Review
`
`Ther Adv Drug Saf
`
`2015, Vol. 6(1) 20 –31
`
`DOI: 10.1177/
`2042098614564776
`
`© The Author(s), 2015.
`Reprints and permissions:
`http://www.sagepub.co.uk/
`journalsPermissions.nav
`
`564776 TAW0010.1177/2042098614564776Therapeutic Advances in Drug SafetyWermeling
`
`research-article2015
`
`Review of naloxone safety for opioid
`overdose: practical considerations for new
`technology and expanded public access
`
`Daniel P. Wermeling
`
`Abstract: Opioid overdose and mortality have increased at an alarming rate prompting new
`public health initiatives to reduce drug poisoning. One initiative is to expand access to the
`opioid antidote naloxone. Naloxone has a long history of safe and effective use by organized
`healthcare systems and providers in the treatment of opioid overdose by paramedics/
`emergency medicine technicians, emergency medicine physicians and anesthesiologists.
`The safety of naloxone in a prehospital setting administered by nonhealthcare professionals
`has not been formally established but will likely parallel medically supervised experiences.
`Naloxone dose and route of administration can produce variable intensity of potential adverse
`reactions and opioid withdrawal symptoms: intravenous administration and higher doses
`produce more adverse events and more severe withdrawal symptoms in those individuals
`who are opioid dependent. More serious adverse reactions after naloxone administration
`occur rarely and may be confounded by the effects of other co-intoxicants and the effects of
`prolonged hypoxia. One component of the new opioid harm reduction initiative is to expand
`naloxone access to high-risk individuals (addicts, abusers, or patients taking high-dose or
`extended-release opioids for pain) and their close family or household contacts. Patients or
`their close contacts receive a naloxone prescription to have the medication on their person
`or in the home for use during an emergency. Contacts are trained on overdose recognition,
`rescue breathing and administration of naloxone by intramuscular injection or nasal spraying
`of the injection prior to the arrival of emergency medical personnel. The safety profile of
`naloxone in traditional medical use must be considered in this new context of outpatient
`prescribing, dispensing and treatment of overdose prior to paramedic arrival. New naloxone
`delivery products are being developed for this prehospital application of naloxone in treatment
`of opioid overdose and prevention of opioid-induced mortality.
`
`Keywords: antidote, drug-delivery systems, naloxone, opioid, overdose
`
`Introduction
`Drug-induced deaths have reached a public
`health crisis level for unintentional mortality;
`overdose deaths now exceed automobile acci-
`dents as a preventable cause of death in the
`United States [Mack, 2013]. Opioids, as a class of
`medications, are responsible for the majority of
`deaths with over 16,500 US deaths (out of roughly
`40,000 drug overdose deaths) recorded by the US
`Centers for Disease Control for 2010. The United
`Kingdom reported 1496 opioid related deaths out
`of 2597 people who died from a drug overdose
`[Lancet, 2013].
`
`Public policy to reduce opioid mortality has taken
`a number of directions [SAHMSA, 2013].
`Medical, public health, and legislative efforts have
`attempted to address the licit and illicit access
`and use of opioids that lead to adverse conse-
`quences [Hewlett and Wermeling, 2013]. Opioid
`use policy reforms and strategies have been pro-
`posed and implemented including: closer atten-
`tion to opioid prescribing guidelines, use of
`prescription drug monitoring programs to iden-
`tify improper prescribers, increased medical and
`interprofessional
`education,
`increased
`law
`enforcement, and medication take-back to return
`
`Correspondence to:
`Daniel P. Wermeling,
`Pharm.D.
`University of Kentucky
`College of Pharmacy, 789
`South Limestone Street,
`Lexington, KY 40536, USA
`dwermel@uky.edu
`
`20
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`law enforcement for
`unused medication to
`destruction. In spite of these public policy efforts
`the adverse consequences of societal exposure to
`opioids continue.
`
`An additional harm-reduction strategy, although
`not widely adopted and validated yet as a poten-
`tial standard of care, has been implemented in
`some locations around the world. The evolving
`practice is to treat opioid overdose prehospital by
`prescribing naloxone, the opioid antidote, to an
`individual or family with one or more residents at
`risk of opioid overdose [Goodman and Gilman,
`2001; Doe-Simkins et  al. 2009; Wheeler et  al.
