following NSAID use than patients without these risk factors because they have a higher risk at baseline
o Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the
heart attack compared to patients who were not treated with NSAIDs after their first heart attack
 There is an increased risk of heart failure with NSAID use, which increases with elevated doses
Center for Drug Evaluation and Research. (2015, July 9). Drug Safety and Availability - FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-
inflammatory drugs (NSAIDs) can cause heart attacks or strokes. Retrieved October 12, 2017, from https://www.fda.gov/Drugs/DrugSafety/ucm451800.htm
NSAID GI Risk Studies
Variability among nonsteroidal anti-inflammatory drugs in risk of upper

gastrointestinal bleeding. Arthritis Rheum 2010
NSAID GI Bleed RR
celecoxib 1.42
ibuprofen 2.69
Traditional NSAID GI Bleeding -Coxib GI Bleeding
diclofenac 3.98
Relative Risks (RR) Relative Risks (RR)
meloxicam 4.15
4.50 1.88
indomethacin 4.15
ketoprofen 5.4
naproxen 5.57
piroxicam 9.94
ketorolac 14.54
Masso Gonzalez EL, et al. Variability among nonsteroidal anti-inflammatory drugs in risk of upper gastrointestinal bleeding. Arthritis Rheum 2010;62:1592-601.
NSAID GI Risk Studies
PRECISION Trial
Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med 2016
• A randomized head-to-head comparison of celecoxib, naproxen, and ibuprofen (no placebo)

in patients with arthritis and CV risk factors or disease
• All patients received esomeprazole
• 70% percent of patients dropped out
 The risk of a serious GI event was lowest with celecoxib

o Celecoxib was linked to one fewer serious GI event for every 200 patients
Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med Nov 13, 2016.
NSAID GI Risk Mechanisms
1. Ion Trapping
o NSAIDS are highly lipophilic weak acids that freely diffuse into gastric cells in non-ionized forms
o Then revert to ionized form slowing the exiting back outside the cell, resulting in NSAID accumulation
o Example: aspirin pKa 3.5, crosses the gastric mucosa (pH 2), then reverts to ionized form within the cell
(pH 7) and thus slowly passes to extracellular fluid
2. Suppression of Prostaglandin Synthesis
o Prostaglandins (PG) increase mucus and bicarbonate secretion
o COX-1 assists in production of PGs
o Thus, COX-1 inhibitors remove natural protective mechanisms of the GI mucosa
3. Anticoagulant effects of NSAIDS
o Thromboxanes (TXAs) facilitate platelet aggregation
o COX-1 assists in production of TXAs
o Thus, COX-1 inhibitors increase anticoagulant effects, increasing the risk of bleeding
GI Protective Medications
Misoprostol
o Reduces the relative risk of gastroduodenal complications by ~40% among patients at higher risk
o Recommended dose is 200 mcg QID, but adverse effects (e.g., diarrhea, cramping) typically limit dosage
o Pregnant women should not handle (or ingest) as per USP 800 (1997)
Proton Pump Inhibitors

o Reduce the risk of bleeding ulcers associated with celecoxib in high-risk patients
H2-blockers
o Typical doses reduce the risk of NSAID-associated duodenal ulcers (but not GI bleeding)
o High-dose H2-blockers reduce the risk of both duodenal and gastric ulcers (but not GI bleeding)
o Benefit is highest in patients with H. pylori
Chan FK, Graham DY. Review article: prevention of non-steroidal anti-inflammatory drug gastrointestinal complications-review and recommendations based on risk assessment. Aliment
Pharmacol Ther 2004;19:1051-61. http://usp.org/sites/default/files/usp/document/our-work/healthcare-quality-safety/general-chapter-800.pdf
GI vs Cardio Risks & NSAID Use
• Low GI risk & Low CV risk → celecoxib

• Low GI risk & High CV risk → Naproxen or low-dose celecoxib (if on aspirin, naproxen + PPI/misoprostol)
• Moderate GI risk & Low CV risk → celecoxib +/- PPI/misoprostol

• Moderate GI risk & High CV risk → 1. naproxen + PPI/misoprostol, 2. Low Dose celecoxib
• High GI risk & Low CV risk → 1. Avoid NSAIDs if possible, 2. celecoxib + PPI/misoprostol
• High GI risk & High CV risk → Avoid NSAIDs
Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009;104:728-38.
Bottom-Line NSAID Controversy
COX-1 Selective COX-2 Selective
Patient with Cardio Risk → naproxen + PPI (unless High GI Risk)

