Intranasal Naloxone for
`At-Home Opioid Rescue
`
`Tens of thousands of lives could be saved from
`accidental opioid overdose deaths if naloxone were
`more widely available and opioid users, caregivers,
`and first responders were trained in its use.
`
`By Stewart B. Leavitt, MA, PhD
`
`Naloxone is a well-tested antidote
`
`for reversing often-fatal respira-
`tory depression due to opioid
`overdose poisoning. So, the prescription
`of naloxone for at-home intranasal
`administration, along with complete
`instructions for its emergency use, may be
`the best antidote for stemming rising
`rates of prescription-opioid overdoses
`and fatalities in the United States popu-
`lation. Yet, there are some major obsta-
`cles to be overcome.
`
`The Rx-Opioid Overdose Crisis
`The annual incidence of opioid-over-
`dose-associated mortality on a nation-
`wide scale has been difficult to assess due
`to incomplete reporting systems, inade-
`quate forensic determinations at autopsy,
`and other factors. According to the 2007
`Annual Report of the American Associa-
`tion of Poison Control Centers, anal-
`gesics of all types were the most fre-
`quently involved agents in human-expo-
`sure calls for help (about 312,000 calls),
`and opioids were the second most fre-
`quently associated with fatalities; coming
`
`after sedatives, hypnotics, and antipsy-
`chotic agents.1
`Data from the U.S. Centers for Disease
`Control indicate that accidental drug
`overdose deaths nationwide escalated by
`more than 800% between 1980 and 2005
`— in 2005 there were about 22,500 acci-
`dental drug overdose fatalities2 and 8,541
`deaths were associated specifically with
`prescription-opioid analgesics.3 Another
`report, from the National Center for
`Health Statistics, notes that from 1999
`through 2006, the number of fatal poi-
`sonings involving opioid analgesics more
`than tripled, rising from 4,000 to 13,800
`deaths. Opioid analgesics were involved
`in nearly 40% of all poisoning deaths in
`2006, with persons aged 35 to 54 years at
`greatest risk.4 While the data vary some-
`what depending on the source, today’s
`opioid overdose crisis clearly touches the
`lives of a great many American individu-
`als and families, regardless of age, social
`class, ethnicity, or gender.
`Individual states have reported data
`reflecting increasing concerns about
`opioid-related overdose fatalities. For
`
`example, in 2006, there were 275 opioid-
`involved fatalities in West Virginia repre-
`senting 93.2% of all deaths attributed to
`pharmaceuticals in that state.5 In 2007,
`2,328 people in Florida died from acci-
`dental opioid-analgesic overdose.6 Also in
`2007, there were 637 opioid overdose
`fatalities in Massachusetts, surpassing
`motor vehicle injury deaths.7
`Similarly, alarming reports have come
`from Maine, North Carolina, Tennessee,
`Washington, Ohio, and other states. In
`2006, Utah, New Mexico, Louisiana, Ken-
`tucky, Oklahoma, West Virginia, and
`Nevada had the highest rates of opioid-
`analgesic-related fatalities in the United
`States, ranging from 14.2 to 19.4 per
`100,000 population compared to a
`national average of 9.14.4,8 Reported
`opioid overdoses may be associated with
`the misuse or diversion of opioid anal-
`gesics as well as with illicit street drugs like
`heroin; however, most accidental opioid
`overdose fatalities today are linked to pre-
`scribed opioid analgesics.2
`Life-threatening opioid overdose takes
`place over time—it is not a sudden cata-
`
`42
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`Practical PAIN MANAGEMENT, October 2010
`©2010 PPM Communications, Inc. Reprinted with permission.
`
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
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`I n t r a n a s a l N a l o x o n e f o r A t - H o m e O p i o i d R e s c u e
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`strophic event—it usually occurs while
`other persons are present or in the vicin-
`ity and it can be averted with proper mon-
`itoring and care.8,9 In one investigation of
`opioid-related deaths, the majority of
`fatalities (65%) occurred within one week
`of a change in medication dose and most
`decedents were discovered in the morning
`at home in bed.10 In most cases, other
`persons were likely present in the home
`and might have saved the victim had they
`been armed with proper knowledge and
`an antidote.
