612
`
`REVIEW
`Naloxone in opioid poisoning: walking the tightrope
`S F J Clarke, P I Dargan, A L Jones
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Emerg Med J 2005;22:612–616. doi: 10.1136/emj.2003.009613
`
`Acute opioid intoxication and overdose are common
`causes of presentation to emergency departments.
`Although naloxone, a pure opioid antagonist, has been
`available for many years, there is still confusion over the
`appropriate dose and route of administration. This article
`looks at the reasons for this uncertainty and undertakes a
`literature review from which a treatment algorithm is
`presented.
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`A lthough naloxone has been used as a
`
`specific antidote for opioid poisoning since
`the 1960s,8 there are variations in the
`recommended doses with the British National
`Formulary advising 0.8–2 mg boluses, repeated as
`necessary up to 10 mg for adults (10 mg/kg
`followed by 100 mg/kg boluses for children),
`suggesting 0.4–2 mg boluses.
`and Poisindex
`There is also wide variation in the route of
`administration.
`There are a number of reasons for this. First,
`opioids exert their effect by binding to a series of
`receptors. Naloxone has antagonist activity at all
`of the receptor types9 and the amount needed to
`provide such an effect depends upon the number
`of receptors occupied. Recent evidence suggests
`that a dose of 13 mg/kg naloxone (approximately
`1 mg in an 80 kg person) produces 50% receptor
`occupancy;10 however, this is also influenced by
`the dose of opioid ingested or
`injected.
`Unfortunately this is seldom known in clinical
`practice,11 and instances have been reported
`where over 20 times the recommended doses of
`naloxone have been needed to counteract mas-
`sive opioid overdoses,12 13 and even more in body
`packers. Numerous case histories have revealed a
`13-fold variation in rate of naloxone infusions
`given for prolonged overdoses.14–22
`Second, opioid antagonists can precipitate
`acute withdrawal symptoms (AWS) in chronic
`opioid users11 23–28 provoking an often violent
`reaction.
`In one early study on the use of
`naloxone to reverse morphine anaesthesia in
`non-opioid dependent, general surgical patients,
`acute withdrawal-like symptoms were observed
`to occur after the administration of 15 mg/kg
`In another
`study,
`behavioural
`naloxone.29
`changes, sweating, and yawning were observed
`in 14 healthy volunteers given 2–4 mg/kg nalox-
`one, and these effects often lasted for a number
`of hours after its administration.30
`Third, the pharmacodynamic actions of nalox-
`one last for a briefer period than all but the most
`short acting opioids;8 24 29 31 although the elim-
`ination half life of naloxone is similar to that of
`
`See end of article for
`authors’ affiliations
`. . . . . . . . . . . . . . . . . . . . . . .
`
`Correspondence to:
`Simon F J Clarke, Acting
`Consultant in Emergency
`Medicine, South
`Manchester University
`Hospital Trust, Manchester,
`UK; sfjclarke@doctors.org.
`uk
`
`Accepted for publication
`1 April 2004
`. . . . . . . . . . . . . . . . . . . . . . .
`
`www.emjonline.com
`
`morphine (60–90 minutes)9 it is redistributed
`away from the brain more rapidly.32 Conse-
`quently, the patients may become renarcotised
`and suffer harm if they self discharge from
`medical care early. Clinicians are clearly walking
`a tightrope between precipitating AWS and
`avoiding renarcotisation.
`Numerous case reports describing possible
`adverse effects of naloxone have been published.
`Pulmonary oedema has been reported but most
`instances have occurred in the postoperative
`period33–39 or in the presence of pre-existing
`cardiorespiratory disease,40 and in many of these
`reports it can be difficult to differentiate between
`the effect of naloxone and the effect of the
`underlying disease process or other drugs that
`have been ingested or administered. Many
`episodes of pulmonary oedema secondary to
`opioid toxicity have been published since it
`was
`first noted by William Osler
`in the
`1880s5 41–50 and it has been suggested that
`naloxone simply reveals the opioid induced
`pulmonary oedema that had been masked by
`the respiratory depression.51
`Seizures52 and arrhythmias53–57 have also been
`noted, but could have been caused by hypoxia,54
`the opioids themselves,44 55 58 their coingestants
`(most notably cocaine),57 or pre-existing dis-
`ease.53 56 Interestingly, a number of episodes of
`severe hypertensive reactions have been reported
`following administration of naloxone to patients
`with pre-existing simple hypertension.59–63
`In
`addition, one report showed a significant rise in
`serum catecholamine concentrations in a patient
`with a phaeochromocytoma following adminis-
`tration of naloxone without prior exposure to
`exogenous opioids.64 Currently, a great deal of
`research is being undertaken on the interaction
`of endogenous opioids and the autonomic
`nervous system and it would seem reasonable
`to postulate that
`the antagonistic action of
`naloxone may have an effect. Canine experi-
`ments have indicated that reducing hypoxia and
`hypercapnia lowers serum catecholamine con-
`centrations. It has been proposed that hyperven-
`tilating patients prior
`to administration of
`naloxone would reduce the risk of sympathetic
`mediated adverse effects,58 65 although this has
`not been verified in human.