Patient with GI Risk → celecoxib + PPI (Avoid NSAIDs if possible)
MONITOR ALL!
Feldman M & McMahon A. Do Cyclooxygenase-2 Inhibitors Provide Benefits Similar to Those of Traditional Nonsteroidal Anti-Inflammatory Drugs,
with Less Gastrointestinal Toxicity? Ann Intern Med. 2000;132:134-143.
NSAID Drug-Drug Interactions
CYP450 2C9
CYP-2C9 Substrate
ibuprofen
naproxen (minor 1A2)
Strong Inducers Strong Inhibitors
flurbiprofen amiodarone fluconazole
indomethacin carbamazepine fluoxetine metronidazole
phenobarbital ritonavir
diclofenac (minor 3A4)
phenytoin rifampin trimethoprim/sulfamethoxazole
piroxicam
meloxicam
mefenamic acid
celecoxib
NSAID Drug-Drug Interactions
Increased Risk of GI Bleeding
Aspirin (~81mg Cardio Dosage)
o Avoid ibuprofen, naproxen, and indomethacin
o Prefer diclofenac, sulindac, meloxicam, or celecoxib
o Take ASA 2 hours before NSAID (if once a day)
SSRIs/SNRIs
o Preferred NSAIDs: diclofenac, sulindac, meloxicam, or celecoxib
o Alternative antidepressants: TCAs (desipramine or nortriptyline)
Spironolactone
Steroids
NSAID Interactions
Afferent Arteriole Kidney Efferent Arteriole
Angiotensin 2 → Vasoconstriction
PGs → Afferent Vasodilation
ACEIs/ARBs Block Angiotensin 2 Monitor
NSAIDs Block PGs
ACEIs/ARBs → Efferent Vasodilation BP, K, & Edema
NSAIDs → Afferent Vasoconstriction
ACEIs/ARBs → Decreased GFR
NSAIDs → Decreased GFR
NSAID Clinical Pearls
 Cautionary Use
o Asthma/COPD (Increased Leukotrienes)
o Impaired Renal Function (Decreases GFR)
o NSAIDs inhibit PG mediated afferent vasodilation
 Preferential Use
o Gout
Rx
o NSAIDs increase urinary excretion of urates
gut.bmj.com
.
NSAID PO Adult Dosing
NSAID Dosing Schedule

Maximum Daily Dose
(mg/day) NSAID Dosing Schedule
Maximum Daily Dose
(mg/day)
Aspirin Q 4 to 6 hours 4,000 Etodolac Q 6 to 8 hours 1,200
Diflunisal Q 8 to 12 hours 1,500 Indomethacin Q 8 to 12 hours 200
Choline Magnesium Trisalicylate Q 8 to 12 hours 4,000 Sulindac Q 12 hours 400
Choline Salicylate Q 4 to 6 hours 5,352 Tolmetin Q 8 hours 1,800
Magnesium Salicylate Q 4 to 6 hours 3,500 Diclofenac Q 8 to 12 hours 150
Salsalate Q 8 to 12 hours 4,000 Ketorolac Q 4 to 6 hours 40
Ibuprofen Q 4 to 6 hours 3,200 Piroxicam QD 40
Naproxen Q 12 hours 1,500 Meloxicam QD 15
Fenoprofen Q 6 to 8 hours 3,200 Nabumetone Q 12 to 24 hours 2,000
Ketoprofen (short-acting) 300 Mefenamic Acid Q 6 hours 1,000
Q 6 to 8 hours QD
Ketoprofen (modified) 200 Meclofenamate Q 4 to 6 hours 400
Flurbiprofen Q 8 to 12 hours 300 Celecoxib Q 12 to 24 hours 400
Oxaprozin QD 1,800
Pasero C & McCafferty M. Pain Assessment & Pharmacological Management. Elsevier Mosby. 2011.
Acetaminophen
Acetaminophen (APAP)
Names
o para-acetylaminophenol (acetaminophen)
o para-Acetyl-P-AminoPhenol (APAP)
o para-acetyl-p-aminophenol (Tylenol®)
o para-acetylaminophenol (paracetamol)
Mechanism of Action
Inhibits PG Synthesis in CNS (Antipyretic/Analgesic)
• Inhibits COX-3 Enzyme (Not COX-1 or COX-2, thus no anti- inflammatory effects)
APAP Metabolism
• Sulfation & Glucuronidation to conjugates

• CYP 2E1, 1A2, & 3A4 convert to NAPQI Toxic
o N-acetyl-P-benzoQuinone Iminine
• Glutathione converts NAPQI to Cysteine &
Mercaptate
Chun BJ, et al. Antidote for Acetaminophen Dosing. J Korean Med Assoc. 2013 Dec;56(12):1067-1075. Korean. https://doi.org/10.5124/jkma.2013.56.12.1067
Acetaminophen Maximum Dosage
Max Recommended Daily Doses

