Blackwell Science, LtdOxford, UKADDAddiction0965-2140© 2005 Society for the Study of Addiction
`
`100
`Review Article
`Take-home naloxone to reduce heroin death
`Catherine T. Baca & Kenneth J. Grant
`
`REVIEW
`
`Take-home naloxone to reduce heroin death
`
`Catherine T. Baca & Kenneth J. Grant
`Center on Alcoholism, Substance Abuse, and Addictions (CASAA) and Family and Community Medicine, University of New Mexico, Albuquerque, New
`Mexico
`
`Correspondence to:
`Catherine T. Baca
`160 Washington SE # 62
`Albuquerque
`NM 87108
`USA
`E-mail: baca5@unm.edu
`
`Submitted 7 September 2004;
`initial review completed 1 February 2005;
`final version accepted 31 May 2005
`
`REVIEW
`
`ABSTRACT
`
`Background This paper reviews the relevant literature related to the distribu-
`tion of take-home naloxone.
`Methods A Medline search was conducted on articles published between Jan-
`uary 1990 and June 2004 to identify scientific literature relevant to this sub-
`ject. Those publications were reviewed, and from them other literature was
`identified and reviewed.
`Results The prevalence, pathophysiology and circumstances of heroin over-
`dose, and also bystander response are included in this review. Naloxone peer dis-
`tribution has been instituted to varying degrees in the United States, Italy,
`Spain, Germany and the United Kingdom.
`Conclusion At this point the evidence supporting naloxone distribution is pri-
`marily anecdotal, although promising. Although the distribution of naloxone
`holds promise for further reducing heroin overdose mortality, problems remain.
`Naloxone alone may be insufficient in some cases to revive the victim, and car-
`diopulmonary resuscitation (CPR), especially rescue breathing, may also be
`needed. A second dose of naloxone might be necessary. Complications following
`resuscitation from overdose may infrequently need in-hospital care. Mortality
`from injecting without anyone else present will be unaffected by take-home
`naloxone. Take-home naloxone should be studied in a rigorous scientific
`manner.
`
`KEYWORDS: Heroin, heroin-related death, naloxone, overdose,
`resuscitation.
`
`INTRODUCTION
`
`PREVALENCE OF HEROIN OVERDOSE
`
`The distribution of the mu-receptor antagonist naloxone
`(brand name Narcan) to be given to victims of heroin
`overdose is a new and innovative approach to reducing
`heroin mortality. Because naloxone reverses respiratory
`depression, which is by far the most common cause of
`death after heroin overdose, its provision during heroin
`overdose can be life-saving.
`This review summarizes the pertinent medical litera-
`ture related to the distribution of take-home naloxone
`which is currently taking place in many countries
`around the world. The focus will be on evidence from the
`addiction medicine and emergency medicine literature
`relevant to the distribution of take-home naloxone.
`
`Overdose is a common occurrence amongst heroin users.
`In San Francisco, USA, 48% of young (median 22 years)
`injection drug user interviewees had already had at least
`one overdose (Ochoa et al. 2001). In London, UK, 38% of
`interviewees had overdosed at least once. In Russia, 59%
`of 763 users had overdosed (Sergeev et al. 2003). In Syd-
`ney, Australia, 68% had overdosed a median of three
`times (Darke, Ross & Hall 1996a).
`Heroin overdose frequently results in death. In Albu-
`querque, USA, Goldstein & Herrera (1995) found a 34%
`mortality rate due to overdose in heroin addicts over a
`22-year period. Hickman et al. (2003) found that more
`than half of deaths among a cohort of 881 heroin users in
`
`© 2005 Society for the Study of Addiction
`
`doi:10.1111/j.1360-0443.2005.01259.x
`
`Addiction, 100, 1823–1831
`
`Opiant Exhibit 2004
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00687
`Page 1
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`1824
`
`Catherine T. Baca & Kenneth J. Grant
`
`London, UK, were due to opioid overdose. In Catalonia,
`Spain, a 10-year mortality rate of 30% was found, of
`which 30% were due to overdose (Sanchez-Carbonell &
`
`Seus 2000). In Rome, Italy, Davoli et al
`. (1993) found that
`32% of deaths in intravenous drug-using males and 41%
`of deaths in intravenous drug-using females were due to
`overdose. Death rates have shown a steady increase in
`Italy from 1984 to 2000 (Preti, Miotto & De Coppi 2002),
`with a 13 times greater mortality rate from 1985 to
`1998 in heroin injectors than in the general population
`(Quaglio
`. 2001).