`
`The Naloxone Solution
`Fortunately, there is an antidote that acts
`rapidly, effectively, and safely—naloxone.
`This agent was FDA-approved in 1971
`and has been used for decades by emer-
`gency medical services (EMS) personnel
`for reversing opioid overdose and reviv-
`ing victims who otherwise would have
`died. Naloxone is an opioid antagonist,
`meaning that it temporarily displaces
`opioids from their receptors in the brain
`and protects the person for a period of
`time from further action by the opioids.
`Naloxone is an unscheduled drug with
`no abuse potential and a very favorable
`safety profile. On rare occasions, nausea,
`vomiting, hypertension, pulmonary
`edema, tachycardia, or arrhythmia have
`been reported following naloxone admin-
`istration11,12; however, it is often unclear
`whether such effects were due to nalox-
`one, the ingested opioid and/or other
`drugs, or the victim’s prior physical con-
`dition. The only contraindication is
`hypersensitivity to naloxone or any com-
`ponent of the formulation.13 If adminis-
`tered to a person who has not taken
`opioids, naloxone simply has no pharma-
`cological effect and naloxone itself has no
`overdose potential.2,14
`Besides its use by EMS teams world-
`wide, some harm-reduction organiza-
`tions—starting in Europe, then in Aus-
`tralia, England, and the United States—
`have provided prescription naloxone
`directly to addicted intravenous-drug
`users (IVDUs; most often heroin users).
`To help curtail opioid overdose deaths,
`these individuals have been provided
`training in recognizing overdose, basic
`life-support techniques (e.g., rescue breath-
`ing, recovery position, etc.), and how to
`administer naloxone. Participants are
`typically provided a container of nalox-
`one and one or more needle-tipped
`syringes for intramuscular injection of the
`
`drug. They are encouraged to share this
`information with drug-using peers so they
`can assist each other during an overdose
`emergency.
`To date, naloxone-distribution pro-
`grams focusing on IVDUs have been ini-
`tiated in 17 states and several cities (New
`York, Baltimore, Boston, San Francisco,
`and Chicago).15 Although these programs
`were somewhat controversial at first, suc-
`cesses have been well-documented. Ac-
`cording to one report, as of 2007 a
`program started in Chicago in 1998 had
`trained and distributed naloxone to
`10,211 participants resulting in 1,011
`documented episodes of life-saving over-
`dose reversal with naloxone.2
`Overall, as of 2008 in the U.S., about
`21,000 persons at risk were trained on
`rescue naloxone and 2,600 overdose
`reversals were reported9—more than a
`10% return in lives saved by the invest-
`ment in naloxone training and distribu-
`tion. A study by the Overdose Prevention
`and Reversal Program at the Lower East
`Side Harm Reduction Center in New York
`City concluded that naloxone is “undeni-
`ably advantageous for individuals to effec-
`tively revive an overdosing friend or
`family member, instead of resorting to
`potentially harmful and less effective
`methods of resuscitation.”2
`Some European countries are promot-
`ing increasingly unrestricted naloxone
`access for more effective overdose preven-
`tion. The United Kingdom added nalox-
`one to its list of emergency medications—
`such as adrenaline and glucagons—that
`may be administered by anyone in a life-
`saving situation and has initiated commu-
`nity-based naloxone distribution pro-
`grams.16 Naloxone has been available
`over-the-counter in Italy since 1998,9 and
`advocates in the United States have sug-
`gested the drug should be changed from
`prescription-only to OTC status.2
`Research from Yale University in 2008
`demonstrated that, with minimal train-
`ing, any individual can learn to recognize
`and effectively respond with naloxone to
`an opioid overdose emergency just as
`effectively as medical professionals.2
`Some programs have found that no more
`than 10 minutes of instruction is required.17
`Clinical trials have found extremely high
`rates of retention of lessons learned
`during naloxone-administration train-
`ing, and many patients took it upon them-
`selves to train family member or friends
`in its proper use.18,19 It should be empha-
`
`sized that most harm reduction programs
`incorporating naloxone have involved
`actively addicted IVDUs, a population of
`individuals typified by low levels of relia-
`bility and motivation; therefore, the
`responsible behaviors of participants and
`successes of these programs are all the
`more noteworthy.