 4g (<60yo)
 3g (>60yo/OTC)
 2g (Liver/Kidney)
Liver Injury Dose

o Lesser of >/= 200mg/kg or 10g
>50K ER Visits Every Year from APAP Overdose

o Accidental > Intentional
Clinical Pharmacology Online Database, FDA, & CDC sites (2018)

Garofoli MP. Tylenol Overdose. On Being a Pharmacist. APhA. Pangilinan JM & Waddell JA.
APAP Overdose Presentation
Diagnosis (Acute Liver Failure, ALF)
o Altered Mental Status
o INR > 1.5
o Increased AST & ALT (up to 400x)
ALF Related Scenarios
Coagulopathy and Hypoprothrombinemia (e.g. bleeding)
o From depressed synthesis and excessive consumption of clotting factors
Metabolic Acidosis
o Increased intracellular lactate production and reduced hepatic uptake of lactate
Hypoglycemia
o Diminished synthesis of glucose
Impaired Renal Function (35-40% of ALF Patients)
o Azotemia (nitrogen in blood) and oliguria (decrease urine output)
Fontana R. Acute Liver Failure including Acetaminophen Overdose. Med Clin N Am. 2008 July ; 92(4): 761-794.
APAP Overdose
Timeline & Symptoms
• 0-24 Hours
• Nausea, Vomiting, & Anorexia
• Diaphoresis (Sweating), Lethargy, & Malaise
Phase 1 • No hepatic injury (Normal AST, ALT, Bilirubin, & INR)
• 1-2 Days
• Improvement of Nausea, Vomiting, & Anorexia
• Abdominal Pain (Right Upper Quadrant)
Phase 2 • Increased LFTs (AST, ALT, Bilirubin, & INR)
• 2-4 Days
• Jaundice (Coagulopathy, Peak LFTs)
• Coma (Encephalopathy)
• Metabolic Acidosis
Phase 3
• Renal Failure
• 4 Days – 2 Weeks
• Recovery phase with resolution of liver injury
Phase 4
Fontana R. Acute Liver Failure including Acetaminophen Overdose. Med Clin N Am. 2008 July ; 92(4): 761-794.
N-Acetylcysteine (NAC)
 N-Acetyl Prodrug of L-cysteine (precursor of glutathione)
MOAs
o Glutathione elimination of NAPQI
o Provided Sulf-Hydryl (SH) group for sulfate pathway
o Antioxidant and increased microcirculatory blood flow
Uses
 Treatment of acetaminophen overdose
o Loosen thick mucus in individuals with CF or COPD
o Claimed antioxidant and liver/kidney protecting effects
APAP
OTC Acetaminophen Formulation Strength
Suppository 80mg, 120mg, 325mg, & 650mg
Infant Drops 80mg/0.8mL

Children’s Suspension 80mg/2.5mL
Children’s Solution/Suspension 160mg/5mL
Solution 325mg/10.15mL
Solution 650mg/20.3mL
Liquid 500mg/15mL
Chewable Tablets 80mg & 160mg
Regular Strength 325mg
Extra Strength 500mg
Extended Release 650mg
https://www.getreliefresponsiblyprofessional.com/sites/getreliefresponsiblyhcp_us/files/PDF/GRRAdultDosingChart.pdf
APAP Pediatric Dosing
Infant and Children APAP Dosing

Q 4 to 6 PRN
Weight Age Dose
6 to 11 lbs. 0 to 3 months 40mg
12 to 17 lbs. 4 to 11 months 80 mg
18 to 23 lbs. 12 to 23 months 120 mg
24 to 35 lbs. 2 to 3 years 160 mg
60 to 71 lbs. 9 to 10 years 400mg
https://medlineplus.gov/ency/patientinstructions/000783.htm
• Learning Objectives
Nociceptive • Recall the treatment guidelines for osteoarthritis

of the hand, knee, and hip.
Pain • Recall non-pharmacological options (e.g. dietary
restrictions) for the prevention of gout attacks.
Conditions • Identify appropriate patient recommendations and

explanations for pharmacological treatment
options in rheumatoid arthritis (DMARDs, Anti-
TNF, Non-TNF, oral small molecule, and
glucocorticoids) based on respective unique
pharmacological characteristics.
3 Main Types of Pain
Nociceptive Mixed Neuropathic

