Article 19
`
`Adverse events after naloxone treatment of episodes of
`suspected acute opioid overdose
`Ingebjørg Buajordeta, Anne-Cathrine Næssb, Dag Jacobsenc and Odd Brørsa
`
`Objective: An increasing and serious heroin overdose
`problem in Oslo has mandated the increasing
`out-of-hospital use of naloxone administered by
`paramedics. The aim of this study was to determine the
`frequencies and characteristics of adverse events related
`to this out-of-hospital administration by paramedics.
`
`Methods: A one-year prospective observational study from
`February 1998 to January 1999 was performed in patients
`suspected to be acutely overdosed by an opioid. A total of
`1192 episodes treated with naloxone administered by the
`Emergency Medical Service system in Oslo, were included.
`The main outcome variable was adverse events observed
`immediately after the administration of naloxone.
`
`Results: The mean age of patients included was 32.6
`years, and 77% were men. Adverse events suspected to be
`related to naloxone treatment were reported in 45% of
`episodes. The most common adverse events were related
`to opioid withdrawal (33%) such as gastrointestinal
`disorders, aggressiveness, tachycardia, shivering, sweating
`and tremor. Cases of confusion/restlessness (32%) might
`be related either to opioid withdrawal or to the effect of the
`heroin in combination with other drugs. Headache and
`
`seizures (25%) were probably related to hypoxia. Most
`events were non-serious. In three episodes (0.3%) the
`patients were hospitalized because of adverse events.
`
`Conclusion: Although adverse events were common
`among patients treated for opioid overdose in an
`out-of-hospital setting, serious complications were rare.
`Out-of-hospital naloxone treatment by paramedics seems
`to save several lives a year without a high risk of serious
`complications. European Journal of Emergency Medicine
`11:19–23 c 2004 Lippincott Williams & Wilkins.
`
`European Journal of Emergency Medicine 2004, 11:19–23
`
`Keywords: adverse events, naloxone treatment, opioid overdose,
`out-of-hospital, paramedics
`
`aClinical Pharmacology and Toxicology Unit, Clinical Chemistry Department,
`bOslo Ambulance Service and cDivision of Medicine, Ullevaal University Hospital,
`Oslo, Norway.
`
`Sponsorship: This study was supported by grants from The Research Council of
`Norway and the Research Forum of Ullevaal University Hospital.
`
`Correspondence and reprint requests to Ingebjørg Buajordet, The Norwegian
`Medicines Agency, Sven Oftedalsvei 8, N-0950 Oslo, Norway.
`Tel: + 47 22 89 77 00; fax: + 47 22 89 77 99; e-mail:
`ingebjorg.buajordet@legemiddelverket.no
`
`Introduction
`In 1980 the incidence of acute self-poisoning in Oslo was
`2.8 per 1000 inhabitants, opioids being the main toxic
`agent in 182 of 1212 episodes studied [1]. The incidence
`of opioid overdose increased and was reported to be
`approximately 850 per year in the 1990s [2,3].
`
`Initially, patients with life-threatening opioid overdose
`were artificially ventilated by ambulance personnel and
`brought to hospital
`for treatment in the emergency
`department, often leaving the hospital alone shortly after
`regaining consciousness and with a high risk of undiscov-
`ered relapse of intoxication. For this reason, treatment
`strategy has changed to outside-hospital treatment with
`assisted ventilation, the administration of naloxone, and
`observation of the patient until he/she has recovered
`sufficiently to be looked after by friends or relatives.
`
`adverse events
`Some addicts have complained of
`associated with naloxone treatment. Several studies have
`reported on the efficacy and safety of out-of-hospital
`treatment of heroin overdoses with naloxone. Most
`0969-9546 c 2004 Lippincott Williams & Wilkins
`
`studies have reported on paramedics treating overdosed
`patients alone or assisted by a physician [3–10]. Only a
`few studies have reported adverse effects or complica-
`tions associated with the administration of the antidote
`[4,7,11,12].