`et al
`The literature is contradictory in considering the rela-
`tionship of the severity of an overdose to the dose of her-
`oin. A correlation has been noted (Bertini
`. 1992).
`et al
`Huber
`
`et al. (1974) found a 10-fold (3.3–33.3 mg) vari-
`ation in the amount of heroin per packet in a study in
`Atlanta, USA. Average street heroin purity and the range
`of heroin purity were found to be correlated with death
`rates (Darke
`
`et al. 1999). Other studies have not noted
`this finding (Kintz
`
`et al. 1989; Zador, Sunjic & Darke
`1996). Heroin users do have difficulty in adjusting their
`dose. However, there are other very important factors,
`especially the tolerance of the individual to heroin and
`the concomitant use of other drugs.
`
`PATHOPHYSIOLOGY OF HEROIN
`OVERDOSE
`
`Although most deaths occur in individuals with a history
`of heroin addiction, most of these individuals commonly
`have reduced tolerance at the time of their deaths
`(Greene, Luke & Dupont 1973; Huber, Stivers & Howard
`1974). Hair analysis in Verona, Italy, found that heroin
`overdose fatalities occurred mainly after a period of absti-
`
`et al. 1998). The period immediately fol-
`nence (Tagliaro
`lowing release from detention is especially dangerous
`(Darke
`. 1996a). Twenty-three per cent of overdose
`et al
`deaths in Glasgow, Scotland occurred within 2 weeks of
`. 2002). It is also hypothesized that tol-
`release (Jones
`et al
`erance to respiratory depression may develop slower than
`tolerance to the euphoric effect, thus increasing the risk
`of overdose (White & Irvine 1999). Warner-Smith
`.
`et al
`(2001) have hypothesized that pre-existing pulmonary
`and hepatic dysfunction may lead to a higher risk of over-
`dose mortality.
`Almost all (99%) heroin overdose death is after intra-
`venous use (Sporer 1999). Death from heroin overdose is
`caused primarily by respiratory depression leading to car-
`diac arrest. Death may occur very rapidly, as reported in
`about 17% of lethal cases (Greene
`
`et al. 1973). The dis-
`covery of a cadaver with the syringe still in the arm is not
`rare (Cami & Domingo-Salvany 1995). More commonly,
`death occurs gradually over an hour or more (Greene
`
`. 1973; Sporer 1999). Others present may be less
`et al
`likely to recognize the danger of a less dramatic, slowly
`developing narcosis (McGregor
`
`et al. 1998).
`Infrequent causes of delayed death from heroin over-
`dose are non-cardiogenic pulmonary edema and aspira-
`
`
`tion pneumonia. Bertini et al. (1992) found a rate of non-
`cardiogenic pulmonary edema of 0.8% and the rate was
`0.9% in the study by Sporer, Firestone & Isaacs (1996).
`The non-cardiogenic pulmonary edema is due probably
`to pulmonary vasoconstriction from hypoxemia. It does
`not occur from opioids not taken in over-dosage. It is usu-
`ally evident within a short period after the overdose. A
`study in Switzerland found only one case (in 160) of
`delayed pulmonary edema after successful resuscitation
`with naloxone (Osterwalder 1995). Opioids are known to
`cause nausea and vomiting, even in therapeutic doses.