Neuropathic Lower
Arthritis Fibromyalgia
Back
Mechanical Lower Back Headache
Post-Op Polyneuropathy
Lower Back
Sickle Cell Crisis (DM/HIV)
Injury Myofascial
Post Herpetic
Skeletal Muscle Trigeminal Neuralgia
Nociceptive Pain
Aching or Throbbing
Somatic
Localized
(Outer Organs)
Bone/Joint/Muscle/Skin
Nociceptive Pain
Tumor: Localized
Visceral
(Inner Organs)
Hollow Viscus:
cramping non- localized
Review of General Nociceptive Conditions
Gout
OA RA
https://www.ra.com/what-is-rheumatoid-arthritis/ra-vs-oa
Bruce SP. Rheumatoid arthritis. In: Chisholm-Burns, MA, et al., editors. Pharmacotherapy; Principles and Practice. 4th ed. New York: McGraw-Hill; 2016
Rheumatoid vs Osteo Arthritis
Rheumatoid Arthritis (RA) Osteoarthritis (OA)
Nature Autoimmune “Wear and tear”
Gender Female 3:1 1:1
Joint Swelling Soft, warm, boggy, and tender Hard & Bony [Crepitus (Crackling)]
Symmetry Symmetric Non-Symmetric
Onset Age Range 35-50y.o. >50y.o.
Onset Rapid (weeks) Slow (years)

Hands & Feet Weight-bearing Joints
Affected Areas Metacarpophalangeal (MCP) & Hip, Knee, & Hand
Proximal Interphalangeal (PIP) Finger Distal Interphalangeal (DIP)
Activity Worse in the morning or after rest Worse with activity
Duration of Morning Joint
Stiffness 1 Hour or More < 30 Minutes
(+) Rheumatoid Factor, ESR >20/30(m/f), CRP
Labs None
>0.7, (+) CCP antibodies, & Increased WBC
https://www.ra.com/what-is-rheumatoid-arthritis/ra-vs-oa
Bruce SP. Rheumatoid arthritis. In: Chisholm-Burns, MA, et al., editors. Pharmacotherapy; Principles and Practice. 4th ed. New York: McGraw-Hill; 2016.
Osteoarthritis Etiology
• More common form of arthritis
• Affects 27 million Americans
• Females 1.5 times more likely than males
• Incidence increases with age

o Typically older than 50y.o. at time of diagnosis
Chisolm-Burns MA, Schwinghammer TL, Wells BG, et al., authors. Osteoarthritis. In: DiPiro JT, et al., editors. Pharmacotherapy Principles and Practice. 4th ed. New York: McGraw-Hill; 2016. 875-895.
Osteoarthritis Pathophysiology
• Multi-factorial degenerative disease
• The earliest stages of OA are characterized by increasing water

content and softening of cartilage in weight-bearing joints
• As the disease progresses, proteoglycan content of cartilage

declines, and eventually, cartilage becomes brittle
• Cartilage wears down over time, allow bones to touch and

deform
Chisolm-Burns MA, Schwinghammer TL, Wells BG, et al., authors. Osteoarthritis. In: DiPiro JT, et al., editors. Pharmacotherapy Principles and Practice. 4th ed. New York: McGraw-Hill; 2016. 875-895.
Osteoarthritis
Risk Factors Symptoms Diagnosis

• Genetics • Hand, Hip, +/- Knee Pain • Physical Exam
• Obesity • Aching or Burning • Tender Joints
• Female gender • Deformed joints • X-ray
• Increasing age • Stiffness in joints • MRI
• Injury to joints • asymmetric or symmetric • Joint Aspiration
• Repetitive use of joints • Crepitus
• Bone spurs
• Limited joint mobility
• No systemic
manifestations
www.mayoclinic.org/diseases-conditions/osteoarthritis/symptoms-causes/syc-20351925
OA Treatment
(ACR 2012)
Hand Knee Hip

• Capsaicin • APAP • APAP
• Topical NSAIDs • PO NSAIDs • PO NSAIDs
Use • PO NSAIDs • Tramadol • Tramadol
• Tramadol • Steroid Injections • Steroid Injections
Avoid •• Steroid
Opioids
Injections • glucosamine/chondroitin
• Capsaicin
• glucosamine/chondroitin
Hochberg MC, et al. American College of Rheumatology 2012 Recommendations for the Use of Non-pharmacologic and
Pharmacologic Therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care & Research. 2012; 64(4): 465-474
Guidelines for Management of Knee Osteoarthritis
American Association of Orthopedic Surgeons (2014)
Core Treatments Appropriate for All Individuals
• Aerobic +/- Aquatic Exercise
• Strength Training
• Weight Management
• Self Management
• Biochemical interventions • Biochemical • Acetaminophen • Balneotherapy

• Topical NSAIDS interventions • Biomechanical Interventions • Duloxetine
• Walking Cane • Topical NSAIDS • Oral COX-2 selective NSAIDS • Intra-articular corticosteroids
• Intra-articular Corticosteroids • Walking Cane • Oral Non-selective NSAIDS • Oral COX-2 selective NSAIDS
• Oral COX-2 selective NSAIDS • Intra-articular NSAIDS • Intra-articular corticosteroids • Biochemical Interventions
• Oral Non-selective NSAIDS • Duloxetine
• Capsaicin Knee only OA + Comorbidities Multiple Joint OA + Comorbidities
Multiple Joint OA - Comorbidities
• Duloxetine
• Paracetamol
Knee only OA - Comorbidities
McAlindon TD, et al. OARSI Guidelines for the Non-Surgical Management of Knee Osteoarthritis. Osteoarthritis and Cartilage. 22 (2014) 363-388.
Knee Osteoarthritis Treatments
Non- Non-Pharmacological Pharmacological