`
`The aim of this study was to determine the frequency
`and characteristics of adverse events related to the out-
`of-hospital administration of naloxone by paramedics in
`Oslo, Norway.
`
`Materials and methods
`The Emergency Medical Service (EMS) system in Oslo is
`a one-tiered centralized community-run system serving a
`population of approximately 500 000 inhabitants. There is
`no central registration of heroin addicts frequenting the
`central area of Oslo, although an estimate of some 6000 is
`given by the Oslo police. There is a tradition among drug
`abusers in Oslo to prefer injecting their drugs, and a hard-
`core injecting drug abuser milieu steadily recruits young
`people to extensive heroin abuse. One explanation for the
`high number of heroin abusers might be the low street
`
`DOI: 10.1097/01.mej.0000114321.47474.d2
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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`

`20 European Journal of Emergency Medicine 2004, Vol 11 No 1
`
`price of heroin in Oslo compared with alcohol prices. The
`annual registered cases of overdose-related death in Oslo
`were 121 (range 115–134) in 1998–2001 [13]. This
`constitutes approximately a third of overdose fatalities in
`Norway [14]. Opioid overdose was the main cause of
`death in these cases.
`
`There is no single law regulating the treatment of drug
`abusers in Norway. The treatment and rehabilitation of
`drug abusers is a responsibility of the individual counties,
`and has predominantly been based on principles of
`voluntary, drug-free rehabilitation. According to section
`31 of the Social Services Act, drug abusers have been
`given help mainly by ‘means of advice, guidance and
`practical assistance’. Assistance and treatment outside
`institutions must be proved to be insufficient before the
`drug abuser can be offered rehabilitation in a suitable
`institution. Compulsory treatment only includes preg-
`nant drug abusers and drug abusers whose life and health
`could be proved to be in continuous danger.
`
`Entry criteria
`The present study includes prospectively all episodes of
`suspected acute opioid overdose treated with naloxone
`out-of-hospital during the period 1 February 1998 to 31
`January 1999. Opioid overdose was diagnosed on site by
`the ambulance personnel based on clinical observation
`(e.g. miosis, respiratory insufficiency, unconsciousness),
`the observation of user equipment on site and by
`information from bystanders. No blood analysis was
`available for toxicological screening to confirm or refute
`the presumed overdose agents.
`
`Treatment procedures, collection of data and evaluation
`procedure
`Paramedics in Oslo have 2 years of training followed by a
`final certification examination. They are specially trained
`in treating suspected opioid overdose with respiratory
`assistance and naloxone. A routine treatment regimen
`established by the EMS senior physician was followed
`during the study period: An initial dose of naloxone 0.4–
`0.8 mg was given intramuscularly, depending on body size,
`combined with an intravenous dose of 0.4 mg naloxone. If
`the patient did not respond satisfactorily, the intravenous
`dose could be repeated up to a maximum of 1.6 mg or a
`total dose of 2.4 mg naloxone. The paramedics should
`observe the patient until he/she was found to be alert
`with adequate respiration and pulse rate and capable of
`standing. The patient was taken to hospital for observa-
`tion or further treatment if he/she was still intoxicated or
`otherwise ill after treatment. There was no system for the
`long-term follow-up of patients in the present study.
`Paramedics reported on overdose agent(s), patient’s sex
`and age, symptoms of overdose, date and hour of
`administering naloxone, the dose and route given, and
`events observed until the patient left or was left by the
`paramedics. A specially designed reporting chart was
`
`used, including some predefined events: severe head-
`ache, confusion/restlessness, aggressiveness, tachycardia
`and seizures. Patient charts were collected daily by the
`authors. Serious events were those that resulted in death,
`were life-threatening or required hospital admission. All
`other events were defined as non-serious. According to
`observations reported by paramedics, each overdose
`episode was classified according to severity in the
`following way: Severe poisoning: life-threatening compli-
`cations or cyanosis, e.g.