`Aspiration of gastric contents after heroin overdose can
`lead to serious aspiration pneumonia. This can be precip-
`itated by a side effect of heroin itself, the effects of con-
`comitant drug use, especially alcohol (Darke & Hall
`2003) or from the rapid onset of withdrawal symptoms
`after the injection of naloxone. Aspiration pneumonia
`was found in only one of 124 heroin overdoses treated in
`
`et al.
`an emergency department in El Paso, USA (Smith
`1992).
`There were no survivors among 16 patients in asys-
`tolic arrest (without advance sign of death) in the study
`by Sporer
`
`et al. (1996). However, prompt provision of
`naloxone and advanced cardiac life support (ACLS) by
`.
`ambulance personnel may still be life-saving. Bertini
`et al
`(1992) reported successful resuscitation of five of seven
`patients in asystole, with only one of these later dying
`from post-anoxic encephalopathy.
`
`CIRCUMSTANCES OF HEROIN
`OVERDOSE
`
`The setting of the heroin overdose strongly influences the
`overdose outcome. Most overdoses occur with other peo-
`. 1998; Powis
`
`et al. 1999;
`ple present (McGregor
`et al
`Sporer 1999). The other person or people present are
`most commonly other intravenous heroin users (Strang
`
`et al. 1999).
`Although most drug users inject with others, there
`are some areas that report high rates of injecting alone. If
`the heroin user is alone, a fatal outcome becomes more
`likely. Davidson
`. (2003) found that in 333 heroin-
`et al
`related deaths in San Francisco, USA, 68% were report-
`edly alone. Take-home naloxone will have little or no
`effect on reducing unwitnessed overdose mortality, as the
`overdose victim would not be in a condition to administer
`it to himself or herself. No cases of self-administration of
`naloxone were found in this review. This is a major limi-
`
`© 2005 Society for the Study of Addiction
`
`Addiction,
`
`100
`, 1823–1831
`
`Opiant Exhibit 2004
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00687
`Page 2
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`tation on the potential of take-home naloxone to reduce
`heroin mortality. It emphasizes the importance of educat-
`ing heroin users on the dangers of using alone.
`
`BYSTANDER RESPONSE
`
`Heroin overdose death can nearly always be prevented by
`the prompt provision of professional emergency services.
`Ambulance personnel in developed countries can admin-
`ister naloxone and provide respiratory support, if neces-
`sary, until the naloxone takes effect. Ambulance response
`times in developed countries in urban areas are usually
`just a few minutes.
`Unfortunately, in many overdoses, bystanders fail to
`call for ambulance services. This failure is due primarily
`to fear of the police. In countries such as the United
`States, the same call to 911 for emergency medical assis-
`tance also notifies the police of the situation. Because the
`use of heroin is illegal and the victim or others present
`may be on parole or have outstanding warrants, this fear
`is rational and understandable. Police view the site of a
`heroin overdose as a crime scene and their presence may
`delay or interfere with emergency care for the victim.
`Davidson
`. (2002) reported that in San Francisco,
`et al
`USA, calling emergency services is often an option of last
`resort, and fear of the police frequently caused the failure
`of bystanders to call emergency services. Three-quarters
`of heroin user respondents in Multnomah County Ore-
`
`et al. 2000).
`gon, USA, reported fear of police (Oxman
`This problem has also been reported in Russia (Sergeev
`
`. 2003), Italy (Preti et al
`. 2002) and Australia (Darke,
`et al
`Ross & Hall 1996b; McGregor
`
`et al. 1998; Hargreaves
`
`et al. 2002). Another potential problem with the police,
`at least in the USA where naloxone requires a prescrip-
`tion, is that people found with naloxone can be cited and
`have the naloxone confiscated (Giuliano 2001). This
`problem would be solved if naloxone were made available
`over the counter. This fear of police is predictably coun-
`try- or region-specific. For example, reluctance to call for
`emergency services due to fear of police was not found in
`Dublin, Ireland (Cullen, Bury & Langton 2000). In West-
`ern Australia, a protocol was implemented limiting police
`
`et al. 2002). An
`presence at overdose events (Hargreaves
`attempt to address this police problem has been training
`in how to report the overdose in such a way as to reduce
`the possibility of a police response. Reporting to the emer-
`gency operator that ‘my friend is unconscious and not
`breathing’ (Anonymous 2000) without saying the cause
`may reduce the possibility of problems from the police.