Pharmacological
• Aerobic exercise • Self Management • Acetaminophen
• Aquatic exercise • Manual therapy + supervised • Oral NSAIDs
• Resistance-based exercise • Topical NSAIDs
exercise • Medially directed patellar taping • Duloxetine
• Weight Management • Wearing wedged insoles • Tramadol
• Thermal agents • Intra-articular corticosteroid
• Walking aids injections
Patients with symptomatic knee OA who had an inadequate response to both non-
pharmacologic and pharmacologic modalities and are either unwilling to undergo or Green = Strong Recommendation
are not candidates for knee replacement Yellow = Conditional
• Opioid analgesics
Hip Osteoarthritis Treatments
Non- Non-Pharmacological Pharmacological

Pharmacological
• Aerobic exercise • Self-management programs • Acetaminophen
• Resistance-based • Manual therapy with supervised • Oral NSAIDs
exercise exercise • Tramadol
• Aquatic exercise • Psychosocial interventions • Intra-articular corticosteroid
• Weight Loss (if • Thermal agents injections
overweight) • Walking aids
Green = Strong Recommendation

Yellow = Conditional
GOUT
OA RA
Gout Overview
• Type of inflammatory arthritis caused by excess uric acid

• Men > Women
• Develops between the ages of 30-50
• Typically affects one joint at a time, but can progress to multiple joints at a time
• Can be asymptomatic
• 90% of gout cases caused by inefficient renal elimination (vs purine metabolism)
Mayo Clinic Staff. Gout [updated August 9th, 2017]. Mayo Foundation for Medical Education and Research.
https://www.mayoclinic.org/diseases-conditions/gout/symptoms-causes/syc-20372897 Accessed 2018.
Gout Pathophysiology
• Endogenous and Dietary Purines

• Kidneys pass Uric Acid (UA) into urine
• Hyperuricemia
o Kidneys not filtering uric acid into urine as efficiently
• UA crystallizes & deposits in joints/tissues
• UA crystals cause inflammation
https://www.mayoclinic.org/diseases-conditions/gout/symptoms-causes/syc-20372897. Accessed 2018.
Gout Pathophysiology
Purines
Xanthine
Xanthine
Xanthine Oxidase Recombinant
Inhibitors
Oxidase Urate Oxidase
Inflammation Crystals Uric Acid Urate Oxidase Allantoin
NSAIDs
Steroids
Uricosurics
Colchicine 30% Fecal 70% Renal
Excretion Excretion URAT1/OAT
4 Inhibitor
http://tmedweb.tulane.edu/pharmwiki/doku.php/gout_its_treatment
Increased Uric Acid Risk Factors
Hyperuricemia Risk Factors

Purine Rich Diet
Obesity
Medical Conditions
(Untreated high blood pressure, diabetes, metabolic syndrome, heart, and kidney diseases)
Urate Elevating Medications

Family History of Gout
Age & Sex Postmenopausal Females &
30-50yo Males
Recent Surgery or Trauma
Dinesh Khanna, et al. 2012 American College of Rheumatology Guidelines for Management of Gout. Part 2: Therapy and
Anti-inflammatory Prophylaxis of Acute Gouty Arthritis. Arthritis Care & Research. 2012; 64 (10): 1447-1461.
Urate-Elevating Medications
Urate-Elevating Medications
Thiazide Diuretics Competition between thiazides and uric acid for transport via OAT1
Loop Diuretics Competition between thiazides and uric acid for transport via OAT1
Niacin Utilizes same transporter as uric acid
Calcineurin Inhibitors Suppress kidney function
Aspirin Can impair the excretion of uric acid from the kidneys
Mayo Clinic Staff. Gout [updated August 9th, 2017]. Mayo Foundation for Medical Education and Research. https://www.mayoclinic.org/diseases-conditions/gout/symptoms-causes/syc-20372897 . Accessed 2018.
Dinesh Khanna, et al. 2012 ACR Guidelines for Management of Gout Part I: Systematic Non-pharmacologic & Pharmacologic Therapeutic Approaches to Hyperuricemia. Arthritis Care & Research. 2012; 64(10):1431-
1446.
Rafey MA, Lipkowitz MS, Leal-Pinto E et al. Uric acid transport. Curr Opin Nephrol Hypertens 2003;12:511-6.
Uric Acid Levels
Normal ranges
• Men: 3.4-7.0 mg/dL
• Women: 2.4-6.0 mg/dL
 Patients can have a normal uric

