`
`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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`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.
`
`REFERENCES
`1. Oxman G, Kowalski S, Drapela L, et al. Heroin overdose deaths:
`Multnomah County, Oregon, 1993-1999. MMWR Morb Mortal
`Wkly Rep. 2000;49:633-636.
`2. Solet D, Hagan H, Nakagawara J, et al. Unintential opiate
`overdose deaths: King County, Washington, 1990-1999. MMWR
`Morb Mortal Wkly Rep. 2000;49:636-640.
`3. Gerostamoulos J, Staikos V, Drummer OH. Heroin-related deaths
`in Victoria: a review of cases for 1997 and 1998. Drug Alcohol
`Depend. 2001;61:123-127.
`4. Darke S, Hall W. Heroin overdose: research and evidence-based
`intervention. J Urban Health. 2003;80:189-200.
`5. Warner-Smith M, Darke S, Lynskey M, et al. Heroin overdose:
`causes and consequences. Addiction. 2001;96:1113-1125.
`6. Hulse GK, English DR, Milne E, et al. The quantification of
`mortality resulting from the regular use of illicit opiates. Addiction.
`1999;94:221-229.
`7. Seal KH, Downing M, Kral AH, et al. Attitudes about prescribing
`take-home naloxone to injection drug users for the management
`of heroin overdose: a survey of street-recruited injectors in the
`San Francisco Bay area. J Urban Health. 2003;80:291-301.
`8. Drug Abuse Warning Network. Emergency department trends from
`DAWN: final estimates 1995-2002 [Drug Abuse Warning Network
`Web site]. Available at: http://dawninfo.samhsa.gov/old_dawn/
`pubs_94_02/edpubs/2002final. Accessed March 8, 2006.
`9. Zacny J, Bigelow G, Compton P, et al. College on Problems of
`Drug Dependence taskforce on prescription opioid non-medical
`use and abuse: position statement. Drug Alcohol Depend. 2003;
`69:215-232.
`
`Volume , . : February
`
`Annals of Emergency Medicine 175
`
`Adapt & Opiant Exhibit 2022
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
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`
`
`Naloxone for Opiate Overdose Prevention
`
`Sporer & Kral
`
`10. Warner-Smith M, Darke S, Day C. Morbidity associated with
`non-fatal heroin overdose. Addiction. 2002;97:963-967.
`11. Darke S, Sims J, McDonald S, et al. Cognitive impairment among
`methadone maintenance patients. Addiction. 2000;95:687-695.
`12. Sporer KA. Acute heroin overdose. Ann Intern Med. 1999;130:
`584-590.
`13. Way EL, Kemp JW, Young JM, et al. The pharmacologic effects of
`heroin in relationship to its rate of biotransformation. J Pharmacol
`Exp Ther. 1960;129:144-154.
`14. Oldendorf WH, Hyman S, Braun L, et al. Blood-brain barrier:
`penetration of morphine, codeine, heroin, and methadone after
`carotid injection. Science. 1972;178:984-986.
`15. White JM, Irvine RJ. Mechanisms of fatal opioid overdose.
`Addiction. 1999;94:961-972.
`16. Seaman SR, Brettle RP, Gore SM. Mortality from overdose among
`injecting drug users recently released from prison: database
`linkage study. BMJ. 1998;316:426-428.
`17. Ochoa KC, Davidson PJ, Evans JL, et al. Heroin overdose among
`young injection drug users in San Francisco. Drug Alcohol
`Depend. 2005;80:297-302.
`18. Tagliaro F, De Battisti Z, Smith FP, et al. Death from heroin
`overdose: findings from hair analysis. Lancet. 1998;351:
`1923-1925.
`19. Darke S, Hall W, Kaye S, et al. Hair morphine concentrations of
`fatal heroin overdose cases and living heroin users. Addiction.
`2002;97:977-984.
`20. Darke S, Ross J, Teesson M, et al. Health service utilization
`and benzodiazepine use among heroin users: findings from the
`Australian Treatment Outcome Study (ATOS). Addiction. 2003;98:
`1129-1135.
`21. Burns JM, Martyres RF, Clode D, et al. Overdose in young people
`using heroin: associations with mental health, prescription drug
`use and personal circumstances. Med J Aust. 2004;181
`(7 suppl):S25-S28.
`22. Martyres RF, Clode D, Burns JM. Seeking drugs or seeking help?
`escalating “doctor shopping” by young heroin users before fatal
`overdose. Med J Aust. 2004;180:211-214.
`23. Seal K, Kral A, Gee L, et al. Predictors and prevention of nonfatal
`overdose among street-recruited injection heroin users in the San
`Francisco Bay area, 1998-1999. Am J Public Health. 2001;91:
`1842-1846.
`24. O’Driscoll PT, McGough J, Hagan H, et al. Predictors of accidental
`fatal drug overdose among a cohort of injection drug users. Am J
`Public Health. 2001;91:984-987.
`25. Galea S, Ahern J, Tardiff K, et al. Racial/ethnic disparities in
`overdose mortality trends in New York City, 1990-1998. J Urban
`Health. 2003;80:201-211.