`Survey results in San Francisco, USA found that the avail-
`ability of naloxone would not change the rate of calling
`. 2003). It is understood
`emergency services (Seal
`et al
`that the fear of police will continue to prevent summon-
`
`Take-home naloxone to reduce heroin death
`
`1825
`
`ing help in overdose emergencies, and is a major reason
`for providing take-home naloxone.
`Untrained people present at overdoses try a variety of
`methods to attempt to aid the overdose victim. These
`include mouth-to-mouth resuscitation, heart massage,
`inflicting pain, walking the person around or injecting
`
`salt or milk or cocaine (Darke et al
`. 1996b). Some of these
`are helpful; many are of uncertain benefit, while some are
`almost certainly harmful. Painful or unpleasant stimuli
`may possibly stimulate enough respiration to prevent
`death. Injections of milk or salt water are of no benefit
`and are potentially harmful. Injection of cocaine could be
`lethal. In urban areas, overdose victims can be trans-
`ported by private vehicle to emergency care. Other vic-
`tims are taken to a public area to be discovered by
`bystanders or where emergency services can be sum-
`moned with less risk of police involvement.
`The person most likely to be present at an overdose is
`another heroin user. A large proportion of heroin users
`have witnessed overdoses (Darke
`
`et al. 1996b). Most edu-
`cational interventions and naloxone distribution pro-
`grams are directed to this population.
`
`NALOXONE: PHARMACOLOGICAL
`CONSIDERATIONS
`
`Naloxone is a pure opioid antagonist (Physicians’ Desk
`Reference 2001). Heroin is an opioid. The administration
`of naloxone is a simple procedure. It is important to make
`resuscitation as simple as possible, as others present at an
`overdose may themselves be intoxicated. Naloxone is
`commonly given by the intravenous (i.v.), intramuscular
`(i.m.) or subcutaneous (s.c.) routes. It can also be given
`through an endotracheal tube (ET). It is given uncom-
`monly by sublingual or intralingual injection. It is not
`effective orally (p.o.). The onset of action of naloxone
`given i.v. is usually within 2 minutes. It is slightly slower
`if given s.c. or i.m. (Du Pont Pharma 2001). The effects
`last 45–90 minutes after i.v. injection (Sporer 1999). A
`study comparing the i.v. to s.c. routes found a slower
`average response time to a respiratory rate of 10 per
`minute after s.c. (5.5 minutes) than i.v. (3.8 minutes)
`
`et al. 1998). However, the time required to
`(Wanger
`obtain i.v. access more than made up for the difference,
`making s.c. a faster route to therapeutic response. The i.v.
`route for administration of take-home naloxone is not
`recommended for bystanders because of the delay associ-
`ated with establishing i.v. access; i.m. administration is
`technically easier than s.c. and much easier than i.v. The
`i.m. route was preferred by most of the take-home nalox-
`one distribution programs found in this literature review.
`Response to naloxone was 94% if given i.m. and a statis-
`
`et al.
`tically insignificant lower 90% if given i.v. (Sporer
`
`© 2005 Society for the Study of Addiction
`
`Addiction,
`
`100
`, 1823–1831
`
`Opiant Exhibit 2004
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00687
`Page 3
`
`

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`1826
`
`Catherine T. Baca & Kenneth J. Grant
`
`1996). The i.m. route is believed to have at least as fast
`absorption as s.c. It has a longer duration of action than
`the i.v. route (Du Pont Pharma 2001) and for this reason,
`patients who are being discharged after short periods of
`observation in the field (Vilke
`
`et al. 2003) are given an
`i.m. injection of naloxone prior to discharge, whether or
`not it be against medical advice. The longer duration of
`action is a definite advantage of the i.m. route.
