Opioid Harm Reduction Strategies:
`Focus on Expanded Access to Intranasal Naloxone
`
`Daniel P. Wermeling, Pharm.D., FCCP, FASHP
`
`Key Words: opioids, antidote, naloxone, overdose.
`(Pharmacotherapy 2010;30(7):627–631)
`
`In 2008, both prescription and illicit opioids,
`alone or in combination with other intoxicants,
`led to over 20,000 overdose deaths in the United
`States.1–4 This statistic is generated through
`reports originating from emergency departments
`and does not include information from coroner
`reports. Thus, this number is likely to be conser-
`vative.
`In addition, over the past decade, incre-
`mental increases in the number of overdose deaths
`have been demonstrated each year.5
`In 2006,
`opioid overdose surpassed firearms as the second
`leading cause of accidental injury death in the
`United States, and rates of mortality from poi-
`soning were higher than from motor vehicle
`accidents among adults aged 34–56 years. The
`average U.S. mortality rate related to opioid
`overdose in 2006 was approximately 7.8/100,000
`persons.5
`In rural Appalachia, during the past 5
`years, over 75% of fatalities were related to the
`use of prescription methadone, hydrocodone,
`and oxycodone. 5–9 Many states and large
`metropolitan areas consider opioid-related
`mortality to be a public health crisis.3, 4, 9
`
`The Opioid Antidote Naloxone
`Naloxone hydrochloride, known chemically as
`17-allyl-4,5␣,-epoxy-3,14-dihydroxymorphinan-
`6-one-hydrochloride, is a potent μ-receptor
`
`From the Department of Pharmacy Practice and Science,
`University of Kentucky College of Pharmacy, Lexington,
`Kentucky.
`The opinions expressed in this editorial are those of the
`author and do not necessarily represent the position of
`Pharmacotherapy or the American College of Clinical
`Pharmacy. Invited editorials are not peer reviewed.
`For reprints, visit http://www.atypon-link.com/PPI/loi/phco.
`For questions or comments, contact Daniel P. Wermeling,
`Pharm.D., FCCP, FASHP, Department of Pharmacy Practice and
`Science, University of Kentucky College of Pharmacy, 789 South
`Limestone Street, Lexington, KY 40536; e-mail: dwermel@uky.edu.
`
`antagonist and antidote for opioid overdose.10–12
`Naloxone was approved by the U.S. Food and
`Drug Administration (FDA) in 1971 and was first
`marketed by Endo Pharmaceuticals (Chadds
`Ford, PA) as Narcan injection. It has subsequently
`become a multisource generic drug manufactured
`by International Medication Systems, Ltd. (South
`El Monte, CA) and Hospira, Inc. (Lake Forest, IL).
`Naloxone injection is available in two strengths:
`0.4 mg/ml and 1.0 mg/ml. Current formulations
`of naloxone are approved for intravenous, intra-
`muscular, and subcutaneous administration.10
`The initial adult dose for known or suspected
`narcotic overdose is 0.4–2 mg, which may be
`repeated, up to a total dose of 10 mg.10
`The standard of care for emergency services
`personnel is to have naloxone available in
`ambulances and emergency drug kits for reversal
`of suspected opioid overdose, whether accidental
`or intentional, in the field. Hospital emergency
`departments also use this drug routinely for this
`purpose. Naloxone is also indicated as a reversal
`agent when the effects of therapeutic use of opioids
`are no longer medically necessary, such as in rever-
`sal of opioid effects after general anesthesia.11, 12
`The drug produces a rapid reversal of narcosis and
`central nervous and respiratory system depression.
`Patients and opioid abusers who may be physically
`dependent on opioids may experience short-lived
`withdrawal symptoms, which rarely are severe.
`Opioid withdrawal, while highly uncomfortable,
`is not a life-threatening phenomenon.