`2012; Sporer and Kral, 2007; Walley et al. 2013a,
`2013b]. Naloxone is a competitive antagonist to
`opioids in the central nervous system and has
`been approved as a prescription medication in the
`US since 1971. It is generally devoid of activity
`unless opioids are present in a person. A recent
`publication provides an excellent overview for the
`management of opioid analgesic overdose and the
`use of naloxone [Boyer, 2012].
`
`The newly evolving practice is intended to move
`the continuum of care forward before the arrival
`of emergency medical services (EMS) at the scene
`[SAMHSA, 2013]. In overdose situations the per-
`son will be unconscious, hypoxic, perhaps apneic,
`and unable to save themselves, yet time is of the
`essence in this medical emergency. Therefore,
`individuals in close contact with a person at risk
`of overdose must recognize overdose and under-
`stand what to do if overdose is suspected. First
`responders are commonly close family contacts or
`police officers. Expanding access to naloxone to
`bystanders is also important because: (1) basic-
`level emergency medical technician (EMT) ser-
`vices in some locales will not stock naloxone
`injection on the ambulance and are not permitted
`to administer an injection; (2) an ambulance is
`not called due to fear of being arrested by police
`authorities likely to respond to the scene; and (3)
`emergency response time in rural areas can be
`long. A five-step process is recommended for the
`first responder encountering a suspected opioid
`overdose.
`
`4. Rescue breathe if patient not breathing.
`5. Stay with the person and monitor their
`response until emergency medical assis-
`tance arrives. After 5 minutes, repeat the
`naloxone dose if person is not awakening or
`breathing well enough (10 or more breaths
`per minute). A repeat dose may be needed
`30–90 minutes later if sedation and respira-
`tory depression recur.
`
`A challenge for expanding access to naloxone is
`that the medication is currently available only as
`an injection for intravenous (IV), intramuscular
`(IM), or subcutaneous (SC) injection [IMS,
`2001; Hospira, 2006; Martindale Pharma, 2014;
`Kaleo, 2014]. Some harm reduction programs
`include the training of first responders on use of
`an injection; however, there has been concern
`about the potential for accidental needlestick
`injury and transmission of hepatitis or HIV infec-
`tion. Some patients will be undergoing acute opi-
`oid withdrawal and will be agitated as they are
`being revived with naloxone, thus increasing the
`risk of an injury to the provider [Doe-Simkins
`et al. 2009]. Medical directors supervising para-
`medics in many large cities have adopted the
`practice of spraying naloxone injection into the
`nasal cavity as a needle-free means of administer-
`ing naloxone, thus reducing the risk of needle
`stick injury [Barton et  al. 2002]. Therefore, an
`unmet medical need is to have more user-friendly,
`needle-free naloxone delivery systems available
`for medical professionals, first-responders and at-
`home family member use.
`
`Consideration of alternative naloxone drug-deliv-
`ery systems is quite complex. The epidemiology
`of the condition itself must be understood.
`Conditions of use in various scenarios must be
`considered. The ability of the person to use the
`delivery system (e.g. human factors or ergonom-
`ics) is critical under the circumstances of an over-
`dose. And of course, the medication, naloxone in
`this case, must be adaptable and safe and effective
`for the clinical condition.
`
`1. Check for signs of opioid overdose (uncon-
`scious and unarousable, slow or absent
`breathing, pale, clammy skin, slow or no
`heart beat).
`2. Call EMS to access immediate medical
`attention.
`3. Administer naloxone.
`
`Epidemiology of opioid overdose
`The Hindu parable regarding blind men examin-
`ing and trying to describe an elephant may well be
`relevant in attempting to understand the opioid
`overdose phenomenon. Overdoses occur as thera-
`peutic misadventures, or adverse effects, from the
`licit use of medications for pain management or
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`Therapeutic Advances in Drug Safety 6(1)
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`opioid maintenance. Other overdoses occur from
`nonmedical use of prescription opioids or illicit
`use of heroin [Osterwalder, 1996; Shah et  al.