acid level while having a gout
attack
Becker MA, Jolly M. Clinical gout and the pathogenesis of hyperuricemia. In: Koopman WJ, Moreland, LW, eds. Arthritis & Allied Conditions. 15th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2005:chap 113.
Gout Symptoms
• Intense joint pain
• Lingering discomfort
• Redness and inflammation of joints

o Tophi Lumps of Uric Acid
• Limited range of motion
Mayo Clinic Staff. Gout [updated August 9th, 2017]. Mayo Foundation for M edical Education and Research.
https://www.mayoclinic.org/diseases-conditions/gout/symptoms-causes/syc-20372897 . Accessed 2018.
Diagnosis of Gout
 Joint fluid test

o Only definitive diagnosis
o Needle is put into joint to extract fluid
o Fluid is then examined under a microscope for crystals
• Blood tests
o ESR, WBC, & Serum UA
• Ultrasound
• Dual energy CT scan
o Expensive, not routinely used
https://www.mayoclinic.org/diseases-conditions/gout/symptoms-causes/syc-20372897. Accessed 2018. q
Gout Disease Severity
Mild Moderate Severe

Simple chronic tophaceous Simple chronic tophaceous Chronic tophaceous gouty
gouty arthropathy gouty arthropathy arthropathy
4 joints OR
> 1 unstable, complicated,
Affecting 1 joint Affecting 2-4 joints tophus/tophi
Staging of Gout
Early Well-Established Late

< 12 hours after attack 12 to 36 hours after attack > 36 hours after attack
onset onset onset
Gout Treatment
Diagnosis and Initial Recommendations
Establish Diagnosis of Gout
Baseline Recommendations for Patients with Diagnosis of Gout

• Patient education, with initiation of diet, lifestyle recommendations
• Consider secondary causes of hyperuricemia
• Consider elimination of non-essential prescription medications that induce
hyperuricemia
• Clinically evaluate gout disease burden
Indications for Pharmacologic ULT

Any patient with establishment of gouty arthritis AND
• Tophus or Tophi
• Frequent attacks (> 2 attacks/year)
• CKD stage 2 or worse
• Past urolithiasis
Dinesh Khanna, et al. 2012 American College of Rheumatology Guidelines for Management of Gout Part I: Systematic Non- pharmacologic
and Pharmacologic Therapeutic Approaches to Hyperuricemia. Arthritis Care & Research. 2012; 64(10):1431-1446.
Gout Dietary Recommendations
Avoid Limit Encourage

Well-Balanced Diet
Organ Meats High in Purine Vegetables
(Liver and Kidney) Beef, Lamb, & Pork Low-Fat Dairy
High Fructose Corn Syrup Sugar Exercise
Alcohol
>2 servings males
Sodium Hydration
>1 serving females
Seafood (sardines,
Any alcohol in active gout shellfish, etc.) Smoking Cessation
Dinesh Khanna, et al. 2012 American College of Rheumatology Guidelines for Management of Gout Part I: Systematic Non- pharmacologic
and Pharmacologic Therapeutic Approaches to Hyperuricemia. Arthritis Care & Research. 2012; 64(10):1431-1446.
Gout Treatment
Maintenance Pharmacological Strategies
Treat to Serum Urate Target
• Minimum target < 6 mg/dL
• Urate levels below <5 mg/dL may be needed
• Utilize NSAID/Colchicine during trials
1st Line (Xanthine Oxidase Inhibitor, XOI) No Evidence of Continued Gout
• Allopurinol or Febuxostat
2nd Line (Uricosuric)
• Probenecid
Tophi No Tophi
Maximize tolerable dose Discontinue after Discontinue > of:

6 Months of 6 Months, or
reaching target 3 Months w/
UA Level target UA Level
If utilizing XOI, Add Uricosuric
Probenecid (or fenofibrate/losartan)
Refractory
pegloticase
Dinesh Khanna, et al. 2012 American College of Rheumatology Guidelines for Management of
Gout Part I: Systematic Non-pharmacologic and Pharmacologic Therapeutic Approaches to
Hyperuricemia. Arthritis Care & Research. 2012; 64(10):1431-1446.
XOI & Uricosurics
Allopurinol (Zyloprim®)
• Starting dose should not exceed 100mg/day or 50mg/day if CKD Stage 4
• Titrate dose q 2 to 5 weeks
• Hypersensitivity in HLA-B*5801 allele positive patients (e.g. Asian Decent) 1st Line
Allopurinol
Febuxostat (Uloric®) OR
• Initial dose 40mg/day Febuxostat
• Increase to 80mg/day if UA does not decline to 6mg/dL NOT Both
• Severe Renal impairment (CrCl 15-29 mL/min): Limit dose to 40mg/day
Probenecid (Benemid® Probalan®)

