TOXICOLOGY/CONCEPTS
`
`Prescription Naloxone: A Novel Approach to Heroin
`Overdose Prevention
`
`Karl A. Sporer, MD
`Alex H. Kral, PhD
`
`From the University of California, San Francisco, Department of Medicine, Section of Emergency
`Medicine, and the Treatment Research Center (Sporer), the Urban Health Program, RTI
`International and the University of California, San Francisco, Department of Family and Community
`Medicine (Kral), San Francisco, CA.
`
`The mortality and morbidity from heroin overdose have increased in the United States and internationally
`in the last decade. The lipid solubility allows the rapid deposition of heroin and its metabolites into the
`central nervous system and accounts for the “rush” experienced by users and for the toxicity. Risk
`factors for fatal and nonfatal heroin overdoses such as recent abstinence, decreased opiate tolerance,
`and polydrug use have been identified. Opiate substitution treatment such as methadone or
`buprenorphine is the only proven method of heroin overdose prevention. Death from a heroin overdose
`most commonly occurs 1 to 3 hours after injection at home in the company of other people. Numerous
`communities have taken advantage of this opportunity for treatment by implementing overdose
`prevention education to active heroin users, as well as prescribing naloxone for home use. Naloxone is
`a specific opiate antagonist without agonist properties or potential for abuse. It is inexpensive and
`nonscheduled and readily reverses the respiratory depression and sedation caused by heroin, as
`well as causing transient withdrawal symptoms. Program implementation considerations, legal
`ramifications, and research needs for prescription naloxone are discussed. [Ann Emerg Med. 2007;
`49:172-177.]
`
`0196-0644/$-see front matter
`Copyright © 2007 by the American College of Emergency Physicians.
`doi:10.1016/j.annemergmed.2006.05.025
`
`SCOPE OF THE HEROIN PROBLEM
`The mortality and morbidity from heroin overdoses
`increased in the United States and internationally during the
`1990s.1-3 InAustralia,theincidenceofheroinoverdosedeaths
`4,5
`increased from 1.3 per million in 1964 to 71.5 in 1997.
`Heroin-related deaths have been implicated in 9.4% of the total
`mortality in all persons aged 15 to 39 years in Australia. Heroin
`has become the leading cause of death among men aged 25 to
`54yearsinOregon. 1,6 InSanFrancisco,heroinoverdosedeaths
`7
`representthethirdleadingcauseofyearsofpotentiallifelost.
`In 2002, the Drug Abuse Warning Network recorded 93,519
`nonfatal heroin overdose–related emergency department (ED) visits
`8 The
`intheUnitedStates,representing a34%increasefrom1995.
`abuse of and overdose deaths related to prescription opioids have
`9
`alsoincreased,butthereislittlepublishedresearchinthisarea.
`The morbidity of nonfatal heroin overdoses has only recently
`been described. In Australia, 33% of patients who had
`experienced a nonfatal heroin overdose were treated in an ED:
`14% of these patients had sufficiently severe injuries, including
`trauma, burns, assault, pneumonia, or peripheral neuropathy,
`torequirehospitalization. 10 Otherstudieshavedemonstrated
`a significant decrease in cognitive function associated with
`nonfatalheroinoverdoses. 11
`
`The unique pharmacology of heroin makes it more likely
`than other opiates to cause a serious overdose. Heroin and other
`opiates produce their effects as agonists on the ␮, ␬, and ⌬
`receptors in the central nervous system. ␮
`1 Receptors are
`responsible for most of the analgesic effects, and ␮
`2 receptors
`are responsible for respiratory depression, delayed
`gastrointestinal motility, miosis, euphoria, and physical
`dependence.12 Heroinismorelipidsolublethanmorphineand
`other opiates; it therefore crosses the blood-brain barrier within
`15 to 20 seconds and achieves relatively high brain levels
`quickly.13 Sixty-eightpercentofintravenousheroinisabsorbed
`into the brain compared with less than 5% of intravenous
`morphine.14 Thislipidsolubilityallowstherapiddepositionof
`heroin and its metabolites in the central nervous system and
`accounts for the “rush” experienced by users and for the
`toxicity.
`
`RISK FACTORS FOR HEROIN OVERDOSE
`Long-term dependent intravenous heroin users who are not
`insubstanceabusetreatmentareatthegreatestriskof aheroin
`overdose.4,12 Heroinoverdosevictimsaredisproportionately
`4,12,15
`maleandcommonlyabusebenzodiazepinesoralcohol.
`A recent period of abstinence, such as during incarceration or
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`
`substance abuse treatment, may lead to decreased tolerance and
`is a time of particular risk. Injection heroin users have 7 times
`the risk of death from an overdose during the first 2 weeks after
`12,16,17 Someauthorshave
`theirreleasefromincarceration.