`2007; Warner et  al. 2011; Rosen et  al. 2013].
`Regardless, medical and public health officials
`will be able to determine root causes of opioid use
`in their communities and region and can adopt
`strategies appropriate for their circumstances.
`
`The Centers for Disease Control and Prevention
`provide some overall descriptive statistics for those
`who have died in the US from overdose [Mack,
`2013]. Most deaths were unintentional, but there
`was a significant note that 13% of drug overdoses
`were suicidal drug poisoning attempts. Considering
`age as a risk factor, middle-aged men carry the high-
`est rate of drug-induced mortality. More deaths
`occur in non-Hispanic white males but highest rates
`occur in US ethnic minorities. The rate of rise of
`deaths in children and adolescents is becoming of
`great concern [Bond et al. 2012; Bailey et al. 2009].
`
`An additional factor to consider is the rural versus
`urban nature of opioid overdose [Rosen et al. 2013;
`Wunsch et al. 2009; Havens et al. 2007]. Large metro-
`politan areas with high population density typically
`report heroin as the opioid most commonly associ-
`ated with adverse outcomes. Rural Appalachian states
`typically report prescription medications implicated
`in most overdoses. Methadone and hydrocodone/oxy-
`codone account for the majority of opioid-related
`deaths in Kentucky and West Virginia. These two
`states represent only 2% of the US population (about
`6 million citizens) but account for 10% of deaths
`nationally. In Kentucky, the largest number of deaths
`occurs in the more urban centers of Louisville and
`Northern Kentucky, yet the highest rates occur in
`rural poverty-stricken counties, exacerbating a declin-
`ing vitality [Bunn and Slavova, 2012].
`
`Certain overdose risk factors are associated with a
`call for EMS [Boyer, 2012; Mack, 2013; Toblin
`et  al. 2010; Wunsch et  al. 2009; Warner et  al.
`2011]:
`
` •
` •
`
`injection of opioid;
`combining opioids with other central nerv-
`ous system depressants;
` • opioid doses greater than 100 mg/day of
`morphine or equivalent;
`loss of opioid tolerance after detoxification
`or incarceration and resuming opioid use;
`comorbid mental health, central nervous
`system,
`renal, hepatic or pulmonary
`diseases;
`
` •
`
` •
`
` • young people experimenting with opioids;
` • accidental ingestion.
`
`Therefore, understanding the high-frequency
`characteristics of opioid overdose is very impor-
`tant in the design of prevention strategies includ-
`ing provision of naloxone to those at highest risk
`[Hasegawa, et al. 2014].
`
`Medical use of the opioid antidote, naloxone
`
`Efficacy of naloxone injection
`Naloxone is approved for use in the United States
`by IV, IM, or SC routes of administration [IMS,
`2001; Hospira, 2006; Kaleo, 2014]. It is suggested
`that the onset of action of the IV route will be
`faster, so is preferred in emergency situations.
`However, obtaining IV access in the prehospital
`setting, especially among injection drug abusers,
`can be time-consuming and difficult [Sporer et al.
`1996; Barton et  al. 2002]. A series of studies,
`beyond the scope of this paper, describe compar-
`ative EMS clinical studies of various naloxone
`doses and routes of administration, including off-
`label administration of naloxone injection as an
`intranasal (IN) spray [Barton et  al. 2005; Belz
`et  al. 2005; Osterwalder 1996; Robertson et  al.
`2009; Wanger et al. 1998; Kelly et al. 2005; Kerr
`et al. 2008, 2009; Merlin et al. 2010; Yealy et al.
`1990]. Times to drug administration and revival
`show comparable efficacy of the tested dosing
`methods. Small differences in efficacy relative to
`percent revived (according to predefined criteria)
`are apparent but perhaps not clinically relevant.
`Some patients required a repeat dose to achieve a
`satisfactory clinical outcome. Several studies also
`provide comparative safety data for examination.