`The intranasal (i.n.) route by aerosol is gaining
`increasing interest. Because absorption is through the
`nasal mucosa, it requires exposure to the nasal mucosa
`and circulation. In one study (Barton
`
`et al. 2002) intra-
`nasal administration was affective even in patients ‘found
`down’ in overdose, but it was not effective in one patient
`who was noted to have a significant amount of epistaxis
`(bleeding from the nose). Naloxone may not be effective
`in patients with excessive mucus or other problems
`affecting access to mucus membranes (Barton
`.
`et al
`2002). The intranasal route holds promise, because it
`eliminates the risks of needle exposures. Barton
`
`et al.
`(2002) found an average response time of 3.4 minutes
`after i.n. administration, with response in 10 of 11 over-
`dose patients. Not surprisingly, the presence of epistaxis
`resulted in the lack of response. Naloxone nasal spray had
`been planned to be distributed in Britain (Abbasi 1998);
`however, no reports were found of naloxone nasal spray
`distribution in Britain having actually occurred. Intrana-
`sal administration of naloxone, in addition to i.m., is
`included in the take-home naloxone program in Balti-
`more, USA (Garza 2003).
`Naloxone is available in the USA in 1 ml and 10 ml
`vials in strengths of 0.4 mg and 1 mg/ml. Because it
`comes in different strengths and different-sized contain-
`ers, there is a concern about possible confusion (Giuliano
`2001). It has a shelf-life of 18 months to 2 years (Lenton
`& Hargreaves 2000). It is uncertain how much potency is
`lost beyond this period.
`Although it adds to the cost, in order to simplify
`administration prefilled syringes with naloxone have
`been proposed (Darke 1999), and are currently being dis-
`tributed in New Mexico, USA. Analogously, epinephrine
`prescribed for take-home emergency use is also dispensed
`in prefilled syringes.
`The dosage of take-home naloxone to be administered
`to a heroin overdose victim has been a somewhat difficult
`issue. A large dose will resuscitate the victim more reli-
`ably, but at the expense of causing more intensely
`unpleasant withdrawal symptoms, leading possibly to
`dangerous immediate use of more heroin. A less than
`effective dose will prolong the hypopnea leading to fur-
`ther injury and possible death. Titration of the dose is
`most often recommended in a medical setting, but may be
`asking too much of lay people who will be under stress
`and possibly intoxicated themselves.
`
`Although recipients of take-home naloxone are gen-
`erally advised to summon emergency services in addition
`to administering naloxone, it is recognized that this will
`not always occur. One criticism of take-home naloxone is
`that a patient may be resuscitated successfully with
`naloxone but have a delayed recurrence of respiratory
`depression. Recipients of take-home naloxone are
`instructed to give additional doses if needed. This is
`because of the shorter half-life of naloxone than of heroin,
`resulting in the recurrence of respiratory depression.
`Watson
`. (1998) found recurrence of opioid symp-
`et al
`toms in two of 10 patients after an initial response to
`naloxone in a hospital emergency department setting.
`However, this may be an over-rated concern for heroin
`(but not for longer-acting opioid agonists). In New South
`Wales, where overdose victims are treated
`
`in situ, only
`0.004% of overdose fatalities occurred in patients who
`had received any naloxone (Darke, Mattick & Degenhardt
`2003). Clarke & Dargan (2002) reviewed the literature
`and concluded that a well patient can be discharged after
`1 hour. Vilke
`
`et al. (2003) found no subsequent related
`deaths in patients treated in the field by ambulance per-
`sonnel with naloxone who refused transport to a hospital.
`Although naloxone will reliably reverse the lethal
`effects of heroin, there can be a lethal delay between the
`administration of naloxone and when it takes effect.