`
`Intranasal Naloxone Can Benefit
`Patients with Pain
`Naloxone is most commonly adminis-
`tered via intramuscular (IM) or intra-
`venous (IV) injection, but it also can be
`administered subcutaneously, or intra-
`nasally using an atomizer device that
`delivers a mist of naloxone to nasal mucus
`membranes. Whereas the filling of
`needle-tipped syringes and their use by
`IVDUs poses few problems, the use of
`needleless intranasal methods would be
`more appealing to, and safe for, the
`general population of patients with pain
`and their caregivers.
`Administration of naloxone intra-
`nasally is an off-label application of the
`drug, but is in use by EMS responders in
`Utah and New Mexico, as well as other
`states, and within community settings by
`overdose prevention groups in Massachu-
`setts and New Mexico.2 Research studies
`attesting to the safety, convenience, and
`effectiveness of intranasal drug delivery
`have been widely reported in the litera-
`ture.20,21 Furthermore, a series of clinical
`studies has demonstrated that intranasal
`naloxone avoids potentially dangerous
`needlesticks and the risk of air embolism
`while maintaining potency and efficacy
`for reversing respiratory depression due
`to opioid overdose.22 Ongoing research
`and evaluations of this have been recom-
`mended.14,23
`There is a website run by independent
`academics and healthcare professionals
`solely dedicated to raising the awareness
`and profile of the use of take-home nalox-
`one as a mechanism for reducing opioid-
`related deaths worldwide.24 Perhaps the
`most significant demonstration in the
`U.S. of take-home intranasal naloxone for
`opioid overdose rescue in the community
`has been taking place in Wilkes County,
`North Carolina.
`Called Project Lazarus, the initiative
`was approved in 2007 to stem the rising
`rate of opioid-analgesic overdose among
`patients being treated for pain. It is an
`opioid overdose rescue program embed-
`ded within a healthcare provider and
`
`Practical PAIN MANAGEMENT, October 2010
`©2010 PPM Communications, Inc. Reprinted with permission.
`
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`Table 1. Groups of Patients Who May Be at Risk of Overmedication or Overdose
`
`The following groups of patients have been identified as potentially benefit-
`ting from having lifesaving naloxone on hand, along with proper education
`in its use, to deal with an opioid overmedication or overdose crisis:
`
`J Any patient receiving a prescription for a higher-dose (>50 mg of morphine
`equivalent/day) of an opioid or for the longer-term management of chronic
`cancer or noncancer pain.
`
`J Patients being rotated from one opioid to another, when there may be
`incomplete cross tolerance.
`
`J Any methadone analgesia prescription to an opioid naïve patient, or for a
`patient rotated from another opioid to methadone.
`
`J Patients released after emergency medical care involving opioid intoxication
`or poisoning.
`
`J High-risk patients with suspected history of substance abuse, dependence,
`or nonmedical opioid use.
`
`Opioid prescription for patients having any of the following…
`
`J Smoking, COPD, emphysema, asthma, sleep apnea, respiratory infection,
`or other respiratory illness or potential obstruction.
`
`J Renal dysfunction, hepatic disease (including hepatitis), cardiac illness,
`HIV/AIDS.
`
`J Known or suspected concurrent heavy alcohol use.
`
`J Concurrent benzodiazepine or other sedative prescription.
`
`J Concurrent antidepressant prescription.
`
`J Patients who may have difficulty accessing emergency medical services
`(distance, remoteness).
`
`J Voluntary request from patient or caregiver.
`
`Additionally, the following special populations would benefit…
`
`J Patients participating in methadone or buprenorphine detox/maintenance
`programs (for addiction); especially during the start-up induction period or
`during “interim methadone maintenance.”
`
`J Patients recently released from opioid detoxification or mandatory absti-
`nence programs (with no opioid tolerance and a potential for opioid
`relapse).
`
`J Prior opioid abusers being released from incarceration (with no opioid toler-
`ance and risk of relapse).