`
`Naloxone safety profile after parenteral use
`One approved US package insert [IMS, 2001] states
`that, in the absence of narcotics, naloxone exhibits
`essentially no pharmacologic activity. Similarly, the
`naloxone package insert by Hospira, Inc. [Hospira,
`2006] states that a small study including volunteers
`receiving 24 mg/70 kg did not demonstrate toxicity.
`
`Adverse events listed in the approved US package
`inserts after the use of naloxone for reversal of
`narcotic depression are provided in Table 1.
`
`After awakening from unconsciousness the over-
`dose victim may experience a relatively short
`
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`Table 1. Adverse effects after naloxone in reversal of
`opioid depression.
`
`System organ class
` MEDRA preferred term
`Cardiac disorders
` Cardiac arrest
` Tachycardia
` Ventricular fibrillation
` Ventricular tachycardia
`Gastrointestinal disorders
` Nausea
` Vomiting
`Investigations
` Blood pressure increased
`Nervous system disorders
` Convulsion
` Tremor
`Psychiatric disorders
` Withdrawal syndrome
`Respiratory, thoracic and mediastinal disorders
` Pulmonary edema
`Skin and subcutaneous tissue disorders
` Hyperhidrosis
`
`period of withdrawal. Unlike alcohol, opioid with-
`drawal symptoms are generally not life-threaten-
`ing, but can make
`the patient physically
`uncomfortable. Symptoms of opioid withdrawal,
`as derived from the Hospira [Hospira, 2006]
`package insert, are included in Table 2.
`
`In addition, when used in the postoperative set-
`ting, the following events are listed in Table 3. The
`most relevant adverse outcomes encountered
`with naloxone injection are those reported for
`opioid reversal in patients who have developed
`physical dependence to an opioid. The following
`authors have published in this area and are briefly
`summarized.
`
`Belz and colleagues [Belz et al. 2006] reported a
`retrospective case series review of patients treated
`in 2004 by EMS responders. A total of 164
`patients aged 14–86 years were treated with
`naloxone by IV (primarily), IM, or IN routes.
`They reported naloxone associated ‘violence’
`described as agitation/combativeness (15%) and
`vomiting in 4% of the cases.
`
`Buajordet and colleagues [Buajordet et  al. 2004]
`conducted a prospective study to assess adverse
`events after naloxone treatment for episodes of
`
`Table 2. Opioid acute withdrawal syndrome symptoms.
`
`System organ class
` MEDRA preferred term
`Cardiac disorders
` Tachycardia
`Gastrointestinal disorders
` Diarrhea
` Nausea
` Vomiting
`General disorders and administration site conditions
` Asthenia
` Chills
` Pain
` Pyrexia
`Investigations
` Blood pressure increased
`Nervous system disorders
` Tremor
`Psychiatric disorders
` Nervousness
` Restlessness
`Respiratory, thoracic and mediastinal disorders
` Rhinorrhea
` Sneezing
` Yawning
`Skin and subcutaneous tissue disorders
` Hyperhidrosis
` Piloerection
`
`suspected acute opioid overdose. This study included
`1192 episodes treated with naloxone. The patients
`had a mean age of 32.6 years and 77% were male.
`Naloxone was administered by an initial IM dose of
`0.4–0.8 mg (depending on body size) plus an imme-
`diate IV dose of 0.4 mg. The paramedic investigators
`recorded adverse reactions on a reporting chart con-
`taining predefined events. Adverse events were
`reported in 538 of the 1192 episodes (45%). In the
`538 episodes which had adverse events, there were
`726 adverse events reported (Table 4).
`
`Buajordet and colleagues reported that adverse
`events were significantly more often seen in cases of
`‘severe poisoning’ than in cases with mild to moder-
`ate poisoning (49% versus 22% of cases). Severe
`poisoning cases included those with life-threatening
`complications (e.g. respiratory arrest) or cyanosis.
`Adverse events led to hospitalization in three epi-
`sodes (0.3%). Events leading to hospitalization
`included one patient with confusion, headache and
`vision disorder; one patient with nausea and vomit-
`ing; and one patient with confusion, tremor and
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`Therapeutic Advances in Drug Safety 6(1)
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`Table 3. Adverse events associated with naloxone in
`postoperative patients.
