Amelia L. Persico, PharmD, MBA

New information on the severe acute respiratory syndrome coronavirus (sars-cov-2), which causes the coronavirus disease 2019 (COVID- 19), continues to emerge daily.

As health care providers navigate the most severe global pandemic in more than a century, concerns arise among those who care for some of our most vulnerable populations. One such population is patients with rheumatologic conditions who take immunosuppressant medications. Patients with conditions such as ankylosing spondylitis (AS), lupus, psoriatic arthritis (PSA), rheumatoid arthritis (RA), and scleroderma may have a higher risk of contracting SARS-CoV-2, regardless of whether they are prescribed immunosuppressants.

Patients on disease-modifying antirheumatic drugs (DMARDs) are at higher risk of infections, including SARS-CoV-2, as well as secondary infections and poor outcomes. Initial mortality reports from the SARS-CoV-2 pandemic have also been higher for this population.

 The risks of infection for patients on DMARDs (biologics and other immunosuppressive agents) are well described in the literature. A study by Quartuccio et al using administrative data from 5596 patients with AS, PSA, or RA identified a relationship between the recent initiation of a biologic and hospitalization for an infection.

 The most common types of infection identified were upper and lower respiratory tract infections. This is particularly important considering that SARS-CoV-2 is a virus of the lower respiratory tract.

Furthermore, patients on DMARDs may overlook their initial infection state. Patients who are immunosuppressed may present with different symptoms than their immunocompetent counterparts. For example, because of decreased ability to mount an immune response, this population may not present with a fever when infected with SARS-CoV-2.

The PSOLAR study (NCT00508547) reported the incidence rate of serious infection for patients undergoing treatment with tumor necrosis factor inhibitors (TNFIs; adalimumab, etanercept, infliximab), ustekinumab, methotrexate, and other DMARDs, such as cyclosporine.

 Serious infection incidence was numerically higher with TNFIs than with other biologics, but these differences were not statistically significant. To date, no confirmative data are available to support relative infection risks among different biologic DMARDs.

The PSOLAR study also reported that diabetes, history of infection, older age, and a level 4 or 5 Physician’s Global Assessment were statistically significant factors for increased risk for serious infection. Importantly, the additional risk factors listed above could increase infection risk even further.

TNFIs have been on the market for 2 decades and are known to increase the risk of infection of SARSCoV- 2.1 Other biologics used in rheumatology, such as B-cell modulators, IL-6 inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, Janus kinase inhibitors, and T-cell modulators, are also immunosuppressive and increase infection risk. The American College of Rheumatology 2015 guidelines for RA recommended the use of combination DMARDs over TNFIs and abatacept over TNFIs if a patient had a history of previous serious infections.

General recommendations remain that first, an individual should choose strategies to minimize the risk of infection, by receiving an annual influenza vaccination, for example, and practicing self-hygiene. If a patient on a biologic or other immunosuppressive agent becomes ill, they should discontinue the medication until resolution of the infection. If a patient was prescribed an antibiotic, antifungal, or antiviral agent to treat an acute infection, the individual should remain off the immunocompromising biologics until they finish their course of the prescribed regimen and the infection resolves before reinitiating biologics.

At this time during the SARS-CoV-2 outbreak, CDC recommendations for patients on immunosuppressive medications do not differ greatly from those for the general population. Patients are advised to avoid contact with people who are sick; to not touch the eyes, mouth, or nose with unwashed hands; to wash hands with soap and water often for at least 20 seconds; and to use alcohol-based hand sanitizer when not near soap and water. All immunocompromised patients should also inform their provider of any travel destinations if they become ill after having traveled abroad or locally and of any acute infection or injury, which could lead to further infection. Patients should also evaluate their health condition prior to each injection of a biologic agent, during which practitioners assess for general wellness, fever symptoms, significant cuts and injuries, and sores. Finally, remind patients frequently of the importance of routine immunizations such as the influenza vaccine and to receive only inactivated vaccines. Patients with planned surgical procedures should discontinue biologic agents for the appropriate period determined by their providers prior to the procedure.

In the backdrop of the pandemic, panic has led many people to seek chloroquine or hydroxychloroquine to either treat their infection or use as prophylaxis against COVID- 19.

 Hydroxychloroquine is a DMARD that serves as the cornerstone of pharmacotherapy for patients with multiple rheumatologic conditions, including lupus and RA. The World Health Organization is in the midst of exploring the potential role of chloroquine and hydroxychloroquine in the management of COVID-19. In the meantime, federal and state authorities have enacted mandates, such as New York State Executive Order 202.10, to preclude dispensation of these medications for other than their FDA-approved indications, unless the patient is enrolled in a bona fide study.

 Large community pharmacy chains, such as CVS Health, Express Scripts, and Walgreens, have also set policies to halt hoarding of chloroquine and hydroxychloroquine.

 These mandates are an effort to reduce drug shortages for those who require these medications chronically for an established rheumatologic disorder.6 Pharmacists have become an important gatekeeper in this regard, as even health care clinicians have been noted to hoard these medications for themselves, their family members, or their friends.