`demonstrated a preponderance of older opiate users among fatal
`opiate overdoses, which may be explained by systemic disease
`processes or by a differing tolerance to the effects of respiratory
`depressionandeuphoria. 5
`Two recent intriguing studies of heroin overdose fatalities
`examined the morphine content of hair, which is a measure of
`18,19 Levels
`theaverageuseofheroinuseoverthelastfewweeks.
`of morphine in the hair of fatal overdoses were much closer to
`those in a control group of abstinent former opiate users than
`to those of regular users, confirming that recent abstinence and
`low tolerance are related to death from heroin overdose.
`More recent research has described other risk factors, such as an
`20-22
`increaseduseofbenzodiazepinesortricyclicantidepressants,
`and issues with social marginalization such as polysubstance
`23-28 Ithasalsobecome
`abuse,incarceration,orhomelessness.
`clear that patients who have completed a course of naltrexone
`treatmentormethadonedetoxificationprogramsareat
`particularrisk. 29-31
`
`OPPORTUNITY FOR INTERVENTION
`Death from a heroin overdose most commonly occurs 1 to 3
`hoursafterinjection. 32 Researchhasshownthatmostofthese
`deaths occur in the company of other people and that medical
`7,33-35 Theconcernof
`helpisnotsoughtorissoughttoolate.
`police involvement has been a consistent barrier for the drug
`23,36,37 Incasesofnonfatalheroin
`usertoaccessthe911system.
`overdoses,emergencymedicalservices(EMS)areonlycontacted
`halfofthetime. 7,34,36,38 Theestimatedmortalityrateinheroin
`12
`overdosesmanagedathomeis10%.
`
`PROVEN OVERDOSE PREVENTION
`Novel approaches are needed to stem the epidemic of heroin
`4,32 Methadone
`overdose–relatedmortalityandmorbidity.
`23,39-45
`maintenancedecreasesdeathsfromheroinoverdose.
`In a meta-analysis, methadone maintenance reduced heroin
`users’ risk of death by 75%, a reduction in mortality almost
`41 French
`entirelycausedbyreductionsinaccidentaloverdose.
`studies performed with buprenorphine maintenance have
`demonstratedsimilarbenefits. 46-48 Arecentreductioninthe
`heroin supply in Australia was associated with a reduction in
`fatalandnonfataloverdoses. 49,50
`Clearly, increasing options for opiate substitution treatment
`with methadone and buprenorphine should be the cornerstone of
`any community’s overdose prevention response. Unfortunately,
`there will likely always be some heroin users who are not ready
`for abstinence programs and will need other interventions.
`Other strategies have emphasized reducing risk factors,
`improving the response of bystanders, medically supervising
`injecting rooms, and changing police policy concerning the
`4,32,34,51-54 Noneof
`arrestofoverdosevictimsandwitnesses.
`
`these interventions have been methodically evaluated for their
`effectiveness in decreasing fatal and nonfatal heroin overdoses.
`
`PRESCRIPTION NALOXONE
`Starting in Europe and progressing to Australia and the
`United States, communities have begun to provide prescription
`32,55-62 In1995,naloxone
`naloxoneforinjectiondrugusers.
`was distributed to heroin users in Germany and England and is
`63,64 Surveysofheroin
`availableoverthecounterinTurin,Italy.
`users demonstrate that most would favor the use of prescription
`naloxone.7,38,65 Athirdofhealthpractitionersinonesurvey
`were interested in participating in a prescription naloxone
`program.66
`In the United States, naloxone was first distributed in 1999
`through underground programs first in Chicago and then in
`San Francisco. There are an unknown number of underground
`programs, organized similarly to underground syringe exchange
`programs, in which activists and drug users operate informal
`networks to provide naloxone and education to heroin injectors.
`In March 2000, the California Medical Association and the San
`Francisco Department of Public Health recommended the use
`of prescription naloxone to injection drug users as part of a
`comprehensive overdose management program. In 2001, the
`San Francisco Department of Public Health sponsored a pilot
`research study that included opiate education and naloxone
`prescription.37
`In January 2001, New Mexico became the first state to
`encourage physicians to prescribe take-home naloxone to
`heroin-injecting patients. In addition, New Mexico’s governor,
`Gary Johnson, led the implementation of legislation that
`releases individuals and medical professionals involved in
`administering and prescribing naloxone from medical liability.
`Connecticut and New York followed with laws that established
`standards for heroin overdose prevention programs and
`provided immunity from civil liability to nonhealth
`professionals by defining the use of naloxone as a first aid or
`emergency treatment.
`There are now several prescription naloxone programs
`operating in the United States, including Chicago, San
`Francisco, northern New Mexico, Baltimore, New York, and
`Mendocino County, with thousands of injection drug users
`67-69
`trainedandprescribednaloxoneduringthelast 7years.