`
`Harm Reduction Strategies for Pain Management
`Morbidity and mortality related to opioid over-
`dose are not limited to the illicit use of prescription
`drugs or heroin. Clearly, our patients are prescribed
`increasingly complex pharmacologic regimens for
`the treatment of malignant and nonmalignant
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`chronic pain. Other central nervous system
`depressant drugs are frequently prescribed in
`conjunction with opioids, often by several
`physicians who are simultaneously treating the
`patient. Concurrent use of alcohol and other
`substances such as marijuana are common
`cointoxicants found in patients who have died
`from opioid overdose. Thus, serious consideration
`should be given to prescribing naloxone to
`patients who are at high risk of an inadvertent
`opioid overdose. Potential indications for
`prescribing naloxone and the patient populations
`targeted could include the following:
`• Any methadone prescription
`• High-dose opioid prescriptions (e.g., high-
`potency, extended-release products)
`• Patients released after an opioid poisoning
`• People with a suspected history of illicit or
`nonmedical use of opioids
`• Concurrent use of opioids with antidepres-
`sants, benzodiazepines, or alcohol
`• Opioid use in patients with major organ dys-
`function (renal, hepatic, cardiac, or pulmonary)
`• Patients released from opioid detoxification
`programs
`An interesting dilemma that arises from the
`notion of prescribing naloxone to patients at risk
`of overdose is that they are very unlikely to be able
`to rescue themselves should they be overcome by
`the effects of an opioid. Thus, a bystander,
`family member, or caregiver will likely by the
`first to witness the overdose and have the first
`opportunity to respond. Even though the patient
`would be prescribed naloxone, it is clearly those
`closely surrounding the patient who need to be
`trained on overdose recognition and treatment
`(administering naloxone, calling 911, and rescue
`breathing for the patient [if apneic]). The ability
`to enable such a program that consists of at-home,
`triage-related emergency medicine requires that
`an exemption be made in most state pharmacy,
`medicine, and nursing practice acts to permit a
`layperson to administer the antidote to another
`person. Similar statutes exist for the adminis-
`tration of epinephrine for anaphylaxis and
`glucagon for insulin shock. Needle-free drug
`delivery systems (discussed below) would also
`facilitate layperson rescue.
`
`Naloxone Nasal Drug Delivery by Emergency
`Medical Technicians
`Federal and state agencies, the pharmaceutical
`industry, and others are adopting prevention and
`intervention strategies in an attempt to reduce
`
`opioid overdose mortality while protecting the
`health of emergency medical services staff.13–18
`Initially, injection-based naloxone served as the
`standard of care. However, many emergency
`medical services programs have now moved
`toward intranasal administration of naloxone
`injection since about 80% of the injection-drug
`abuse population is hepatitis C or human
`immunodeficiency virus positive, particularly in
`large metropolitan areas.15, 17, 18 The emergency
`medical services program has created an intra-
`nasal naloxone administration system (Figure 1).
`The system combines an FDA-approved naloxone
`injection product with a Luer-fitted tip without a
`needle and an approved medical device—a
`disposable nasal solution atomizer—called the
`Mucosal Atomization Device (MAD; Wolfe Tory
`Medical, Salt Lake City, UT). Emergency medical
`services programs in Boston, Denver, and San
`Francisco use this drug administration technique
`as the standard of care.19–22
`An additional reason to advocate intranasal
`delivery of naloxone is that there are different
`tiers of responsibility and professional scopes of
`practice within the emergency medical services
`staff. For example, paramedics are authorized to
`start intravenous lines and administer injections
`whereas emergency medical technicians (EMTs)
`are not. Moreover, EMTs more commonly provide
`emergency medical services in rural regions of the
`United States. Thus, providing a mechanism so
`that EMTs can administer naloxone seems to be
`warranted.
`A group of authors first demonstrated the use
`of intranasal delivery of naloxone in a study
`published in 2002.19 Thirty patients in Denver
`encountered by paramedics received 2 mg/2 ml of
`naloxone injection used with the MAD nasal
`spray atomizer. One ml was administered into
`each naris on initial contact. Eighty-three percent
`of the patients with a suspected opioid overdose
`responded to intranasal naloxone, with an
`average response time of 3.4 minutes. Sixty-four
`percent of the patients did not require intravenous
`line placement. These authors were the first to
`suggest that nasal naloxone rescue administered
`by emergency medical services can work in
`practice.
`Th same group of authors published an expanded
`version of their study 3 years later (2005).20
`Response rates to treatment remained similar.
`Additional data on time to first patient contact,
`time to drug administration, and time to achieve
`a spontaneous respiratory rate of at least 10
`breaths/minute were reported. The average time
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`to clinical response was slightly longer with
`intranasal compared with intravenous adminis-
`tration. Of importance, however, was that the
`time from first contact to clinical response was
`not different between intravenous and intranasal
`administration, as the time spent starting an
`intravenous line is saved with intranasal adminis-
`tration. Given the same elapsed time until patient
`outcome in most circumstances, and the hazards
`of needlesticks in this population, there is a
`strong argument for use of nasal delivery.
`A similar randomized trial, also reported in
`2005, comparing intranasal naloxone 2 mg with
`intramuscular naloxone 2 mg produced similar
`results.21 Two other reports published in 2005
`and 2009 compared intravenous naloxone with
`intranasal naloxone in the “prehospital” setting
`of the San Francisco emergency medical services
`area.22, 23 One hundred fifty-four patients were
`enrolled; 100 received intravenous and 54 received
`intranasal treatment. Time to clinical response to
`naloxone was reported to be the same between
`groups. Similar to the findings of one of the
`previous studies,20 the mean time from patient
`contact to clinical response was not different (20.3
`min for intranasal versus 20.7 min for intravenous).