`
`System organ class
` MEDRA preferred term
`Cardiac disorders
` Cardiac arrest*
` Cardiac failure*
` Cardiovascular disorder
` Tachycardia*
` Ventricular fibrillation*
` Ventricular tachycardia*
`Gastrointestinal disorders
` Nausea
` Vomiting
`General disorders and administration site conditions
`
`Injection site reaction
`Investigations
` Blood pressure increased
`Nervous system disorders
` Convulsion
` Grand mal convulsion
` Paraesthesia
` Tremor
`Psychiatric disorders
` Agitation
` Hallucination
`Respiratory, thoracic and mediastinal disorders
` Dyspnea*
` Hypoxia
` Pulmonary edema*
` Respiratory depression
`Skin and subcutaneous tissue disorders
` Hyperhidrosis
`Surgical and medical procedures
` Reversal of opiate activity
`Vascular disorders
` Flushing
` Hot Flashes
` Hypotension*
` Hypertension*
`
`*Sometimes resulting in death, coma and encephalopa-
`thy as sequelae.
`
`‘feeling bad’. The authors concluded that serious
`complications after naloxone were rare.
`
`Osterwalder [Osterwalder, 1996] conducted a
`prospective study of 485 patients admitted to the
`hospital (538 times) for acute intoxication with
`heroin or heroin mixtures. Of these, 453 received
`naloxone either IV, IM, or IV plus IM (the
`
`Table 4. Events reported after IM plus IV naloxone
`treatment for suspected opioid overdose [Buajordet
`et al. 2004].
`
`Event
`
`
`
`Confusion*
`Headache*
`Nausea/vomiting*
`Aggressiveness*
`Tachycardia*
`Shivering
`Seizures*
`Sweating
`Tremor
`Miscellaneous
`
`Number of
`events (%)
`
`Number
`of events
`(% of total
`treatments)
`
`n=726
`
`235 (32)
`157 (22)
`66 (9)
`62 (8)
`47 (6)
`33 (5)
`27 (4)
`24 (3)
`9 (1)
`66 (9)
`
`n=1192
`
`235 (20)
`157 (13)
`66 (6)
`62 (5)
`47 (4)
`33 (3)
`27 (4)
`24 (2)
`9 (1)
`66 (6)
`
`* These events were predefined/listed in the reporting
`chart used by paramedics.
`
`majority of patients). Dosing was not specified by
`protocol, but the median IV dose given was 0.2
`mg naloxone (range 0.1–2.8 mg); the median IM
`dose was 0.2 mg (range 0.1–0.9 mg). Patients
`averaged 24 years old (range 15–47 years).
`
`A total of 30 patients had 46 ‘complications’
`(Table 5). Eight patients died: five due to cardio-
`circulatory arrest, two due to pneumonia, and one
`due to pulmonary edema. Another patient died
`after generalized convulsions, having had prena-
`loxone asystole in the emergency room, along with
`hyperthermia and hypoxemic encephalopathy.
`
`Osterwalder concluded that naloxone may cause
`life-threatening complications in over 1% of heroin-
`overdosed patients, and suggested that lower nalox-
`one doses should be used. In addition, he suggested
`that using a bag/valve/mask device to hyperventilate
`patients for 2–5 minutes before initiating treatment
`with an opioid antagonist may be beneficial. His
`conclusion can be contrasted with the retrospective
`study by Yealy and colleagues described next.
`
`Yealy and colleagues [Yealy et al. 1990] performed a
`retrospective review of prehospital records to investi-
`gate the safety of naloxone administered by para-
`medics in the prehospital setting over a 1-year period.
`Patients eligible for treatment with naloxone under
`this EMS treatment protocol were patients with an
`acutely depressed level of consciousness with blood
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`Table 5. Complications seen before or after naloxone administration (or patients may have never received
`naloxone) for acute intoxication with heroin or heroin mixtures (n = 538) [Osterwalder, 1996].