`26. Galea S, Ahern J, Vlahov D, et al. Income distribution and risk of
`fatal drug overdose in New York City neighborhoods. Drug Alcohol
`Depend. 2003;70:139-148.
`27. Latkin CA, Hua W, Tobin K. Social network correlates of self-
`reported non-fatal overdose. Drug Alcohol Depend. 2004;73:61-67.
`28. Neale J, Robertson M. Recent life problems and non-fatal
`overdose among heroin users entering treatment. Addiction.
`2005;100:168-175.
`29. Miotto K, McCann MJ, Rawson RA, et al. Overdose, suicide
`attempts and death among a cohort of naltrexone-treated opioid
`addicts. Drug Alcohol Depend. 1997;45:131-134.
`30. Digiusto E, Shakeshaft A, Ritter A, et al. Serious adverse events
`in the Australian National Evaluation of Pharmacotherapies for
`Opioid Dependence (NEPOD). Addiction. 2004;99:450-460.
`31. Oliver P, Horspool M, Keen J. Fatal opiate overdose following
`regimen changes in naltrexone treatment. Addiction. 2005;100:
`560-561.
`
`32. Sporer KA. Strategies for preventing heroin overdose. BMJ. 2003;
`326:442-444.
`33. Zador D, Sunjic S, Darke S. Heroin-related deaths in New South
`Wales, 1992: toxicological findings and circumstances. Med J
`Aust. 1996;164:204-207.
`34. Davidson PJ, McLean RL, Kral AH, et al. Fatal heroin-related
`overdose in San Francisco, 1997-2000: a case for targeted
`intervention. J Urban Health. 2003;80:261-273.
`35. Davidson PJ, Ochoa KC, Hahn JA, et al. Witnessing heroin-related
`overdoses: the experiences of young injectors in San Francisco.
`Addiction. 2002;97:1511-1516.
`36. Tobin KE, Davey MA, Latkin CA. Calling emergency medical
`services during drug overdose: an examination of individual,
`social and setting correlates. Addiction. 2005;100:397-404.
`37. Seal KH, Thawley R, Gee L, et al. Naloxone distribution and
`cardiopulmonary resuscitation training for injection drug users to
`prevent heroin overdose death: a pilot intervention study. J Urban
`Health. 2005;82:303-311.
`38. Strang J, Best D, Man L, et al. Peer-initiated overdose
`resuscitation: fellow drug users could be mobilised to implement
`resuscitation. Int J Drug Policy. 2000;11:437-445.
`39. Davoli M, Perucci CA, Forastiere F, et al. Risk factors for
`overdose mortality: a case-control study within a cohort of
`intravenous drug users. Int J Epidemiol. 1993;22:273-277.
`40. Gunne LM, Gronbladh L. The Swedish methadone maintenance
`program: a controlled study. Drug Alcohol Depend. 1981;7:
`249-256.
`41. Caplehorn JR, Dalton MS, Haldar F, et al. Methadone
`maintenance and addicts’ risk of fatal heroin overdose. Subst
`Use Misuse. 1996;31:177-196.
`42. van Ameijden EJ, Langendam MW, Coutinho RA. Dose-effect
`relationship between overdose mortality and prescribed
`methadone dosage in low-threshold maintenance programs.
`Addict Behav. 1999;24:559-563.
`43. Stewart D, Gossop M, Marsden J. Reductions in non-fatal
`overdose after drug misuse treatment: results from the National
`Treatment Outcome Research Study (NTORS). J Subst Abuse
`Treat. 2002;22:1-9.
`44. Bartu A, Freeman NC, Gawthorne GS, et al. Mortality in a cohort
`of opiate and amphetamine users in Perth, Western Australia.
`Addiction. 2004;99:53-60.
`45. Brugal MT, Domingo-Salvany A, Puig R, et al. Evaluating the
`impact of methadone maintenance programmes on mortality due
`to overdose and aids in a cohort of heroin users in Spain.
`Addiction. 2005;100:981-989.
`46. Ling W, Smith D. Buprenorphine: blending practice and research.
`J Subst Abuse Treat. 2002;23:87-92.
`47. Sporer KA. Buprenorphine: a primer for emergency physicians.
`Ann Emerg Med. 2004;43:580-584.
`48. Gueye PN, Megarbane B, Borron SW, et al. Trends in opiate and
`opioid poisonings in addicts in north-east Paris and suburbs,
`1995-99. Addiction. 2002;97:1295-1304.
`49. Degenhardt LJ, Conroy E, Gilmour S, et al. The effect of a
`reduction in heroin supply on fatal and non-fatal drug overdoses
`in New South Wales, Australia. Med J Aust. 2005;182:20-23.
`50. Degenhardt L, Day C, Dietze P, et al. Effects of a sustained
`heroin shortage in three Australian states. Addiction. 2005;100:
`908-920.
`51. Bammer G. What can a trial contribute to the debate about
`supervised injecting rooms? Aust N Z JPublic Health. 2000;24:
`214-215.