• 2nd Line, but first choice among uricosuric agents
• Initial 250mg twice daily for one week 2nd Line
• Increase to 500mg twice daily
• Can increase by 500mg every 4 weeks until UA <6mg/dL (Max Daily Dose 2g)
• CrCL < 50 ml/min not recommended
• Fenofibrate and losartan can used as an ULT strategy
• Contraindicated for 1st Line if history of Urolithiasis
Khanna D, et al. 2012 American college of rheumatology guidelines for management of gout part 1: systematic nonpharmacologic and pharmacologic therapeutic
approaches to hyperuricemia. Arthritis Care & Research. October 2012;64(10):1431-1446.
Lesinurad (Zurampic®)
• Urate Transporter Inhibitor

o Inhibits URAT1 & OAT4 (responsible for reabsorption of uric acid in the kidneys)
o Inhibitors lead to increased uric acid excretion in urine
 FDA Approved in 2015 for combo therapy with a XOI
o Three Phase III trials- CLEAR1, CLEAR2, and CRYSTAL
o 1,537 patients total enrolled
o CLEAR1 and CLEAR2-compared lesinurad to placebo
o CRYSTAL compared lesinurad to febuxostat
• Dose: 200mg QD.
• CYP-3A4 Mild Inducer & CYP-2C9 Substrate
 Notable Side Effect: Increased Serum Creatinine
Lesinurad [package insert]. San Diego, CA: AstraZeneca; 2015.
Gout Treatment
Maintenance Pharmacological Strategies
Treat to Serum Urate Target
• Minimum target < 6 mg/dL
• Urate levels below <5 mg/dL may be needed
• Utilize NSAID/Colchicine during trials
1st Line (Xanthine Oxidase Inhibitor, XOI) No Evidence of Continued Gout
• Allopurinol or Febuxostat
2nd Line (Uricosuric)
• Probenecid
Tophi No Tophi
Maximize tolerable dose Discontinue after Discontinue > of:

6 Months of 6 Months, or
reaching target 3 Months w/
UA Level target UA Level
If utilizing XOI, Add Uricosuric
Probenecid (or fenofibrate/losartan)
Refractory
pegloticase
Gout Part I: Systematic Non-pharmacologic and Pharmacologic Therapeutic Approaches to
Hyperuricemia. Arthritis Care & Research. 2012; 64(10):1431-1446.
Rasburicase (Elitek®)
Recombinant version of urate oxidase (Uricase)

o Catalyzes oxidation of uric acid into inactive and more soluble allantoin
o Reduction in uric acid levels within 4 hours of administration
t ½: 16 to 23 hours
o Dose can be every 3 days
Pharmacogenetics: Test for G6PDH deficiency

o Prevent methemoglobinemia
Notable Side Effects

o Hypophosphatemia, peripheral edema, nausea, & vomiting
Choi HK, Mount DB, Reginato AM. American College of Physicians, American Physiological Society Pathogenesis of gout. Ann Intern Med. 2005;143:499- 516.
Pegloticase (Krystexxa®)
PEGylated version of recombinant urate oxidase (Uricase)

o Urate oxidase catalyzes oxidation of uric acid into inactive & more soluble allantoin
• Only FDA approved treatment for patients with chronic refractory gout
• PEGylating increases t ½ to ~12 days

o Dosed once every 2-4 weeks
• FDA approval trials

o Two replicate, multi-center, randomized, double-blind, placebo-controlled trials of 6 months duration
o 8 mg pegloticase infusions studied in two dose regimens (every 2 and 4 weeks vs. placebo)
Sundy JS, et al. Efficacy and Tolerability of Pegoticase for the Treatment of Chronic Gout in Patients Refractory to Conventional Treatment. JAMA. 2011;306(7):711-720.
Gout Treatment
Acute Pharmacological Strategies
Mild/Moderate Pain Severe Pain
Initial Combination Therapy

Colchicine & NSAID
Initial Monotherapy
Colchicine & Systemic Corticosteroid
NSAID
Colchicine & Intraarticular Corticosteroid
Colchicine
NSAID & Intraarticular Corticosteroid
Systemic Corticosteroids
PO & Intraarticular Corticosteroid
Off-Label Therapies in Development

Alternate Monotherapy IL-1 Inhibitor, etc.
*Without treatment, acute gout attacks typically resolve within 5 to 7 days

