Alongside the growing prevalence of chronic pain and prescription opioid use, drug-related overdose continues to claim the lives of 17,000 Americans each year.1
 
Deaths from unintentional opioid overdose have increased 56% since 2010.2 In 2013, 83% of the opioid overdoses were unintentional.
 
In 2010, there were approximately 136,000 emergency room visits related to opioid-induced respiratory depression (OIRD) and overdose.3 Needless to say, opioid overdoses are claiming thousands of lives and drastically increasing health care costs. 
 
For these reasons, President Barack Obama has issued a memorandum directing 2 steps to combat prescription drug abuse and the heroin epidemic: more prescriber training and expanded access to naloxone. The memorandum outlined efforts to include state, local, and private sectors in addressing this problem, fostering a multidisciplinary network of various professions.
 
The White House announced the following pharmacy actions in combating the opioid problem:
  • CVS Health will pursue collaborative agreements with physicians to utilize a standing order to dispense naloxone without a prescription.
  • Rite Aid will train 6000 pharmacists on naloxone use over the next year. 
  • The American Pharmacists Association will educate pharmacists, student pharmacists, and stakeholders on opioid use, misuse, and abuse.
  • American Society of Health-System Pharmacists will provide training and resources to 40,000 pharmacists, student pharmacists, and pharmacy technician.
  • The National Association of Boards of Pharmacy will expand prescription drug monitoring program data to Arizona, Delaware, Kentucky, and North Dakota in 2016.
When naloxone is administered by first responders outside an institutional setting, it can improve outcomes for emergency opioid reversal prior to a patient reaching the emergency department.4 There are currently 2 FDA-approved naloxone formulations for take-home use: the auto-injector approved on April 3, 2014,5 and the new intranasal formulation approved on November 18, 2015.
 
Intramuscular naloxone is also available, but it is not FDA-approved for take-home use, as it requires significant training and understanding by the administrator on device assembly for the drug and needle. This method also carries a risk of needle sticks and can cause confusion among pharmacists on proper dispensing and billing for each piece required.
 
Photo comparisons of take-home naloxone products are available here.
 
Who Should Receive Take-Home Naloxone?
The American Medical Association released a statement in July 2015 advocating for dual prescribing of naloxone and opioids to patients at risk for drug overdose.6 This, of course, begged the question: who are those at risk? 
 
Some believe every patient receiving chronic opioid therapy is at risk. Until recently, there has not been a validated risk assessment tool to ascertain otherwise.
 
There is the Atherosclerotic Cardiovascular Disease (ASCVD) score to guide statin therapy,7 the Fracture Risk Assessment (FRAX) tool to guide osteoporosis therapy,8 and the CHADS2-VASc score to guide anticoagulant therapy,9 but heretofore, there has been no numerical risk scoring system to guide naloxone prescribing. 
 
The Risk Index for Overdose or Serious Opioid-Induced Respiratory Depression (RIOSORD)
The authors behind the RIOSORD score first validated this risk index in US veterans.10 Readers can access an automated 15-question Excel sheet scoring tool based on this original validation here.

Subsequently, the same authors validated RIOSORD in the general population, which was presented in poster form and is provided here with their permission.11 This was a case-control analysis in a cohort of 18 million patients using prescription claims data.
 
The authors identified 7234 cases of overdose or serious opioid-induced respiratory depression (OSORD) and compared them with 28,932 controls. Common risk factors associated with OSORD were assigned a score for each risk factor using multivariable logistic regression modeling.
 
This newer RIOSORD tool for the general population is a 16-question survey, which is available here in an automated Excel file for ease of use by pharmacists. It has a total maximum score of 146 points.
 
The calculated total RIOSORD score corresponds to an average predicted probability of OSORD of 2% to 84%.
 
Risk Factors Associated with OSORD13
Coexisting conditions associated with increased risk for OSORD include bipolar disorder or schizophrenia and conditions that alter drug metabolism (eg, renal or hepatic impairment, chronic headache, heart failure, pulmonary disease, non-malignant pancreatic disorder, and cerebrovascular disease).  
 
History of substance abuse is the comorbidity identified with the most significant risk, as patients with it have a 12-fold increase in OSORD risk. It is important to note, however, that health care conditions affecting a patient’s OSORD score must be active conditions for which the patient had a related health care visit in the past 6 months.

The opioid medication, dose, and formulation also contribute to OSORD risk. The use of methadone, fentanyl, morphine, and hydromorphone has been identified as an independent risk factor.
 
Opioid doses exceeding a morphine equivalent daily dose of ≥100 mg were found to have a 2-fold increased risk of a patient experiencing OSORD. Extended-release or long-acting opioids also increase the risk for OSORD. 
 