Pharmacists play a key role in educating the public and controlling distribution of medications. It is imperative that health care providers and patients are aware that DMARD use may lead to immunosuppression that could increase infection risk during this unprecedented public health crisis. Critically, they should also realize the potential for afebrile presentation of infection, the importance of holding biologics if an infection is present, and the need to seek health care promptly. Furthermore, the general population must understand the risks imposed on patients with rheumatologic disorders if their maintenance medications are depleted.

, is a PGY-2 pain and palliative care pharmacy resident, and 

, is a clinical pharmacy specialist for rheumatology, both at Albany Stratton VA Medical Center in Albany, New York.

Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB

, is CEO and founder of Remitigate LLC and the owner and managing editor of paindr. com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts, an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences in Albany, New York, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center.

Quartuccio L, Zabotti A, Del Zotto S, Zanier L, De Vita S, Valent F. Risk of serious infection among patients receiving biologics for chronic inflammatory diseases: usefulness of administrative data. 

. 2019;15:87- 93. doi: 10.1016/j.jare.2018.09.003.

Yang Y, Peng F, Wang R, et al. The deadly coronaviruses: the 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China [published online March 3, 2020]. 

Ritchlin CT, Stahle M, Poulin Y, et al. Serious infections in patients with self-reported psoriatic arthritis from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) treated with biologics. 

 2019;3:52. doi: 10.1186/s41927- 019-0094-3.

Singh JA, Saag KG, Bridge SL Jr, et al; American College of Rheumatology. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. 

 (Hoboken). 2016;68(1):1-25. doi: 10.1002/acr.22783.

World Health Organization. COVID-1 informal consultation on the potential role of chloroquine in the clinical management of COVID19 Infection. who.int/blueprint/ priority-diseases/key-action/RD-Blueprint-expert-group-on- CQ-call-Mar-13-2020.pdf?ua=1. Published March 13, 2020. Accessed March 26, 2020.

No. 202.10: continuing temporary suspension and modification of laws relating to the disaster emergency. New York State website. governor.ny.gov/news/no-20210-continuing-temporary- suspension-and-modification-laws-relating-disaster-emergency. Published March 23, 2020. Accessed March 26, 2020.

Humer C, Mishra M. Pharmacies set policies to stop U.S. hoarding of potential coronavirus treatments. Reuters website. reuters.com/article/us-health-coronavirus-cvs-health/pharmacies- set-policies-to-stop-u-s-hoarding-of-potential-coronavirus- treatments-idUSKBN21C2CQ. Published March 25, 2020. Accessed March 26, 2020.

Rowland C. As Trump touts an unproven coronavirus treatment, supplies evaporate for patients who need those drugs. 

. March 23, 2020. washingtonpost.com/ business/2020/03/20/hospitals-doctors-are-wiping-out-supplies- an-unproven-coronavirus-treatment/. Accessed March 26, 2020.

Articles

Panic and a host of interactions are entwined with disease-modifying antirheumatic drugs.

Exercise Caution Amid the COVID-19 Pandemic

The landscape of pain management over the last 3 decades has cycled from the opiophobia of the late 80s and early 90s through opiophilia and back again.

 Notable pit stops along the way included “pain as the fifth vital sign,” the acceptance of opioid use in chronic noncancer pain, and the advent of “The Opioid Crisis.” 

There has been a definitive decline in the rate of opioid prescribing, yet the CDC reports of opioid related deaths continue to rise.

 As it stands today, illicit opioids, specifically illicit fentanyl/fentanyl analogs, top the charts in opioid related deaths. Between 2015 and 2016, heroin and illicit fentanyl contributed to 35,000 opioid related deaths, and prescription drugs accounted for fewer than 15,000.

 researchers explored the idea that the key to revealing  the veracity of how the opioid epidemic has evolved may lie in the logistics of overdose death reporting, and the pharmacology and pharmacokinetics of prescription and illicit fentanyl.

In the article "Fentanyl: Separating Fact from Fiction

," fentanyl and fentanyl analogs are divided into 3 groups; pharmaceutical fentanyl, pharmaceutical fentanyl derivatives and illicit fentanyl. Pharmaceutical fentanyl is a full mu-opioid receptor agonist with a potency 50-100 times greater than morphine.

 It is a substrate of cytochrome P450 3A4 (CYP3A4), which makes it prone to drug-drug interactions and pharmacogenomic variability due to genetic polymorphisms. Fentanyl is metabolized by CYP3A4 to the inactive molecule, norfentanyl. Depending on the formulation, the kinetics and elimination half-life of pharmaceutical fentanyl vary with half-life ranges from 3.65 hours to 27 hours with consideration to continuous release formulations.

 Otherwise, fentanyl itself has a very short half-life closer to the 3-hour range.

There are 3 fentanyl derivatives approved for use in humans: alfentanil, remifentanil and sufentanil. All 3 are limited in use to the inpatient setting and alfentanil and remifentanil are rarely seen as drugs of abuse. Sufentanil, however, has been detected in combination with other illicit drugs in overdose victims along with a fourth fentanyl derivative, carfentanil, which is approved only for use as a tranquilizing agent in large mammals.