`Because of this, naloxone distribution programs often
`include training in adult cardiopulmonary resuscitation
`(CPR) along with the provision of naloxone and injection
`equipment (Abbasi 1998). In a partially conscious
`patient, the placement into the recovery position (lying
`on the left side with the right hip and right knee flexed) to
`help maintain the airway and prevent aspiration, may be
`all that is required initially. A patient who has apnea or
`hypopnea will need respiratory support which can be
`provided by
`rescue breathing
`(mouth-to-mouth).
`Patients in cardiac arrest will need closed heart massage.
`Successful training of ‘drug misusers’ in CPR has been
`demonstrated (Dettmer, Saunders & Strang 2001; Gra-
`ham
`. 2001). Dietze, Cantwell & Burgess (2002)
`et al
`reported a significantly lower rate of hospitalization in
`heroin overdoses who had received bystander CPR.
`Naloxone is an extremely safe drug. Its profile is
`remarkably safe (Goldfrank
`. 1998). The only con-
`et al
`traindication to its use is hypersensitivity (American
`Heart Association 1994). Naloxone has ‘essentially no
`pharmacologic activity’ in the absence of opioids or opi-
`oid agonists (Physicians’ Desk Reference 2001). Multiple
`doses of 90 mg daily, nine times the maximum recom-
`mended dose for opioid intoxication, produced no behav-
`ioral or physiological changes (Du Pont Pharma 2001). It
`has essentially no agonist properties or abuse potential.
`One mg of naloxone will completely antagonize 25 mg of
`i.v. heroin (Rosen & Barken 1998). Because it causes an
`
`© 2005 Society for the Study of Addiction
`
`Addiction,
`
`100
`, 1823–1831
`
`Opiant Exhibit 2004
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00687
`Page 4
`
`

`

`immediate withdrawal syndrome in individuals who are
`physically dependent on opioids, its use can rarely be fol-
`lowed by brief withdrawal seizures. Administration of
`naloxone to 813 patients by paramedics in Pittsburgh,
`USA, was followed by one patient having a seizure (Yealy
`. 1990). Abrupt opioid withdrawal precipitated by
`et al
`naloxone can result in an angry or agitated patient.
`Sporer
`
`et al. (1996) found that 7% required restraints.
`Resuscitated victims may not believe that the unpleasant
`withdrawal symptoms are a consequence of saving his or
`her life. Because of these concerns, it is recommended
`that naloxone be given in the lowest effective dose. How-
`ever, unpleasant withdrawal symptoms may be unavoid-
`able in the treatment of severe hypopnea (Haddad,
`Shannon & Winchester 1998).
`Opponents of the distribution of take-home naloxone
`(Ashworth & Kidd 2001; Mountain 2001) quote the
`study by Osterwalder (1996), which reported severe
`adverse reactions after naloxone administration in six of
`453 patients. In the Osterwalder study, an episode of
`asystole occurred in a patient in severe respiratory acido-
`sis. An episode of pulmonary edema could be explained
`by the toxicity of the heroin. Three convulsions could be
`explained by cerebral hypoxia or the withdrawal syn-
`drome. An episode of violent behavior can be explained
`by the intensely unpleasant experience of sudden opioid
`withdrawal. Thus, none of the adverse effects reported by
`Osterwalder can be attributed reliably to naloxone toxic-
`ity. Hoffman & Goldfrank (1995) concluded after a review
`of the literature that the complications attributed to
`naloxone are erroneous or, at most, extremely rare.
`Concern over the cost of naloxone has been raised
`(Darke & Hall 1997). Because a death rate of only about
`.
`3% per overdose was found in Australia (Darke
`et al
`2003), it is likely that many uses of naloxone will not
`have been necessary to prevent mortality. However,
`naloxone also has the benefit of preventing hypoxic brain
`injury by reducing respiratory depression. Even if 30 or
`even 300 doses must be distributed to prevent one death,
`the cost per life saved would still be much less than other
`life-saving interventions undertaken commonly in devel-
`oped countries.
`
`NALOXONE USE IN MIXED OVERDOSES
`
`Many studies have found that often one or more other
`. 1997).