`The authors concluded that intranasal naloxone is a
`viable alternative rescue treatment given the hazards
`associated with obtaining intravenous access in this
`patient population.
`
`Take-Home Naloxone for Opioid Abusers
`
`Several large metropolitan cities that have
`significant injection-based drug abuse, primarily
`heroin, adopted pilot studies in the 1990s to
`determine if addicts could be trained to rescue
`other individuals who may be experiencing an
`overdose; a summary of evidence addressing this
`point was published in 2001. 24 The basic
`premise was that needle-exchange programs
`commonly have repeated access by addicts. Also,
`it was generally understood that abuse occurs in
`small groups of individuals and that a fellow
`addict is likely to be the observer and potential
`first responder to a person overcome by the effects
`of heroin and in need of resuscitation. The initial
`programs developed a medical protocol in which
`naloxone injection was prescribed to an addict
`who was trained on overdose recognition and
`treatment. A simple kit was provided to the
`addict that contained naloxone injection along
`with a needle or nasal atomizer adaptor, a rescue
`breathing mask, and a message to call 911. The
`concept was simple—give naloxone, rescue
`breathe if apneic, and call for emergency medical
`services.
`In a 2005 pilot study conducted in San
`Francisco, pairs of heroin users were trained to
`recognize overdose and complete the three-step
`process of naloxone administration, rescue
`
`A
`
`B
`
`Figure 1. The intranasal naloxone administration system, which combines a naloxone injection product with a Luer-fitted tip
`without a needle and an approved medical device—a disposable nasal solution atomizer called the Mucosal Atomization Device
`(panel A); use of the system is demonstrated in panel B.
`
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`breathing, and calling 911 for help.25 Twenty-
`four pairs were enrolled and were followed for 1
`year after receiving training and a naloxone rescue
`kit. Twenty witnessed overdoses were reported,
`and the rescue methods were employed. All
`subjects survived the overdose incidents.
`In 2006, the multiyear experience of the
`Chicago Recovery Alliance, a program similar to
`the San Francisco pilot study, was reported.26
`Over several years, the Alliance distributed over
`3500 vials of naloxone injection to addicts. The
`study reported 319 incidents of overdose
`reversals by their peers. During the study period,
`the Cook County medical examiner reported a
`20% decrease in opioid deaths in the first year
`and an additional 10% reduction for each of the
`second and third years of implementation.
`Similar programs have been described for
`Boston, New York City, Baltimore, and the state
`of New Mexico27; one article explained how to
`establish medical programs for heroin overdose
`prevention in other locales.28 In 2008, an evalua-
`tion of six different naloxone training and distri-
`bution programs in the United States was pub-
`lished,29 followed by additional critical considera-
`tions for training on intervention and preventing
`overdoses.30, 31
`It is a simple notion that family
`caregivers—meaning a spouse, loved one, girlfriend
`or boyfriend, or any family member in close
`contact with an addict—should be trained on
`recognition of suspected overdose and what to do
`if it occurs. A family member of an addict is
`likely to be the first responder and can provide
`rescue until arrival of emergency medical services.
`In 2009, experience with intranasal delivery of
`naloxone injection and training of addicts on
`drug overdose prevention in Boston was described.17
`The article further outlines the regulatory and legal
`barriers that must be overcome to establish a
`harm reduction program.
`In the most recent
`summary of expanded access to naloxone, a
`global overview of the opioid overdose epidemic,
`the nature of programs in existence, and how
`additional considerations of FDA regulatory
`status—including developing and approving a
`naloxone product designed for nasal delivery, and
`over-the-counter status for naloxone—could help
`expand access, are provided.18
`
`The Role of the Pharmacist
`A tremendous opportunity exists for pharmacists
`in helping to reduce opioid-related morbidity and
`mortality. The paradigms discussed above related
`to therapeutic use of opioids in pain manage-
`
`ment, emergency medicine, and the abusing
`population deserve consideration. Pharmacists
`can take a leading role in developing legislation
`that is permissive of naloxone rescue. Clearly,
`pharmacists can assist in the training and dissemi-
`nation of information regarding the proposed
`rescue program with their local community emer-
`gency medical services staff. Finally, pharmacy
`organizations should take a leading role in
`designing opioid harm reduction strategies,
`research studies, and operational models for
`pharmacists in their communities.
`
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