`In contrast with the above concerns, extremely
`high doses (up to 5.4 mg/kg boluses and 4 mg/
`kg/h infusions) of naloxone have been given to
`non-opioid dependent
`subjects without any
`reported adverse effects.66–68
`The aim of this review is to find evidence of the
`optimum dose and route for administration of
`
`Abbreviations: AWS, acute withdrawal symptoms
`
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`Naloxone in opioid poisoning
`
`613
`
`naloxone and for how long patients need to be observed
`before it is safe to discharge them.
`
`METHODS
`The Medline and Embase databases were searched using the
`following terms:
`‘‘naloxone or naloxone’’ and ‘‘narcotics or opioid or opiate’’
`or ‘‘morphine or buprenorphine or codeine or dextromoramide
`or diphenoxylate or dipipanone or dextropropoxyphene or
`fentanyl
`diamorphine or dihydrocodeine or alfentenil or
`or remifentanil or meptazinol or methadone or nalbuphine
`or oxycodone or pentazocine or pethidine or phenazocine or
`tramadol’’ and ‘‘overdose’’ or ‘‘overdos$’’ or ‘‘poisons’’ or
`‘‘poison$’’ or ‘‘acute intoxic$’’ or ‘‘acute toxic$’’ and limited to
`human studies.
`Studies were deemed to be relevant if they compared doses
`and routes of administration of naloxone or if they produced
`evidence about rates and timing of complications. Case
`histories were reviewed but were included only if they could
`be reasonably grouped together for comparison.
`All papers, including review articles and case histories, had
`their references scrutinised for further articles that were in
`turn retrieved and reviewed; this process was repeated until
`no further articles were found (a total of five rounds).
`
`SEARCH RESULTS
`The initial search produced 185 papers; the subsequent series
`of reference reviews produced 10 relevant articles.65 69–77 These
`papers are summarised in tables 1 and 2, which can be found
`on the electronic version of this article.
`
`DISCUSSION
`Effect of dose on AWS
`AWS include agitation, nausea, vomiting, piloerection,
`diarrhoea, lacrimation, yawning, and rhinorrhoea; these are
`generally not
`life threatening.78 Reported rates of AWS
`related complications vary widely from 7–46% with 2–4 mg
`boluses70 72 73 76 to 47% with a median of 0.9 mg;71 however,
`the actual outcome measures were not directly comparable.
`Only one study records AWS (12%),72 with one US paper
`quoting the number of patients (7%) who required restraint
`(presumably the most severely affected patients)76 and the
`other studies describing the proportion of patients who
`discharged against medical advice (18–47%).70 71 73 Patients
`self discharge for many reasons—for example, fear of police
`involvement—so that the numbers who do abscond do not
`necessarily equate to those who experience AWS, although
`clearly they are no longer narcotised in order to be able to
`leave the emergency department.
`Another potential problem in interpreting the data is the
`lack of information comparing absolute doses given and rates
`of administration with AWS, and state of drug dependency/
`tolerance prior to AWS. Wanger’s study77 stated that the
`paramedics had the impression that patients who were given
`naloxone subcutaneously had a smoother emergence than
`those given it intravenously in spite of a larger dose. It is
`likely that this is because of a slower increase in concentra-
`tions at the receptors, but further research would be needed
`to confirm this; it may also reflect paramedics’ preference for
`an easier route of administration.
`
`subcutaneously, with 55% overall having further naloxone
`in the former study compared with 15% (subcutaneously)
`and 35% (intravenously) in the latter paper. This marked
`variation may be explained by the studies having dif-
`ferent thresholds for giving further doses of naloxone as
`opposed to treating the patients conservatively, as well as
`very different half lives of opioids taken—heroin versus
`methadone.
`Watson72 found that recurrence of toxicity was significantly
`more likely when long acting opioids were ingested, although
`route of opioid administration and use of coingestants
`surprisingly did not have any noticeable effect.