Gout. Part 2: Therapy and Anti- inflammatory Prophylaxis of Acute Gouty Arthritis. Arthritis Care &
Research. 2012; 64 (10): 1447-1461.
Gout Treatment
Acute Pharmacological Strategies
NSAIDs
• Naproxen, indomethacin, and sulindac are FDA approved
• High-dose celecoxib
Colchicine
• Only use within 36 hours
• Start with loading dose of 1.2mg followed by 0.6mg one hour later
• Then can be used QD or BID until symptoms resolve
Systemic Corticosteroid
• Prednisone or prednisolone at least 0.5mg/kg/day for 5 to 10 days followed by 7 to 10 days tapering dosage
Khanna D, Et al. 2012 American college of rheumatology guidelines for management of gout part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care & Research. October
2012;64(10):1447-1461
Gout Treatment
Medication Review
Acute Maintenance Refractory

Xanthine Oxidase Inhibitors (XOI) allopurinol
NSAIDS Pegloticase
or febuxostat
Uricosurics probenecid, fenofibrate, or

colchicine Rasburicase
losartan
Corticosteroids URAT1/OAT4 Inhibitor (Combo w/ XOI) lesinurad

Differential Diagnosis & Treatment
Gout Pseudogout
Hypercalcemia
Hyperuricemia Similar treatments except not XOI
Mayo Clinic Staff. Pseudogout [updated August 9th, 2017]. Mayo Foundation for Medical Education and Research. Available at:
https://www.mayoclinic.org/diseases-conditions/pseudogout/diagnosis-treatment/drc-20376988. Accessed 2018.
RA
OA Gout

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COVID-19 Vaccination

in Patients with Cancer:

Dr. Nabil Elhadi Omar

Date: March 16, 2021

2 Review of vaccine development process

3 Summary of available COVID-19 Vaccines

Answers to the most common questions about the

5 Review of the guidelines

6 Summary and conclusion

A novel coronavirus was identified as the cause by

Asymptomatic or Pre-  Test positive for SARS-CoV-2 using a virologic test

Mild  have any of the various signs and symptoms of COVID-19

A novel coronavirus was identified

January 2020 April 2020

With a fast-moving pandemic, no one is safe, unless everyone is safe

A novel coronavirus was identified

January 2020 April 2020

A novel coronavirus was

January 2020 April 2020 11 Dec. 2020

Rolled out in Vaccine

mRNA 21 days 95%

mRNA 28 days 94.1%

Viral vector 28 days 63.09%

Viral vector - 66%

Viral vector 21 days 91.6%

Subunit vaccine 21 days 95.6%

Indicated inactivated vaccines should be given ≥2 weeks prior to chemotherapy and

A1 Patients with cancer currently receiving chemotherapy or other immunosuppressive therapy

Patients with cancer currently receiving chemotherapy or other immunosuppressive therapy

A2 Yes, if they have no contraindications.

CDC: Immunocompromised individuals can receive COVID-19 vaccination if they have no

Immediate allergic reaction of any severity to polysorbate (due to potential cross-reactive

A3 Yes, persons with immunocompromising conditions or who take immunosuppressive

A3.1 Yes, the FDA EUA recommends that immunocompromised individuals

 Pain or swelling at the injection site

 To take pain relievers (like ibuprofen or acetaminophen) every 4–6

If anaphylaxis is suspected, take the following steps:

Axillary adenopathy (swollen/tender lymph nodes)

Hematopoietic stem cell Rituximab

No specific timing is recommended relative to surgery from a vaccine

A In order to generate optimal protective immunity following vaccination,

Hematopoietic stem cell Rituximab

Treatment Timing of vaccine administration

Autologous HCT Vaccination may be initiated 2- 3 months after HCT

A • Severe, uncontrolled acute GVHD grades III – IV

Do cancer patients need to be vaccinated? Yes

16. [Internet]. https://www.asco.org/sites/new-www.asco.org/files/content-files/2021-MSK_COVID19_VACCINE_GUIDELINES_final_V.2.pdf. 2021 [cited 24 February 2021]. Available

1. Recognize appropriate patient recommendations and explanations for non-prescription

White Willow Bark

Caution: Drug Interactions

L-Methylfolate Product ~ Pricing

Rx 15mg (Deplin®, etc.) $200-$500

Rx 7.5mg (Deplin®, etc.) $100-$500

Rx 3mg (Metanx®, etc.) $75-$225

Non-FDA Approved Supplements 1-5mg $12-$60

• Histamine promotes pain “transmission”

• Antihistamines have very little evidence of analgesia or

o Commonly used for analgesia of bone pain

o Promethazine commonly used as an adjunct to

enhanced/prolonged effect with other analgesics Espresso (shot) 40

12oz. Can of Soda 40-50

• or simply by affecting one’s mood

• Botulinum toxin is a neurotoxin which is produced by the Gram-positive anaerobic bacteria