 This drug is 100 times more potent than fentanyl and is being found with increasing frequency in the serum of overdose decedents.

The illicit fentanyl compounds or, nonpharmaceutical fentanyl, are a moving target in terms of street availability and illicit synthesis. This group is comprised of compounds that are illegally altered to create new products which can evade current tests and medical examiners. Illicit fentanyl has been detected as the sole ingredient in drug overdoses, in combination with legally obtained substances (such as legitimate prescriptions, alcohol or over the counter products) and in combination with other licit and illicit substances.

According to the CDC morbidity and mortality weekly report, only 3 states reported detecting carfentanil in overdose deaths during the second half of 2016, but by the end of the first half of 2017, 7 states had reported overdose deaths associated with carfentanil.

 In the same timeframe, the number of counties in which overdose deaths with carfentanil present occurred increased from 54 to 77 with Ohio reporting the highest numbers of carfentanil overdose deaths.

 Between October 2016 and February 2017. the number decreased slightly in proportion with an increase in acrylfentanyl and furanylfentanyl (both forms of nonpharmaceutical fentanyl) deaths.

Further complicating the landscape, the DEA reports that fentanyl and its analogues are often produced in China and then shipped internationally where they are mixed into the heroin supply or combined with other non-opioid drugs and pressed into a tablet form.

This practice partially explains why overdoses with these substances are often misidentified as heroin overdoses or pinned on other prescription opioids present in the body at the time of the overdose.

The reporting of these overdoses often neglects important pharmacological insight into drug metabolism and leads to erroneous documentation.

 When these overdoses are documented as caused by fentanyl or fentanyl analogs, a common misconception follows whereby it is assumed that prescription fentanyl was the cause of these overdoses and further blame is pushed onto prescribers and prescription opioids. As the authors reported, diagnosis codes used for opioid overdose do not differentiate between licit and illicit opioids nor do they capture the nuance of polysubstance overdose.

As a potential bright spot in the effort to shed full light on the true causes of opioid drug overdoses, the state unintentional overdose reporting system (SUDORS) aims to collect information on all substances that contributed to death as well as “all substances for which the decedent tested positive”.

 This database has been receiving reports since August 2017, and as of August 2018, 32 states and District of Columbia are contributing data.

 This is important because the multitude of substances, licit and illicit, that may be present in the body at the time of overdose death could all be considered for their potential contribution. Further, the CDC's Project—Improving the Quality and Timeliness of Data on Drug Overdose Deaths has joined medical examiners, coroners, public health experts and health IT to expedite their processes with the goal of having 90% of drug-related death records made available for public health surveillance and decision-making within 90 days of death.

 It seems that this effort could be further improved with the addition of a pharmacist to the team to fully appreciate the pharmacological and pharmacokinetic complexities of today’s opioid overdose.  

Overall, prescription fentanyl is rarely abused or obtained illegally in comparison to other opioids, such as morphine, oxycodone, and hydrocodone. It is especially important for practicing pharmacists to consider the implications of illicit fentanyl, to separate them from illicit fentanyl analogues that can be up to 1000x more potent than prescription fentanyl, and to educate providers and the community on the differences.

This article was co-written with Amelia L. Persico, PharmD, MBA. Dr. Persico is a graduate of Albany College of Pharmacy & Health Sciences and Union Graduate College. She has practiced as a community pharmacy manager and is currently a PGY1 Pharmacy Resident at the Stratton Veterans Administration Medical Center in Albany, New York.

Information provided is the sole work of the authors, and the stated opinions or assertions do not reflect the opinions of employers, employee affiliates, or any pharmaceutical companies listed. It was not prepared as part of the authors’ duties as federal employees. 

Mark R Jones; et al. A Brief History of the Opioid Epidemic and Strategies for Pain Medicine. 

Bettinger, J; et al. Fentanyl: Separating Fact from Fiction. PPM 6Aug2018;18(5). https://www.practicalpainmanagement.com/treatments/pharmacological/opioids/fentanyl-separating-fact-fiction. Accessed October 2, 2018.

O’Donnell, Julie, R. Matthew Gladden, Christine L. Mattson, Mbabazi Kariisa. Notes from the field: Overdose Deaths with Carfentanil and Other Fentanyl Analogs Detected-10 States, July 2016-June 2017. 

https://www.cdc.gov/mmwr/volumes/67/wr/mm6727a4.htm

Knierim, PE. Tackling Fentanyl: The China Connection. 9 Sep 2018. Department of Justice DEA. https://www.dea.gov/. Accessed October 12, 2018.

CDC. Project- Improving the Quality and Timeliness of Data on Drug Overdose Deaths. CDC website. https://www.cdc.gov/surveillance/projects/improving-data-on-drug-overdose-deaths.html. Accessed October 17, 2018.

Despite a decline in the rate of opioid prescribing, the CDC reports that the number of opioid related deaths continues to rise. The pharmacology and pharmacokinetics of prescription and illicit fentanyl could help to shed light on why the opioid epidemic has taken the path that it has. 