`drugs were present in fatal overdoses (Darke
`et al
`Central nervous depressants, especially ethanol and ben-
`zodiazepines, have additive effects to the central nervous
`depressant effects of heroin. Beswick, Best & Burn (2002)
`found that this combination was present in eight of 11
`
`et al. (1997) found
`witnessed overdose fatalities. Darke
`that ethanol was present in about half of fatal heroin
`
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`Take-home naloxone to reduce heroin death
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`1827
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`overdoses in Sydney, Australia with a significant inverse
`correlation between blood alcohol and blood morphine
`concentrations. A study of heroin deaths in Maryland,
`USA, found that concomitant use of ethanol was a clear
`risk factor (Levine, Green & Smialek 1994). There is no
`contraindication to the use of naloxone in the presence of
`ethanol and/or benzodiazepines. Lethal overdoses of eth-
`anol alone or benzodiazepines alone are relatively rare.
`Naloxone would be expected to prevent death from opioid
`respiratory insufficiency, even in the presence of other
`central nervous system (CNS) depressants, although it
`would not be effective for respiratory distress due to
`severe alcohol poisoning alone.
`The concomitant use of cocaine is more problematic.
`Coffin
`
`et al. (2003) found in 7451 accidental overdose
`deaths in New York City, USA that this combination of
`opioids and cocaine was the most frequently observed
`
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`drug combination. O’Driscoll et al. (2001) also found that
`this combination was particularly lethal in Seattle, USA.
`Because of cocaine’s stimulant properties, its administra-
`tion is sometimes used by bystanders in an ill-advised
`attempt to treat an overdose victim (Beswick
`. 2002).
`et al
`Concomitant cocaine use could also increase impulsive
`use of opioids or other respiratory depressants.
`
`NALOXONE DISTRIBUTION
`
`Narcan distribution, along with training in overdose
`management, has resulted in treating 60 overdoses in
`Barcelona, Spain (Trujols 2001). In 2001 New Mexico
`began providing naloxone to drug users in efforts to
`reduce overdose death (Shah, Lathrop & Landen 2003).
`A naloxone distribution program in Chicago, USA,
`involves two physician volunteers who provide naloxone
`prescriptions (Bigg 2002). Chicago Recovery Alliance
`(2004) has reported that as of 1 January 2004, over 200
`lives had been saved by naloxone. Naloxone was distrib-
`uted to injection drug users in Torino, Italy leading to
`. 2003). Dettmer
`.
`successful resuscitations (Seal
`et al
`et al
`(2001) reported 29 administrations by 22 individuals
`who had been trained in its use in Berlin, Germany.
`Ninety per cent of the usages of naloxone were judged to
`be appropriate with the remainder being of uncertain
`benefit or pointless.
`Naloxone can also be administered as part of the med-
`ical attention provided at safer injection facilities (SIFs).
`SIFs also have the advantage of reducing HIV and hepa-
`titis C transmission by providing sterile injecting equip-
`ment. SIFs have been in operation in 26 European cities
`and Sydney, Australia (Wood
`
`et al. 2003). The dispensing
`of take-home naloxone at discharge from emergency ser-
`vices, either with or against medical advice, to heroin
`users just resuscitated would target individuals at high
`
`© 2005 Society for the Study of Addiction
`
`Addiction,
`
`100
`, 1823–1831
`
`Opiant Exhibit 2004
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00687
`Page 5
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`

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`1828
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`Catherine T. Baca & Kenneth J. Grant
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`risk and be clearly indicated to treat any re-emergence of
`overdose (Strang
`
`et al. 1996).
`The issue of naloxone distribution is dependent on the
`political climate. How the distribution of naloxone is
`viewed is related to how the problem is framed. Like
`syringe exchange programs, opponents are fearful that
`the intervention sends a message that drug use is con-
`doned, and will therefore view the problem through the
`lens of drug policy. Proponents will define the problem as
`public health promotion, disease prevention and harm
`reduction (Burris, Strathdee & Vernick 2003). Even if
`naloxone distribution to opioid users and their families is
`shown to reduce overdose death, this may or may not
`result in a change in policy, dependent upon the perspec-
`tive of the policy makers.