`
`Route of administration of naloxone
`Only two papers compared routes of administration.76 77 Both
`studies used different criteria to define opioid intoxication (in
`terms of history and clinical findings) and naloxone was
`given in the prehospital setting; therefore, it is difficult to
`generalise the findings to other patient populations. In spite
`of these concerns, Sporer76 showed that 2 mg naloxone
`intramuscularly works as well as 2 mg intravenously (94%
`and 90% response rates, respectively); this is perhaps not
`surprising considering the relatively large dose given and it
`was not possible to distinguish differences in complication
`rate between the study groups.
`Wanger’s study77 revealed that 0.8 mg naloxone subcuta-
`neously worked as rapidly as 0.4 mg intravenously from time
`of arrival at the patient’s side to time of clinical effect,
`because the slower time of effect from administration was
`offset by not having to gain intravenous access first.
`Neither of these studies settles concerns about unpredict-
`able and erratic absorption from the intramuscular/subcuta-
`neous injection sites in those patients who are hypotensive,
`but they may be useful alternative routes when intravenous
`access is difficult to obtain. No studies have evaluated the
`absorption kinetics of
`intramuscular administration of
`naloxone. It is likely that variables—including depth of
`injection, dose given, muscle blood flow, site, and so forth—
`would all alter the kinetics of absorption by the intramus-
`cular route, particularly in the opioid poisoned patient with
`hypotension.
`Recent case series and reports have suggested that both
`intranasal79 80 and nebulised81 naloxone may be effective,
`although they are subject to similar unanswered pharmaco-
`kinetic concerns. Also, there is no evidence about the rates of
`renarcotisation and AWS.
`Goldfrank’s study75 provides a good practical dosing guide
`for patients who require prolonged opioid antagonism. It was
`a small study where the end point measured plasma
`naloxone levels and not clinical effect; however, it claimed
`only to be an initial guide to treatment, and stressed the
`importance of close observation of the patient and titration of
`dose as necessary. This makes sense because of individual
`tolerance and susceptibility to opioids—for example, clinical
`observation has shown that corpulent patients will absorb
`opioids into fatty tissues from which it is expected to
`redistribute out more slowly and such patients tend to need
`more prolonged naloxone infusions. Further research is
`required to
`validate
`formally
`and prospectively
`the
`Goldfrank protocol.
`
`Effect of dose on recurrence of toxicity
`Four papers quote the percentage of patients who require a
`second dose of naloxone,72 74 76 77 again with marked varia-
`tion across the world and between centres in the same
`country. Watson’s72 and Sporer’s76 patients were given 2 mg
`boluses, and 14% and 35%, respectively, were given a
`In Christenson’s74 and Wanger’s77 studies,
`second dose.
`patients were given either 0.4 mg intravenously or 0.8 mg
`
`Timing of complications
`Christenson et al74 suggested that if patients fulfilled certain
`criteria 1 hour after administration of naloxone then they
`could be discharged safely. However, one of their patients
`who had taken heroin needed further naloxone after 2 hours
`and Watson et al72 similarly noted that patients who had
`taken long acting opioids developed renarcosis up to 2 hours
`after their initial treatment. Since the half life of naloxone is
`
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`614
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`Clarke, Dargan, Jones
`
`Opioid overdose
`History/clinical signs
`
`NO
`
`RR < 10/min.74
`or
`SpO2 < 92% (on air)74
`
`Observe 2 hours74,76
`RR, SpO2, GCS
`
`STABLE
`
`Discharge
`
`DETERIORATES
`
`YES
`
`Supplemental oxygen or
`Bag-Valve-Mask ventilation
`as necessary
`
`Secure IV access
`
`YES
`
`NO
`
`IV Bolus (titrated)
`Suggested 0.1 mg/min.
`Aim for:
`RR > 10/min.; GCS 13–14;
`no AWS
`
`CONSIDER
`ALTERNATIVE
`DIAGNOSIS IF NO
`RESPONSE TO
`INITIAL DOSE
`
`SC/IM Bolus69,77
`0.8 mg sc
`0.4 mg im
`
`LONG-ACTING
`OPIOID
`
`SHORT-ACTING
`OPIOID
`
`RECURRENCE +
`IV ACCESS GAINED
`
`RECURRENCE +
`NO IV ACCESS
`
`IV Infusion75
`2/3 of initial bolus
`dose/hour
`+
`1
`/2
`consider bolus dose
`at 15 mins.