`As of February 2006, prescription naloxone programs have
`reported more than 900 episodes of peer reversal of a heroin
`overdose(Table).
`
`LEGALITIES OF A NALOXONE
`PRESCRIPTION PROGRAM
`Naloxone, a specific opiate antagonist available by
`prescription, is inexpensive and nonscheduled, has no abuse
`potential, and is effective at reversing the adverse effects of
`heroin.70,71 Itiscommonpracticeforparamedicstouse
`naloxone in most emergency medical systems. Prescription
`61 Thereis
`naloxoneisconsideredanoff-labeluseofthedrug.
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`Sporer & Kral
`
`Table. Large and established naloxone prescription programs
`in the United States (February 2006).
`
`City
`
`Chicago
`New Mexico
`San Francisco
`Baltimore
`New York City
`
`Year of
`Establishment
`
`Number of
`Trainings/
`Prescriptions
`
`1999
`2001
`2003
`2004
`2005
`
`4,600
`1,312
`650
`951
`938
`
`Number of
`Reported
`Overdose
`Reversals
`
`416
`222
`141
`131
`73
`
`Chicago: D. Bigg, written communication, March 2006; New Mexico: P. Fiuty,
`written communication, March 2006; San Francisco: E. Huriaux, written commu-
`nication, March 2006; Baltimore: M. Rucker, written communication, March
`2006; New York: S. Stancliff, written communication, March 2006.
`
`considerable precedent for allowing physicians to provide
`patients or their families with other injectable preparations.
`Home prescriptions such as rectal valium and glucagon are
`dispensed with the expectation that a family member will
`administer the medication.
`All prescriptions must be written by an appropriate health
`care physician, with a physician-patient relationship,
`appropriate recordkeeping, and proper labeling of the
`medication.61 Allofthecurrentnaloxoneprogramsthatare
`sanctioned by their local department of public health in the
`United States (San Francisco, New Mexico, Baltimore, and
`New York) dispense naloxone in properly labeled kits contained
`37
`inneedle-proofhardenedplasticcontainersorsunglasscases.
`Clear procedures for refilling the medication should be
`developed, and local pharmacies should be asked to stock
`naloxone and honor these prescriptions.
`
`IMPLEMENTATION OF A NALOXONE
`PRESCRIPTION PROGRAM
`Most naloxone prescription programs include an initial
`educational component. Several curriculums have been developed
`andareavailableonline(http://www.anypositivechange.organd
`http://www.harmreduction.org).OurlocalexperienceinSan
`Francisco indicates that shorter (15 to 20 minutes) sessions at
`syringe exchange program sites are superior to longer classroom
`venues. Important points for consideration in an educational
`componentareincludedintheFigure.
`The intramuscular route of administration of naloxone is
`the most easily taught, and this route has been shown to be
`effective.72,73 Thesubcutaneousrouteiscomparabletothe
`intravenousroutebutposessomeproblemsineducation.
`The intranasal route of administration was compared to
`the intramuscular route in one open-label out-of-hospital
`randomized trial. The intranasal group took slightly longer
`to achieve the end point of an adequate respiratory rate and
`had a higher need for rescue intramuscular naloxone, but the
`complication rate (agitation, vomiting, signs of withdrawal) was
`73 Theintranasalroutehasdrawbacks
`muchlowerinthisgroup.
`
`74
`
`1. Sites such as syringe exchange programs, drug treatment
`centers, and jails are logical institutions within which
`these programs can be placed.
`
`2. Educational points for prescription naloxone education
`A. The differentiation between the normal deep lethargy
`of opiate use (a deep nod) and an opiate overdose.
`The lack of a response to a sternal rub or other
`vigorous stimulation, blue lips, and absent breathing
`are all signs of a significant overdose requiring further
`treatment.
`B. Rescue breathing should be taught and emphasized.
`The recovery position should be stressed if rescue
`breathing is not used. One study has demonstrated a
`modest decrease in hospitalization rates of nonfatal
`opiate overdose patients when bystander
`cardiopulmonary resuscitation was performed.80
`C. The use of other stimulation such as ice, milk, and
`amphetamines should be discouraged.
`D. The importance of contacting EMS and the need for
`hospital evaluation after an overdose must be stressed
`because of the complications that can arise.
`E. The short half-life of naloxone in comparison to
`heroin and other opiates should be highlighted. The
`importance of not using more heroin or other opiates
`within a few hours of revival should be stressed.
`F. The proper dosing and administration of
`intramuscular naloxone should be taught.
`
`3. The prescription should be provided by a licensed health
`care provider.
`
`4. Medical records of the patient encounter and prescription
`need to be maintained.
`
`5. Any prescribed medication must be properly labeled with
`the patient’s name and instructions for use.
`
`6. A system for medication refills should be established.