`Naloxone is a prescription drug in many countries.
`Italy was the only country found in this review to have
`made it available over the counter (Coffin
`. 2003).
`et al
`(No report of the effects of making naloxone available
`over-the-counter in Italy was found.) For take-home
`naloxone to be available, it therefore needs to be pre-
`scribed by a health care provider. For it to be pre-
`scribed, its use must be acceptable to the prescriber.
`Take-home naloxone for emergency use in heroin over-
`dose emergencies is similar to the advice (no longer rec-
`ommended) of keeping syrup of ipecac for emergency
`use in other poisonings (Committee on Injury, Violence
`& Poison Prevention 2003). The prescription of a
`parenteral drug to be administered not by the adult to
`whom it is prescribed but by bystanders for emergency
`resuscitation is unusual, but not without precedent.
`Epinephrine is prescribed to patients with severe aller-
`gies to be administered by bystanders if the patient suf-
`fers anaphylaxis. Glucagon is prescribed to patients
`with diabetes to be administered by bystanders if the
`patient suffers a severe insulin reaction. Coffin
`.
`et al
`(2003) found that a third of providers surveyed would
`consider prescribing take-home naloxone. To make its
`prescription more widespread, New Mexico, USA, has
`limited liability of prescribers of take-home naloxone
`(Huffman 2001).
`
`CONCLUSIONS
`
`The administration of naloxone is the single most impor-
`tant resuscitative action during heroin overdoses. Nalox-
`one is a very safe medication and fears about its use are
`not well-founded. Currently, i.m. is the route preferred as
`it is the easiest to perform and has the longest duration of
`action. The i.n. route holds promise for the future. Train-
`ing programs should give primary importance to the
`provision of naloxone to overdose victims. Assisted venti-
`lation mouth-to-mouth may sometimes be necessary to
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`maintain life until the naloxone takes effect. However,
`this is less important than the administration of naloxone
`and the teaching of this technique is of lesser importance.
`Chest compression is less likely to be of benefit in the her-
`oin overdose setting, although it is included in most CPR
`training programs.
`Because fear of police is frequently a reason why an
`ambulance is not summoned, a change in police response
`may also reduce overdose mortality. If drug users believed
`calling for an ambulance would not result in arrest, an
`ambulance with professional emergency services would
`be much more likely to be utilized. Naloxone peer distri-
`bution is part of the political debate over harm reduction
`strategies. Opponents of harm reduction strategies
`believe they encourage drug use.
`Although the distribution of naloxone holds great
`promise for reducing heroin overdose mortality, problems
`remain. Naloxone alone may be insufficient in some cases
`to revive the victim and CPR, especially rescue breathing,
`may also be needed. A second dose of naloxone might also
`be necessary. Complications following resuscitation from
`overdose may infrequently need in-hospital care. Mortal-
`ity from injecting while alone will be unaffected by take-
`home naloxone. Changes in police behavior could have a
`very positive effect in reducing heroin overdose mortality.
`These issues are being addressed in various ways in the
`existing programs. Medical personnel with access to
`known heroin users, such as family practitioners, emer-
`gency medical personnel or workers in syringe exchange
`programs, may advise the users of treatment available
`locally. Until the users are ready for treatment, it would be
`helpful to warn them of the added danger of injecting
`alone and using other drugs with heroin. Users should
`also be warned of the increased vulnerability to overdose
`when they have not used heroin for a period of time and
`tolerance is decreased.
`Take-home naloxone has important public health
`implications. Aside from the intranasal route, which is
`rarely used, naloxone is given parenterally. This intro-
`duces the possibility of transmission of infectious agents,
`particularly HIV or hepatitis B or C. However, medical
`personnel may combine syringe exchange, naloxone dis-
`tribution and user education, thus enhancing the possi-
`bility of reducing disease transmission.
`Providing naloxone to current users fac