Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP
Dr. Jeff Fudin graduated from Albany College of Pharmacy & Health Sciences with a BS and PharmD. He is a Diplomate to the Academy of Integrative Pain Management, a Fellow to ACCP, ASHP, & FSMB, a member of several other professional organizations. He is CEO of Remitigate (remitigate.com), an opioid safety software development LLC. Dr. Fudin is a section editor for Pain Medicine & Co_Editor-A-Large for Practical Pain Management. He practices as a clinical pharmacy specialist (WOC) and director of PGY-2 pharmacy pain residency programs at the Stratton Veterans Administration Medical Center in Albany, New York and has academic affiliations with Western New England University and Albany Colleges of Pharmacy.
With 100 million patients with chronic pain and 44 people dying every day in the United States from opioid overdose, there is a clear role for pharmacist retrospection, evaluation, intervention, and direct patient counseling to help mitigate risks for opioid-induced respiratory depression (OIRD) and resultant morbidity and mortality.1
Fortunately, the opioid antagonist naloxone has been available for 40 years and can be a lifesaving antidote in the right place at the right time.
Naloxone was approved in 1976 for the treatment of emergency opioid overdose. Until recently, the opioid overdose antidote has mostly been used in hospital settings, especially institutional emergency departments (EDs).2
But the surge in opioid overdoses over the last decade has encouraged the use of naloxone outside of hospital settings worldwide. Now, naloxone is more commonplace and routinely administered by Emergency Medical Services (EMS) and police officers throughout the country, though regulations vary from state to state and county to county.
Naloxone is available through intravenous (IV), intramuscular (IM), and intranasal (IM) routes of administration. In April 2015, the FDA approved the first naloxone auto-injector delivery system (Evzio), which it fast-tracked because of the important lifesaving impact expected from widespread availability of an easy-to-use device with voice prompts and intuitive, simple administration.3 It is the first and only FDA-approved naloxone intended for in-home use and emergency treatment of known or suspected opioid overdose, characterized by decreased breathing or heart rates, or loss of consciousness.
In July 2015, the American Medical Association (AMA) Task Force to Reduce Opioid Abuse released recommendations to address the urgent drug abuse epidemic.
"America's patients who live with acute and chronic pain deserve compassionate, high-quality, and personalized care, and we will do everything we can to create a health care response that ensures they live longer, fuller, and productive lives," stated AMA Board Chair-Elect Patrice A. Harris, MD, MA.4
Since 1996, there have been an increasing number of opioid overdose risk prevention initiatives that provide public access to naloxone and corresponding education on opioid overdose. Examples of such programs include the Drug Overdose Prevention and Education (DOPE) Project in San Francisco, Project Lazarus in North Carolina, and naloxone distribution programs in Massachusetts, New Mexico, and New York City.5
Overdose Education and Naloxone Distribution (OEND), a statewide opioid overdose risk mitigation launched in Massachusetts, has demonstrated a significant decline in related mortality in communities that adopted the program between 2006 and 2009.6 New Mexico’s Department of Health has been dispensing intranasal naloxone as part of its needle exchange program for more than a decade. Standing orders is another strategy to increase access to naloxone, and it has been implemented in several states such as Colorado, Massachusetts, New Mexico, and North Carolina.5
Nevertheless, there is a need to improve and implement these strategies in other health care settings, including the community pharmacy.
One recent study identified common risk factors of opioid-induced respiratory depression (OIRD) in a cohort of veteran patients.7 To determine the probability of serious OIRD, the authors developed a 17-question survey with a total maximum score of 115 (Table 1).