`
`for
`community education program
`proper opioid use and misuse prevention
`(and is similar in principle to the newer
`patient/caregiver education program,
`Opioids911-Safety).25
`The
`Project
`Lazarus protocol goes a step further,
`asking healthcare providers in the area
`prescribing opioid analgesics to also pre-
`scribe intranasal naloxone (for pickup at
`a local pharmacy) to a broad range of
`patients who may be at risk of overmed-
`ication or overdose (see Table 1).2,9,14,26
`According to the Drug Policy Alliance,
`“support is growing among some physi-
`cians and other health professionals for
`regularly pairing naloxone with all opioid
`prescriptions. Under this scenario, physi-
`cians would routinely write a prescription
`for naloxone to accompany every pre-
`scription for opioid medications. Such a
`convention would have the dual benefits
`of safeguarding the life of the patient and
`normalizing naloxone by educating the
`greater public about its function and
`proper use.”2 And it also must be recog-
`nized that, besides potentially rescuing
`the patient for whom opioids were pre-
`scribed, intranasal naloxone could be a
`lifesaving measure for family members or
`others (even household pets) who inad-
`vertently or intentionally consume the
`patient’s opioid medication and experi-
`ence an opioid intoxication or poisoning
`crisis.14
`Cost of take-home naloxone should not
`be a prohibitive factor. The material cost
`of the intranasal naloxone kit available as
`part of Project Lazarus is estimated at
`about $25, including two prefilled nalox-
`one syringes and an atomizer tip.9 The
`naloxone component probably would
`remain viable for several years and the
`syringes and atomizer tip are nonperish-
`able items. The prescribing of intranasal
`naloxone for at-home administration typ-
`ically specifies two prefilled needleless
`syringes (each 2 mL [1mg/mL], Luer lock
`taper) with an atomizer tip attachment
`(Luer lock connection). A logistical chal-
`lenge at present is that, while the two
`items are available separately from differ-
`ent pharmacy supply sources, they are not
`typically stocked as a kit by community
`pharmacies; therefore, strategies for
`achieving easy access need to be consid-
`ered.
`Another appropriate naloxone-deliv-
`ery system for use by patients and care-
`givers might be an Autoinjector (e.g.,
`similar to the EpiPen®) for easy and safe
`
`
`
`4444
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`Practical PAIN MANAGEMENT, October 2010
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`
`IM administration. However, such a
`device is not available and manufacturers
`have expressed no interest in its develop-
`ment.
`
`Concerns Unfounded, Yet Obstacles
`Remain
`Past concerns about expanding access to
`naloxone in the general population have
`centered on potential unintended conse-
`quences of encouraging risky behaviors
`by opioid consumers, such as (a) recklessly
`using larger opioid doses since an anti-
`dote is at hand, (b) failing to seek timely
`medical attention in the event of an emer-
`gency, or (c) ingesting additional opioids
`after naloxone administration to counter
`its effects. However, the many research
`projects to date investigating these issues
`have unanimously demonstrated that
`such concerns are unfounded.2 Further-
`more, it has been stressed that, just as lay
`family members, friends, or other care-
`givers can be trusted to administer epi-
`nephrine to reverse anaphylactic shock,
`naloxone can be used to avert opioid poi-
`soning fatalities in the community.8,9
`Another concern might be legal issues
`surrounding naloxone prescription and
`distribution in the U.S. The report of a
`special project at the Temple University
`School of Law examining such concerns
`noted that naloxone is not a controlled
`substance as defined by federal or state
`laws, and the drug may be prescribed by
`physicians in every state (almost all states
`also allow advanced practice nurses
`[APNs] and physician assistants [PAs] to
`prescribe naloxone).27 Furthermore,
`almost all states allow physicians, and
`APNs/PAs in many cases, to directly dis-
`pense naloxone without restrictions, and
`the remainder allow dispensing with
`minor restrictions. And, it is deemed legal
`and appropriate in all states to teach over-
`dose response and naloxone administra-
`tion techniques to persons receiving a
`prescription for naloxone and others who
`might be in a position to administer it in
`an emergency.