Co-prescribing of antidepressants and benzodiazepines increases the risk for OSORD. Benzodiazepines could cause further suppression of respiratory drive, while several antidepressants inhibit CYP3A4 and/or CYP2D6. Both are responsible for the metabolism of several opioids, the result of which could elevate blood levels of active drug by reducing metabolism to the inactive forms.
 
Aside from these interactions, many antidepressants carry their own inherent risk of sedation, especially tricyclics.
 
How Can I Use RIOSORD in a Community Pharmacy?
Community pharmacists have an excellent opportunity to identify patients at risk for OSORD and provide critical counseling points. They can help facilitate cost barriers to obtaining naloxone in the retail setting, in addition to identifying patients most at risk for an unintentional overdose based on the RIOSORD tool.
 
The patient’s medication history could provide valuable information about morphine equivalence, drug-drug interactions, and conditions based on prescribed medications. Signs and symptoms of OSORD are important key counseling points for patients receiving chronic opioid therapy and those newly initiated on opioids.
 
It is critical to educate patients and caregivers who pick up medications for patients, recognizing that the caregiver is likely to be the first responder in an event of overdose. Caregivers should be educated on the signs and symptoms of OSORD, as well as on how to respond during this life-threatening situation.
 
Once naloxone is dispensed and counseling is complete, recipients must understand that a plan of action for the drug is important, similar to housing a fire extinguisher in the event of a fire.
 
Role of Community Pharmacy in Naloxone Distribution
There are approximately 59,000 to 67,000 community pharmacies that can facilitate naloxone distribution.14 As of today, naloxone is available without a prescription in 15 states: Rhode Island, Massachusetts, Arkansas, California, Minnesota, Mississippi, Montana, New Jersey, North Dakota, Pennsylvania, South Carolina, Tennessee, Utah, New Mexico, and Wisconsin.15

What about the other 35 states? One approach is collaboration with physicians in which pharmacies can utilize a collaborative practice agreement to dispense naloxone under the supervision of an agreed-upon physician.
 
For instance, on December 7, 2015, New York City Mayor Bill de Blasio and First Lady Chirlane McCray announced efforts to make naloxone available by avoiding the typical prescription process in New York City.14 These efforts entail using a physician’s standing order to dispense naloxone to patients at more than 150 participating pharmacies.15

As of July 2015, there are 132 accredited colleges and schools of pharmacy in the United States.16 As part of their training and experiential education, students could and should utilize the RIOSORD tool to identify at-risk patients, qualify them for naloxone, and provide the corresponding training. This also allows licensed pharmacy interns to take a more active role in a major public health problem, participate in a community service initiative, and engage in direct patient care.   
 
Risk Mitigation and Patient Education
How can prescribers and pharmacists include RIOSORD in patient education? Realizing a patient’s elevated RIOSORD score can lead to a conversation about the possibility of an accidental overdose, and also possible risk-reducing strategies.
 
For example, a health care provider could tell a patient, “patients with risk factors similar to yours were predicted to have a probability of X% for accidental overdose or opioid-induced respiratory depression.” It might even help to encourage patients to seek psychotherapy in an effort to reduce benzodiazepine intake and become less reliant on sedative-hypnotics if opioids are required.

Providers can also educate patients on associated risk factors in order to inform them of any changes that could increase their risk for OIRD. For instance, if patients are made aware that antidepressants increase their risk for OIRD, and they were prescribed sertraline 50 mg by a psychiatrist, then they could contact their pain provider and ask how this affects their risk for OIRD.

RIOSORD also provides a starting point for pharmacists to educate prescribers on risks for opioid overdose, especially potential drug-drug interactions and polypharmacy, which allows for prospective risk mitigation.   
 
Conclusion
With the availability of naloxone for take-home use, no one should lament over the loss of a loved one because a life-saving medication was not easily accessible.
 
“Not one more friend, not one more loved one must be mourned because life-saving medicines weren't easily available,” stated New York City First Lady Chirlane McCray. “With a simple nasal spray or injection that is as easy to use as an EpiPen, we can end opioid overdose deaths in our city.”14

We can’t agree that naloxone availability will end opioid overdose deaths, but it certainly is our professional responsibility to ensure that we’ve taken every step to reduce risks. We believe there is a unique opportunity for our colleagues to step up to the plate and hit a lifesaving grand slam, but a multi-disciplinary multipronged approach is needed to reign in this health care crisis.
 
Pharmacists, physicians, and student clinicians have an excellent opportunity to mitigate opioid overdose risks by employing the validated RIOSORD tool. RIOSORD can aid opioid prescribers in identifying at risk patients, and it can also help encourage a candid dialogue among pharmacists, patients, and caregivers to reduce patient harm.
 