`
`Observe 2 hours74,76
`
`NO RECURRENCE
`
`Admit
`
`Discharge
`
`Figure 1 Flowchart of treatment of opioid overdose.
`
`60–90 minutes, it would seem logical to observe patients for
`signs of recurrent toxicity for at least 2 hours, although
`further studies are needed to validate this.
`
`With one exception, all other serious complications became
`apparent within 20 minutes of arrival and treatment in the
`emergency department.65 70 71 The one exception was a case of
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`Naloxone in opioid poisoning
`
`615
`
`fatal pulmonary oedema, where the patient was found dead
`7 hours after discharge (9 hours after ingestion of opioid). In
`this case, further opioid ingestion cannot be ruled out, and in
`any case it would seem that genuinely delayed adverse events
`are rare. Because it would be difficult to persuade opioid
`addicts to stay for 8 hours after they have had naloxone, it
`would be reasonable to discharge them if
`they fulfil
`Christenson’s criteria 2 hours after naloxone.
`
`nebulised naloxone may be useful alternatives to parenteral
`administration, the authors think that the evidence is not
`strong enough yet to add them to the algorithm; however,
`they could be easily included in the flowchart as further
`evidence becomes available.
`Opioid overdose is a challenging condition that requires a
`difficult balancing act between over and under treatment
`with naloxone.
`
`Research difficulties
`The reasons for the dearth of randomised controlled clinical
`trials have been summarised recently by Whyte et al.82
`Legal, political, and ethical difficulties, particularly in the
`context of obtaining consent, often hinder the recruitment of
`adequate numbers of patients. In addition, trials would have
`to be prohibitively large to achieve sufficient power when
`measuring outcomes that are rare.
`It is difficult to eliminate confounding factors, such as the
`wide range of different opioids, co-ingestants, and adulter-
`ants that can be taken, the variety of routes by which they
`can be taken (orally, intravenously, subcutaneously, nasally,
`or by smoking), and the complex treatment regimes that are
`given. It is often difficult to determine what individual
`patients have taken because usually they do not know.
`The external validity of the studies can be questioned
`because many are undertaken in regional poisons centres
`whereas most patients are treated in general hospitals where
`there is limited access to specialised toxochemical laboratory
`facilities. Similarly, it can be argued that patients who agree
`to participate in research are not representative of the whole
`population of opioid overdose patients.
`Blinding of
`treatments is extremely difficult because
`patients are often in the emergency department for such a
`short period before they are discharged that the clinician who
`administers the treatment is usually the one who has to
`review the response to that treatment.
`The research undertaken so far has relied heavily on
`observational
`studies, which have a number of well
`recognised limitations, such as difficulty in minimising
`confounding factors and retrospective data collection.
`Studies have often used different inclusion criteria in terms
`of degrees of sedation and respiratory rate as well as different
`thresholds for giving further doses of naloxone, which makes
`direct comparison of studies difficult.
`Follow up of patients is difficult; Smith et al70 managed to
`contact only 32% of the patients who had been discharged.
`Other studies compared the lists of patients discharged with
`ambulance service records and death certificates issued by
`the local coroners. They may have been lost to follow up if
`they had given misleading demographical details and after
`discharge were taken to another healthcare facility by private
`transport, or if they had died later and been given an
`alternative cause of death.
`In spite of these difficulties, a number of conclusions can
`be drawn but further trials are needed to validate them
`clinically in the emergency department and thus help
`clinicians walk the tightrope between over and under treating
`these patients. Clinical judgement and meticulous observa-
`tion are required to successfully manage opioid intoxicated
`patients.
`
`CONCLUSIONS
`Although the evidence base is sparse at present, the following
`algorithm has been devised to summarise the research in a
`way that is clinically useful. References have been included
`where relevant otherwise the recommendations are based on
`consensus derived from the clinical experience of Medical
`Toxicology Units
`in Europe,
`the USA, and Australia.
`Although recent studies have suggested that intranasal and
`
`. . . . . . . . . . . . . . . . . . . . .
`Authors’ affiliations
`S F J Clarke, Acting Consultant in Emergency Medicine, South
`Manchester University Hospital Trust, Manchester, UK
`P I Dargan, Consultant Physician and Clinical Toxicologist
`A L Jones, Consultant Physician and Clinical Toxicologist, Honorary
`Senior Lecturer in Clinical Pharmacology, National Poisons Information
`Service (London), Guy’s and St Thomas’ NHS Trust, London, UK
`
`Competing interests: none declared
`
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`www.emjonline.com
`
`Opiant Exhibit 2193
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
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