Table 1: Risk Index for Overdose or Serious Opioid-Induced Respiratory Depression (RIOSORD) 7
|In the past 6 months, has the patient had a health care visit (outpatient, inpatient, or ED) involving:|
|Chronic hepatitis or cirrhosis?||9|
|Bipolar disorder or schizophrenia?||7|
|Chronic pulmonary disease? (e.g., emphysema, chronic bronchitis, asthma, pneumoconiosis, asbestosis)||5|
|Chronic kidney disease with clinically significant renal impairment?||5|
|Active traumatic injury, excluding burns? (e.g., fracture, dislocation, contusion, laceration, wound)||4|
|Does the patient consume:|
|An extended-release or long-acting (ER/LA) formulation of any prescription opioid or opioid with long and/or variable half-life? (e.g.,OxyContin, Oramorph-SR, methadone, fentanyl patch, levorphanol)||9|
|Methadone? (Methadone is a long-acting opioid, so also write Y for “ER/LA formulation”)||9|
|Oxycodone? (If it has an ER/LA formulation [e.g., OxyContin], also write Y for “ER/LA formulation”)||3|
|A prescription antidepressant? (e.g., fluoxetine, citalopram, venlafaxine, amitriptyline)||7|
|A prescription benzodiazepine? (e.g., diazepam, alprazolam)||4|
Is the patient’s current maximum prescribed opioid dose:
|>100 mg morphine equivalents per day?||16|
|50-100 mg morphine equivalents per day?||9|
|20-50 mg morphine equivalents per day?||5|
|In the past 6 months, has the patient:|
|Had 1 or more ED visits?||11|
|Been hospitalized for 1 or more days?||8|
Opioid dependence, psychiatric disorder, pulmonary disease, liver disease, use of an extended-release opioid, use of an antidepressant, use of a benzodiazepine, daily morphine equivalents, and recent hospitalizations or emergency department visits were all identified as relevant risk factors for OIRD.
Each of these variables correlates with an average predicted probability of OIRD by incremental risk of 3%, 14%, 24%, and up to 94% (Table 2).
Table 2: OIRD probability based on calculated risk index7
|Risk index (score)||OIRD probability (%)|
Renal or hepatic impairment could impair opioid metabolism and elimination, leading to increased risk for accumulation and toxicity. Chronic pulmonary disease is another risk factor that puts patients at respiratory compromise.
Polypharmacy with benzodiazepines and antidepressants were prevalent risk factors due to increased sedation and potential drug-drug interactions. Several antidepressants are inhibitors of CYP3A4 and CYP2D6, both of which are mainly responsible for metabolism of various opioids.
Macrolide antibiotics, with the exception of azithromycin, are commonly prescribed and potent inhibitors of CYP3A4, an important enzyme for converting oxycodone and hydrocodone to their inactive metabolites. This inhibition and resultant elevated serum levels of active drug can happen within 24 to 48 hours of commencing therapy.
Certain opioid doses and formulations were associated with higher likelihood of toxicity. Morphine equivalent daily dose (MEDD) was directly proportional to the risk of OIRD, with the highest risk in patients taking MEDD ≥100 mg. Use of ER/LA formulations were correlated to increased risk of OIRD. Methadone is another independent risk factor because of its variable pharmacokinetic profile and multiple drug interactions.
Community pharmacists have the opportunity to identify patients at risk for opioid overdose based on these risk factors, especially those involving select drugs, drug classes, drug interactions, and comorbid disease states, even those identified by prescribed drugs. Signs and symptoms of OIRD is an important key counseling point for patients receiving chronic opioid therapy and those newly initiated on opioids.
Community pharmacists can provide valuable education on opioid overdose risk and increase public health awareness on the availability of a potentially lifesaving intervention, naloxone.
You are working in a community pharmacy and a patient presents to pick up a new prescription for clonazepam. The patient also asks to have his inhalers refilled and wishes to know when his fentanyl is due to be filled. You inquire and find out that the patient has chronic obstructive pulmonary disease (COPD).