`
`7. Primary care providers can be instructed in the use of
`prescription naloxone for patients who are still actively
`using heroin. Local pharmacies can be involved in
`honoring these prescriptions.
`
`Figure. Implementation of a prescription naloxone program.
`
`but could be a reasonable compromise in patients averse to
`using needles.
`
`POTENTIAL ADVERSE OUTCOMES RELATED
`TO PRESCRIPTION NALOXONE
`There are potential adverse outcomes related to prescription
`naloxone that must be evaluated. There has been concern
`that heroin users will increase their use because they have a
`
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`
`75 Theonlypublished
`“parachute”incaseofoverdose.
`prospective evaluation of this concept demonstrated no increase
`in the frequency of reported heroin injections or rate of personal
`overdoses.37 Itcouldbearguedthatdistributingnaloxonemay
`be construed as implicitly condoning the use of heroin and that
`the safety conferred by naloxone in the home may encourage
`peopletostartusingheroin.However,therehasbeenno
`documentation of this phenomenon.
`There may be medical and legal implications of naloxone
`being used by people for whom it was not prescribed. In the
`Sealetal 37 study,only15%ofthosetreatedwerethepatient
`for whom naloxone was prescribed. The half-life of naloxone is
`shorter than that of heroin; sedation and respiratory depression
`mayrecurin15%ofsuspectedheroinoverdosepatientstreated
`withnaloxone. 76 Theremaybereluctanceonthepartofactive
`heroin users to administer naloxone to acquaintances because of
`the universally detested withdrawal reaction that accompanies
`its use. Naloxone treatment of opiate overdose is associated with
`common complications such as transient moderate to severe
`withdrawal (17% to 33%) and is associated with a small but
`consistent rate of complications such as seizures, pulmonary
`edema,andarrhythmias. 72,76-78 Useofunsterileneedlesto
`administer naloxone may transmit HIV, hepatitis C, or other
`blood-borne infections.
`Prescribing naloxone to a patient who has completed an
`abstinence program may send mixed signals, though it could be
`presented as a benevolent service to their peers. Finally, there are
`concerns that the 911 system will not be used after successful
`resuscitation, which is disconcerting because previous case series
`of nonfatal opiate overdoses have demonstrated a 5% to 12%
`72,79 Twostudiesof
`prevalenceofacutehospitaladmission.
`prescription naloxone programs demonstrated that EMS was
`called in only 10% to 31% of cases in which an opiate overdose
`37,63 Thisincidencewas
`patientwassuccessfullyresuscitated.
`lower than the 30% to 50% previously reported among
`witnesses of an opiate overdose that did not involve the use of
`prescription naloxone.
`
`RESEARCH NEEDS
`Current prescription naloxone programs have had little
`formal evaluation, and published reports are limited by small
`sample size, low response rates, significant selection bias, and no
`75 Structured,scientifically
`formalassessmentofcomplications.
`sound evaluations of prescription naloxone programs are needed
`as the number of programs grows. First, we need to evaluate
`whether these programs are achieving the intended goal of
`preventing heroin overdose fatalities. Such evaluation efforts
`need to include assessment of unintended negative consequences
`of the programs. If they are shown to be successful without
`undue negative consequences, we will need a second level of
`evaluation that involves assessing what are the best practices of
`such programs. These evaluations would provide important
`information to guide the implementation and design of existing
`and future prescription naloxone programs.
`
`The international increase in heroin overdose has led public
`health authorities and investigators to seek innovative methods
`of decreasing its morbidity and mortality. Communities should
`implement proven heroin overdose tactics such as increasing
`treatment options for methadone or buprenorphine
`maintenance as their cornerstone strategy. When properly
`implemented, prescription naloxone can be a legal and safe
`program. As a complement to opiate substitution treatment,
`prescription naloxone programs should be considered a
`standard part of care and should be implemented in
`vulnerable populations. Their effects on mortality, on
`complication rates, and on patterns of consumption of
`opiates should be carefully studied.
`
`Supervising editor: Richard D. Dart, MD, PhD
`
`Funding and support: The authors report this study did not
`receive any outside funding or support but discloses that KAS
`receives compensation for AED medical direction from
`American Health and Safety Training, Inc.
`
`Publication dates: Received for publication February 7, 2006.
`Revisions received March 30, 2006, and April 25, 2006.
`Accepted for publication May 23, 2006. Available online July
`12, 2006.
`
`Reprints not available from the authors.
`
`Address for correspondence: Karl Sporer, MD, Emergency
`Services, Room 1E21, San Francisco General Hospital, 1001
`Potrero Ave, San Francisco, CA 94110; 415-206-5749, fax
`415-206-5818; E-mail ksporer@sfghed.ucsf.edu.
`
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`176 Annals of Emergency Medicine
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`Volume , .  : February 
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`Opiant Exhibit 2022
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 5
`
`

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`Sporer & Kral
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