`
`Event
`
`Number reported
`
`Percentage of 538
`
`Resulting in death
`
`Percentage of 538
`
`Cardiocirculatory arrest
`Delayed onset of
`consciousness and
`normal respiration
`Pulmonary edema
`Aspiration
`Hyperthermia
`Generalized seizures
`Rhabdomyolysis
`Pneumonia
`Hypoglycemia
`Hypothermia
`
`9
`8
`
`8
`5
`4
`3
`3
`2
`2
`2
`
`1.7
`1.5
`
`1.5
`0.9
`0.7
`0.6
`0.6
`0.3
`0.3
`0.3
`
`5
`
`1
`
`1*
`
`2
`
`0.9
`
`
`0.2
`
`
`0.2
`
`0.3
`
`
`
`*Patient had asystole, hyperthermia (40°C) and hypoxemic encephalopathy before naloxone.
`
`Table 6. Events seen after naloxone administration in the prehospital setting [Yealy et al. 1990].
`
`Event
`
`Number reported (percentage of 813)
`
`Comment
`
`Generalized tonic-clonic seizure
`Vomiting
`Significant hypertension*
`SBP increases > 30 mmHg
`
`Significant hypotension**
`
`1 (0.1%)
`2 (0.2%)
`1 (0.1%)
`7 (0.9%)
`
`2 (0.2%)
`
`Underlying seizure disorder
`One patient received ipecac
`Total dose 1.2 mg
`Systolic blood pressure (SBP)
`between 100 and 160 mmHg
`
`
`No patient had ventricular tachycardia, fibrillation, or asystole; pulmonary edema was not assessed.
`*If SBP increased by more than 30 mmHg and above 160 mmHg.
`**If SBP decreased to less than 120 mmHg and dropped by 30 mmHg.
`
`glucose over 80 mg/dl or who had no response to
`glucose administration. In some cases, naloxone was
`given prior to ascertainment of hypoglycemic status.
`Charts for 813 patients were eligible for review.
`Patients had a mean age of 42.4 ± 9.7 years and
`59% were male. Most patients (800) received nalox-
`one IV with initial doses of 0.4–0.8 mg and the mean
`dose was 0.9 mg (range 0.4–2.4 mg). The remaining
`13 patients received naloxone by either the IM, SC,
`intra-tracheal or sublingual routes. Adverse events
`reported are as shown in Table 6.
`
`The authors concluded that a protocol change to
`smaller doses of naloxone does not appear to be
`warranted.
`
`revived and then refuse further medical care, leav-
`ing against medical advice (AMA). Two publica-
`tions report on the medical examiner records of
`overdose deaths [Vilke et al. 1999, 2003] over a
`1-year and 5-year period, respectively. These
`studies each compare databases of patients who
`received naloxone for opioid overdose and then
`left AMA to the databases of the medical exam-
`iner for deaths within 12 hours of the naloxone
`treatment. In these two studies, there were no
`cross-reports found, indicating that patients who
`were treated with naloxone for overdose and then
`refused further medical treatment (leaving AMA),
`were not later found dead.
`
`Post-treatment recurrence of respiratory
`depression
`A concern has been raised about prehospital
`administration of naloxone, as some patients are
`
`Safety profile after intranasal administration of
`naloxone injection
`Of the reports describing the response to nalox-
`one delivered nasally, only two studies described
`the adverse events seen in detail.
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`Therapeutic Advances in Drug Safety 6(1)
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`Table 7. Adverse events after naloxone 2 mg by
`intramuscular (IM) or intranasal (IN) routes [Kelly
`et al. 2005].
`
`Table 8. Adverse events after naloxone 2 mg by
`intramuscular (IM) or intranasal (IN) route [Kerr et al.
`2009].