You check the patient’s profile and find the following medications:
- Oxycodone 10 mg: Take 1 tablet by mouth every 4 hours as needed
- Fentanyl 100 mcg: Apply 1 patch transdermally every 72 hours
- Fluoxetine 20 mg: Take 1 capsule by mouth daily
- Advair Diskus 250/50: Inhale the contents of 1 capsule twice daily
- Spiriva 18 mcg: Inhale the contents of 1 capsule daily
- Lisinopril/HCTZ 20/12.5 mg: Take 1 tablet by mouth daily
- Metformin ER 1000 mg: Take 1 tablet by mouth twice daily
COPD: +5 points
MEDD 240 mg: +16 points8
Antidepressant use (fluoxetine): +7 points
Benzodiazepine use (clonazepam): +4 points
Extended release opioid (fentanyl): +9 points
Total score= 41 points*
This score indicates that the patient has a 37% chance of an accidental OIRD.
Note: This risk index score was studied and validated in a veteran population only, although there is presumed applicability in the general population.
Barriers to naloxone implementation
Despite naloxone’s availability for in-home use, it remains underused. There are various barriers to widespread naloxone prescribing for qualified patients, some of which include:
- Lack of knowledge about naloxone’s availability for in-home use.
- Lack of health care professionals' training and knowledge of the naloxone auto-injector, Evzio.
- Time constraints and overworked pharmacists who are evaluated on the number of prescriptions filled and vaccines administered, rather than the number of patients counseled.
- Confidentiality concerns of counseling patients on naloxone use in a community pharmacy with limited privacy.
- Misinterpretation that naloxone reversal is only for “addicted patients” without consideration to the above risk factors in whom opioids are legitimately prescribed.
Moreover, the pharmacist’s responsibility might include calling the prescriber’s office to recommend take-home naloxone. While some states allow pharmacists to dispense naloxone without a prescription, most have variable requirements for a prescription or specified hours of training for pharmacist prescribers.
Pharmacists have come to a crossroad where responsibility, professional obligation, and ethics meet fear, time constraints, profits, and even greed. The next time a patient presents with an opioid prescription with risks for overdose, remember the Pharmacist's Oath, 3 points of which squarely apply:9
I will consider the welfare of humanity and relief of human suffering my primary concerns.
I will apply my knowledge, experience, and skills to the best of my ability to assure optimal drug therapy outcomes for the patients I serve.
I will embrace and advocate change in the profession of pharmacy that improves patient care.
This article was collaboratively written with Mena Raouf, a 2016 PharmD Candidate at Albany College of Pharmacy and Health Sciences. He is currently working under the mentorship of Dr. Fudin as part of his clinical experiential training.
This article is the sole work of the authors and stated opinions/assertions do not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies listed.
1) US Centers for Disease Control and Prevention. Prescription Drug Overdose Data. [Internet] Available from: http://www.cdc.gov/drugoverdose/data/overdose.html
2) Martin WR. Naloxone. Ann Intern Med. 1976 Dec;85(6):765-8.
3) Evzio [package insert]. Richmond, VA: Kaleo, Inc.; 2014.
4) Harris PA. American Medical Association. What physicians can do to stop the opioid overdose epidemic. An AMA Viewpoints post. [Internet] July 2015. Available from: http://www.ama-assn.org/ama/ama-wire/post/physicians-can-stop-opioid-overdose-epidemic
5) Wheeler E, Jones S, Gilber MK et al, Opioid Overdose Prevention Programs Providing Naloxone to Laypersons — United States, 2014. US Centers for Disease Control and Disease Prevention Morbidity and Mortality Weekly Report. June 19, 2015 / 64(23);631-635.
6) Walley AY, Xuan Z, Hackman HH, et al. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis. BMJ. 2013;346:f174.
7) Zedler B, Xie L, Wang L et al. Development of a Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in Veterans’ Health Administration Patients. Pain Medicine. Jun 2015. 16;1566-1579.
8) Practical Pain Management. Opioid Calculator. [Internet] Available from: http://opioidcalculator.practicalpainmanagement.com/
9) American Pharmacists Association. Oath of a Pharmacist. [Cited 9 September 2015] [Internet] Available from: http://www.pharmacist.com/oath-pharmacist.