`Despite these findings, some health-
`care providers might be concerned about
`prescribing and possibly distributing
`naloxone because of legal liability con-
`cerns. Several reviews of existing law have
`concluded that prescribing naloxone and
`providing proper training in its use does
`not expose physicians to unusual risks of
`medical liability as long as the physician
`acts (1) in good faith, (2) in the course of
`
`professional practice, and (3) for a legiti-
`mate medical purpose.2,27
`Experts generally agree that any
`medical liability can be reduced by ensur-
`ing that those who are given a naloxone
`prescription understand how it works and
`are instructed in its proper use. They also
`point to the routine practice of making
`available lifesaving medications—such as
`glucagon for diabetes or epinephrine for
`anaphylaxis (both of which have greater
`adverse reaction potential than nalox-
`one)—to third parties (caregivers, family,
`friends) for emergency administration.
`And, the experts note that there is wide
`latitude in federal law for the prescription
`
`est in pursuing the marketing of a take-
`home intranasal naloxone kit.
`
`Conclusion
`As Jill Harris, Managing Director of
`Public Policy at the Drug Policy Alliance,
`has noted: “Tens of thousands of lives
`could be saved if naloxone were more
`widely available and more people (includ-
`ing doctors, pharmacists and other
`healthcare professionals, as well as law
`enforcement professionals many of whom
`are currently unfamiliar with naloxone),
`were trained in its use. Providing take-
`home naloxone to opioid users, along
`with instructions for its use, could signif-
`
`“...support is growing among some physicians and other health
`professionals for regularly pairing naloxone with all opioid
`prescriptions. Under this scenario, physicians would routinely
`write a prescription for naloxone to accompany every prescription
`for opioid medications.”
`
`of drugs for applications beyond those
`indicated on their labels, which would be
`the case with intranasally-administered
`naloxone.2,28 Finally, most of the past con-
`cerns have centered on the prescribing of
`naloxone with needle-tipped syringes to
`actively-addicted intravenous-drug users
`(IVDUs), which
`is not relevant to
`intranasal naloxone for patients with pain
`who are legitimately prescribed opioid
`analgesics.
`Still, there are two current and seem-
`ingly insurmountable obstacles blocking
`intranasal naloxone for at-home opioid
`rescue. First, there is no widespread dis-
`tribution of prefilled naloxone syringes
`and atomizer tips; in fact, there does not
`even appear to be a single mail-order
`source where both items can be purchased
`together. Therefore, today, a qualified
`healthcare provider cannot simply write
`an intranasal naloxone prescription for
`delivery at a local pharmacy along with
`the patient’s opioid prescription. Second,
`U.S. government agencies have not
`shown any interest in intranasal naloxone
`as a risk-mitigation strategy having robust
`potential for countering rising concerns
`about prescription-opioid overdoses and
`deaths. Reasons for such disinterest are
`unclear and baffling; and further, perhaps
`as a consequence, manufacturers and dis-
`tributors also have not shown any inter-
`
`icantly reduce the number of accidental
`overdose deaths.”29
`Yet, probably nothing will be done on
`a nationwide scale to make this antidote
`more readily accessible until healthcare
`professionals, their patients, and relevant
`stakeholder organizations recognize the
`life-saving potential of intranasal nalox-
`one and demand its availability. I
`
`Disclosure
`The author has no financial interests in
`or any relationships with manufacturers,
`distributors, or marketers of naloxone
`products.
`
`Stewart B. Leavitt, MA, PhD, is the Executive
`Director of Pain Treatment Topics (pain-
`topics.org) and Opioids911-Safety (www.
`opioids911.org), and has more than 25 years
`of experience in healthcare education and
`medical communications serving several gov-
`ernment agencies and numerous public and
`private organizations. He was educated in bio-
`medical communications at the University of
`Illinois College of Medicine, Chicago, and then
`served as a commissioned officer in the U.S.
`Public Health Service at the National Insti-
`tutes of Health. He went on to earn masters
`and doctorate degrees
`specializing
`in
`health/medical research and education at
`Northwestern University, Evanston, Illinois.
`He is a member of the American Academy of
`
`Practical PAIN MANAGEMENT, October 2010
`©2010 PPM Communications, Inc. Reprinted with permission.
`
`
`
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`Pain Management, the American Pain Society,
`a founding member of the International Asso-
`ciation for Pain & Chemical Dependency, and
`a participant in the U.S. Pain Care Forum.
`
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`46
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`Practical PAIN MANAGEMENT, October 2010
`©2010 PPM Communications, Inc. Reprinted with permission.
`
`Opiant Exhibit 2180
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
`
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