`
`Event term
`
`IM (n = 71)
`
`IN (n = 84)
`
`Event term
`
`IM (n = 89)
`
`IN (n = 83)
`
`
`
`Agitation and/or
`irritation
`Nausea and/
`orvomiting
`Headache
`Tremor
`Sweating
`
`n (%)
`
`n (%)
`
`10 (14%)
`
`2 (2.4%)
`
`4 (5.6%)
`
`6 (7.1%)
`
`2 (2.8%)
`1 (1.4%)
`0 (0%)
`
`0 (0%)
`1 (1.2%)
`1 (1.2%)
`
`
`
`
`
`‘Minor events’
`
` Agitation and/or
`irritation
` Nausea and/or
`vomiting
` Headache
`‘Major event’
` Convulsion
`
`n (%)
`
`n (%)
`
`17 (19.1%)
`7 (7.9%)
`
`16 (19.3%)
`5 (6.0%)
`
`7 (7.9%)
`
`7 (8.4%)
`
`3 (3.3%)
`
`4 (4.8%)
`
`1 (1.1%)
`
`0 (0%)
`
`Kelly and colleagues [Kelly et al. 2005] conducted
`a prospective, randomized trial comparing 2 mg
`IM naloxone with 2 mg/5 ml IN naloxone given
`by a mucosal atomizer. A total of 182 patients
`were enrolled, of whom 155 were evaluable. The
`patients averaged 28–30 years in age (range 13–
`57) and 72% were male. Patients who received
`IM naloxone responded faster than the IN group
`with respect to time until respirations >10/min-
`ute (6 minutes to response for IM versus 8 min-
`utes to response for IN, p = 0.006). Time to
`Glasgow Coma Scale greater than 11 was not sig-
`nificantly different. In the IM group, 13% of
`patients needed ‘rescue’ naloxone, versus 26% in
`the IN group. Note the high volume (5 ml) used
`to deliver IN naloxone. The dilute naloxone solu-
`tion is unable to be retained in the nasal cavity
`and likely was lost for possible absorption
`[Cosantino et al. 2007; Wermeling, 2012].
`
`There were no major adverse events in either
`group. Adverse events (described as mild) are
`listed in Table 7.
`
`In a follow up to the study by Kelly and col-
`leagues, Kerr and coworkers [Kerr et al. 2009]
`compared safety and effectiveness of a spe-
`cially prepared concentrated naloxone formu-
`lation (2 mg/ml) given via the IN versus IM
`routes in a randomized, controlled, open-label
`trial. A total of 172 patients suspected of her-
`oin overdose were treated by emergency medi-
`cal personnel and enrolled into the study: 83
`received 1 mg/0.5 ml into each nostril (2 mg
`total) and 89 patients received 2 mg/ml IM. A
`total of 74% of the patients were male, and the
`average age was 31. The adverse events seen
`were similar between the two groups. The
`authors concluded that a low adverse event
`
`rate was observed in both arms, as shown in
`Table 8.
`
`Discussion of significant adverse events
`The summary of adverse event data from the
`previous studies suggests the following consid-
`erations. The dose and route of administration
`are significant factors with regard to the occur-
`rence and intensity of adverse reactions [Cantwell
`et al. 2005]. IV administration can provide rapid
`and relatively higher exposure to naloxone in an
`emergency as compared with routes requiring
`drug absorption. Moreover, the IV route of
`administration results in rapid clearance of
`naloxone and may necessitate repeated dosing
`until the intoxicant is metabolized and elimi-
`nated. Routes of administration having an
`absorption phase, depending upon the dose, may
`provide a slower onset of revival that may be bet-
`ter tolerated during the recovery period. New
`products with an absorption phase adequate to
`reverse the overdose, but, not providing peak lev-
`els of naloxone similar to an IV dose, are likely to
`be successful in this new prehospital treatment
`context. A balance should be struck between
`rapidity of opioid reversal versus frequency and
`intensity of adverse reactions and opioid with-
`drawal symptoms.
`
`The differences in IN response rates and adverse
`reactions across studies are likely due to the dif-
`ferences in formulation approaches of the rela-
`tively dilute naloxone solutions. Products
`designed for nasal delivery are typically formu-
`lated such that the dose is delivered in about
`100–200 µl, a volume that can be retained in the
`nasal cavity [Costantino et al. 2007; Wermeling,
`2012].
`
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`Withdrawal symptoms
`Unlike withdrawal symptoms precipitated by
`withdrawal of other agents, opioid withdrawal is
`generally not life-threatening. Withdrawal symp-
`toms induced by naloxone administration tend to
`dissipate in a period of 30–60 minutes due to the
`relatively short half-life of naloxone [Ngai et  al.