As pharmacists, we are the front-line clinicians that can and should make a difference. Lawmakers need to recognize that pharmacists are poised in the most crucial environment to have the largest impact. 
 
In this instance, the Oath of a Pharmacist couldn’t be more applicable:

I will consider the welfare of humanity and relief of suffering my primary concerns. I will apply my knowledge, experience, and skills to the best of my ability to assure optimal outcomes for my patients.17

This article was written collaboratively with Dr. Jacqueline Pratt Cleary and Mena Raouf. 
 
Dr. Pratt Cleary is a PGY2 Pain and Palliative Care Resident at the Stratton VA Medical Center in Albany, New York, under the mentorship of Dr. Jeffrey Fudin. Her research interests include risk stratification prior to and following opioid therapy with emphasis on requisite naloxone qualification for in-home use. Prior to completion of a PGY1 General Practice Residency at Sentara Healthcare System in Norfolk, Virginia, she earned her BS in Biochemistry at Furman University and her Doctor of Pharmacy at South Carolina College of Pharmacy MUSC Campus.
 
Mena Raouf is a 2016 PharmD Candidate at the Albany College of Pharmacy and Health Sciences, with a concentration in Nephrology. He hopes to complete PGY1 and PGY2 Pharmacy Residencies and practice as a clinical pharmacist specialist. He is currently under the mentorship of Dr. Jeffrey Fudin subsequent to completion of an advanced practice rotation in pain management.
 
Dr. Fudin discloses that he has worked as a consultant and speaker for Kaléo Pharma. 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. 
 
References:
1. Centers for Disease Control and Prevention. Prescription Drug Overdose Data. http://www.cdc.gov/drugoverdose/data/overdose.html. Accessed December 15, 2015.
2. Hasegawa K, et al. Trends in U.S. emergency department visits for opioid overdose, 1993-2010. Pain Medicine. 2014 Oct;15(10):1765-70.
3. Yokell MA, et al. Presentation of prescription and nonprescription opioid overdoses to US emergency departments. JAMA Int Med. 2014 Dec;174(12):2034-7.
4. Martin WR. Naloxone. Ann Intern Med. 1976 Dec;85(6):765-8.
5. Evzio [package insert]. Richmond, VA: Kaleo, Inc;2014.
6. Harris, PA. It’s about saving lives: Increasing access to naloxone. AMA Wire. June 29, 2015.
7. American College of Cardiology. ASCVD Risk Estimator. http://tools.acc.org/ASCVD-Risk-Estimator/. Accessed December 15, 2015.
8. WHO. Fracture Risk Assessment Tool. http://www.shef.ac.uk/FRAX/. Accessed December 15, 2015.
9. Lane D, Lip G. Use of the CHA2DS2-VASc and HAS-BLED scores to aid decision making for thromboprophylaxis in nonvalvular atrial fibrillation. Circulation. 2012;126:860-5. 
10. 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. 2015 Jun;16:1566-79.
11. Zedler B, Saunders W, Joyce A, et al. Validation of a screening risk index for overdose or serious prescription opioid-induced respiratory depression prescription opioid use and deaths from overdose or opioid-induced respiratory depression. Presented at the 2015 AAPM Annual Meeting. March 2015.
12. Department of Health and Human Services Health Resources and Services Administration Bureau of Health Professions. Adequacy of pharmacist supply: 2004 to 2030. http://bhpr.hrsa.gov/healthworkforce/reports/pharmsupply20042030.pdf. Accessed December 15, 2015.
13. New Mexico Board of Pharmacy. Pharmacist prescriptive authority of naloxone rescue kit protocol. http://www.rld.state.nm.us/uploads/filelinks/e3740e56e0fe428e991dca5bd25a7519/nrk_protocol_bop_dale_tinker.pdf. Accessed December 15, 2015.
14. Office of the Mayor of the City of New York. De Blasio Administration launches comprehensive effort to reduce opioid misuse and overdose deaths across the city. nyc.gov. December 7, 2015.
15. NYC Health. New York City pharmacies that carry naloxone. http://www.nyc.gov/html/doh/downloads/pdf/basas/naloxone-list-of-pharmacy.pdf. Accessed December 15, 2015.
16. American Association of Colleges of Pharmacy. Pharmacy school locator. http://www.aacp.org/resources/student/pages/schoollocator.aspx. Accessed December 15, 2015.
17. American Pharmacists Association. Oath of a pharmacist. http://www.pharmacist.com/oath-pharmacist. Accessed December 15, 2015.