`52. Yamey G. UN condemns Australian plans for “safe injecting
`rooms.” BMJ (Clin Res Ed). 2000;320:667.
`53. Dietze P, Jolley D, Cvetkovski S. Patterns and characteristics of
`ambulance attendance at heroin overdose at a local-area level in
`
`176 Annals of Emergency Medicine
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`Naloxone for Opiate Overdose Prevention
`
`Melbourne, Australia: implications for service provision. J Urban
`Health. 2003;80:248-260.
`54. Tobin KE, Latkin CA. The relationship between depressive
`symptoms and nonfatal overdose among a sample of drug users
`in Baltimore, Maryland. J Urban Health. 2003;80:220-229.
`55. Hall WD. How can we reduce heroin “overdose” deaths? Med J
`Aust. 1996;164:197-198.
`56. Strang J, Darke S, Hall W, et al. Heroin overdose: the case for
`take-home naloxone. BMJ. 1996;312:1435-1436.
`57. Darke S, Hall W. The distribution of naloxone to heroin users.
`Addiction. 1997;92:1195-1199.
`58. Abbasi K. Deaths from heroin overdose are preventable. BMJ.
`1998;316:331.
`59. Hall W, Zador D. Challenge of reducing drug-related deaths.
`Lancet. 2000;356:7-8.
`60. Lenton SR, Hargreaves KM. Should we conduct a trial of
`distributing naloxone to heroin users for peer administration to
`prevent fatal overdose? Med J Aust. 2000;173:260-263.
`61. Burris S, Norland J, Edlin B. Legal aspects of providing naloxone
`to heroin users in the United States. Int J Drug Policy. 2001;12:
`237-248.
`62. Baca CT, Grant KJ. Take-home naloxone to reduce heroin death.
`Addiction. 2005;100:1823-1831.
`63. Dettmer K, Saunders B, Strang J. Take home naloxone and the
`prevention of deaths from opiate overdose: two pilot schemes.
`BMJ. 2001:895-896.
`64. Simini B. Naloxone supplied to Italian heroin addicts. Lancet.
`1998;352:967.
`65. Sergeev B, Karpets A, Sarang A, et al. Prevalence and
`circumstances of opiate overdose among injection drug users in
`the Russian Federation. J Urban Health. 2003;80:212-219.
`66. Coffin PO, Fuller C, Vadnai L, et al. Preliminary evidence of health
`care provider support for naloxone prescription as overdose
`fatality prevention strategy in New York City. J Urban Health.
`2003;80:288-290.
`67. Bigg D. Data on take home naloxone are unclear but not
`condemnatory. BMJ. 2002;324:678.
`
`68. Seal KH, Thawley R, Hammond JP, et al. Providing naloxone and
`training to IDUs can save lives. Paper presented at: American
`Public Health Association annual meeting, November 15-19 2003,
`San Francisco, CA.
`69. Galea S, Worthington N, Piper TM, et al. Provision of naloxone to
`injection drug users as an overdose prevention strategy: early
`evidence from a pilot study in New York City. Addict Behav. 2006;
`31:907-912.
`70. Chamberlain J, Klein B. A comprehensive review of naloxone for
`the emergency physician. Am J Emerg Med. 1994;12:650-660.
`71. Clarke SF, Dargan PI, Jones AL. Naloxone in opioid poisoning:
`walking the tightrope. Emerg Med J. 2005;22:612-616.
`72. Sporer KA, Firestone J, Isaacs SM. Out-of-hospital treatment of
`opioid overdoses in an urban setting. Acad Emerg Med. 1996;3:
`660-667.
`73. Kelly AM, Kerr D, Dietze P, et al. Randomised trial of intranasal
`versus intramuscular naloxone in prehospital treatment for
`suspected opioid overdose. Med J Aust. 2005;182:24-27.
`74. Wanger K, Brough L, Macmillan I, et al. Intravenous vs
`subcutaneous naloxone for out-of-hospital management of
`presumed opioid overdose. Acad Emerg Med. 1998;5:293-299.
`75. Mountain D. Take home naloxone for opiate addicts: big
`conclusions are drawn from little evidence. BMJ. 2001;323:934.
`76. Mirakbari SM, Innes GD, Christenson J, et al. Do co-intoxicants
`increase adverse event rates in the first 24 hours in patients
`resuscitated from acute opioid overdose? J Toxicol Clin Toxicol.
`2003;41:947-953.
`77. Osterwalder JJ. Naloxone for intoxications with intravenous heroin
`and heroin mixtures: harmless or hazardous? a prospective
`clinical study. J Toxicol Clin Toxicol. 1996;34:409-416.
`78. Buajordet I, Naess AC, Jacobsen D, et al. Adverse events after
`naloxone treatment of episodes of suspected acute opioid
`overdose. Eur J Emerg Med. 2004;11:19-23.
`79. Daly FFS, Fatovich DM, Bartu A, et al. A prospective study of
`opioid overdose. Emerg