`1976; Dowling et  al. 2008]. Due to naloxone’s
`high metabolic clearance and the fact that most
`opioids have a longer persistence in the blood
`stream, the symptoms of withdrawal dissipate,
`and in about 15–20% of cases, administration of
`a repeat dose of naloxone may become necessary
`if overt toxicity such as central nervous system
`and respiratory depression recur [Boyer, 2012].
`
`event of a severe opioid overdose. In postopera-
`tive patients, there are questions as to the contrib-
`uting factor of pre-existing cardiac disease in the
`patients or concomitant administration of poten-
`tially cardiotoxic drugs. It has been suggested that
`the pathogenesis of pulmonary edema associated
`with the use of naloxone is similar to neurogenic
`pulmonary edema, i.e. a centrally mediated mas-
`sive catecholamine response leading to a dramatic
`shift of blood volume into the pulmonary vascular
`bed resulting in increased hydrostatic pressures.
`An additional theory is that the airway may be
`partially or mostly obstructed and creating nega-
`tive pulmonary pressure edema [Boyer, 2012].
`
`Seizures
`Seizures are a well-known complication after severe
`cerebral hypoxia. Patients encountered by EMS
`personnel in the setting of opioid overdose may
`have been hypoxic for an unknown duration. The
`contribution by naloxone to a seizure is unclear.
`
`Cardiac arrest
`The package insert for naloxone [IMS, 2001]
`states that abrupt reversal of narcotic depression
`with naloxone may result
`in:
`tachycardia,
`increased blood pressure, seizures and cardiac
`arrest. In the context of hypoxia (as in after a nar-
`cotic overdose), seizures and cardiac arrest can
`occur. Likewise, in the overdose setting, co-con-
`sumed drugs may be contributory, such as cocaine
`[Shah et al. 2007].
`
`Tachycardia
`Buajordet and colleagues [Buajordet et al. 2004]
`reported tachycardia in the range of 80–180 bpm.
`None of these patients were hospitalized, proba-
`bly due to resolution of the tachycardia before
`termination of observation by EMS personnel.
`Tachycardia is also listed as one symptom of opi-
`oid withdrawal [Hospira, 2006].
`
`Pulmonary edema
`Pulmonary edema was not reported by Buajordet
`and colleagues, but it was reported by Osterwalder.
`
`In addition, it has been reported after postopera-
`tive narcotic reversal (package inserts). The
`mechanism for pulmonary edema is unclear.
`Pulmonary edema can be observed as a terminal
`
`Practical considerations for expanding
`access to naloxone
`Naloxone is a prescription injection-based medi-
`cation that has traditionally been administered by
`paramedics, emergency medicine physicians and
`anesthesiologists in organized healthcare settings.
`A new practice of expanding access to naloxone
`for non-medical first responders is in develop-
`ment, with 24 states having legislation authoriz-
`ing this medical practice akin to state legislation
`authorizing epinephrine auto-injector prescribing
`and third-party drug administration for treatment
`of suspected anaphylaxis or severe asthma.
`Expanding access to naloxone requires considera-
`tion for the prescribing, dispensing and coun-
`seling to patient contacts and families regarding
`overdose recognition, rescue breathing, calling for
`EMS and administering naloxone. In general,
`organized healthcare at this time does not have
`systems in place to support prescribing and dis-
`pensing naloxone and counseling at-risk families
`on opioid overdose prevention and treatment.
`
`Physicians and prescribers in primary care and in
`substance abuse treatment may be unaware of the
`potential to use naloxone, albeit in an off-label
`manner of nasal spraying of the injection, or an
`approved auto-injector, to prevent opioid over-
`dose related mortality and morbidity in the out-
`patient
`setting. A
`significant
`educational
`programming activity is necessary to broaden
`knowledge in the general medical community
`[Walley et al. 2013a, 2013b]. Prescribers have no
`standard of care for opioid overdose prevention in
`households.
`
`Pharmacy systems traditionally stock naloxone in a
`hospital or surgical setting; certainly not in a com-
`munity outpatient retail pharmacy setting [Bailey
`
`http://taw.sagepub.com
`
`27
`
`DP Wermeling
`
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`Therapeutic Advances in Drug Safety