`respiratory arrest or severe
`cyanosis. Moderate poisoning: moderate respiratory de-
`pression, but without
`life-threatening complications.
`Mild poisoning:
`somnolence, confusion and miosis.
`All episodes were included in the study if naloxone
`treatment was given.
`
`Results
`During the study period 2172 emergency calls for the
`ambulance service to patients with suspected overdoses
`were received in the EMS. The criteria for out-of-hospital
`naloxone treatment was fulfilled in 1192 of these(55%).
`The mean age was 32 years (range 17–88). Men (mean
`age 33 years, range 17–56) were involved in 945 (79%) of
`the episodes. Women had a mean age of 30 years (range
`18–88). Most patients were in their twenties (27%) or
`thirties (51%). In 183 episodes (15%) patients were
`referred to outpatient clinics or hospitals after treatment.
`In 43 of these episodes (23%) the patient did not respond
`satisfactorily on naloxone treatment. Others were taken
`care of because they had problems unrelated to naloxone
`treatment, e.g. fall
`injuries observed before naloxone
`treatment. The agents causing overdoses are listed, as
`reported by the paramedics (Table 1). Women were more
`frequently overdosed with heroin in combination with
`drugs than in combination with alcohol (P = 0.001),
`whereas men were more frequently overdosed with
`heroin in combination with alcohol than in combination
`with drugs (P < 0.0001). Eighty-seven per cent of all
`episodes were classified as severe poisoning. Mild or
`moderate poisoning was significantly more frequent in
`women than in men (19 versus 11%, P = 0.0003), as
`shown in Table 2. The total naloxone dose given for
`severe poisoning varied from 0.2 to 2.8 mg (mean 1.2 mg);
`for moderate poisoning from 0.4 to 1.6 mg (mean 0.8 mg)
`and for mild poisoning from 0.4 to 1.2 mg (mean 0.6 mg).
`
`Table 1. Assumed overdose agents in the 1192 episodes as
`reported by paramedics.
`
`Overdose agents
`
`Heroin
`Heroin + alcohol
`Heroin + drugs
`Heroin + drugs + alcohol
`Others, e.g. amphetamine and ecstacy,
`benzodiazepines or unknown toxic agents
`
`Men
`N = 945
`(%)
`
`482 (51)
`221 (23)
`150 (16)
`57 (6)
`35 (4)
`
`Women
`N = 247
`(%)
`
`134 (54)
`29 (12)
`56 (23)
`13 (5)
`15 (6)
`
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`

`Adverse events after naloxone treatment Buajordet et al. 21
`
`Table 2. Episodes of poisoning treated in the out-of-hospital setting and events in relation to the seriousness of poisoning.
`
`Serious poisonings
`n = 1036
`(%)
`
`Moderate or mild poisonings
`n = 156
`(%)
`
`Number of episodes according to sex:
`Men
`Women
`Number of episodes with events (%)
`Total number of events
`
`837 (89)
`199 (81)
`503 (49)
`683 (94)
`
`108 (11)
`48 (19)
`35 (22)
`42 (6)
`
`All
`N = 1192
`
`945
`247
`538 (45)
`726
`
`Table 3. Events reported after naloxone treatment.
`
`Events
`
`Confusiona
`Headachea
`Nausea/vomitinga
`Aggressivenessa
`Tachycardiaa
`Shivering
`Seizuresa
`Sweating
`Tremor
`Miscellaneous
`
`No. of events (%)
`n = 726
`
`235 (32)
`157 (22)
`66 (9)
`62 (8)
`47 (6)
`33 (5)
`27 (4)
`24 (3)
`9 (1)
`66 (9)
`
`aPredefined events noted in the reporting charts used by the paramedics.
`
`reported adverse
`
`Frequency and characteristics of
`events
`Most patients were observed by ambulance personnel for
`only a short time after recovery. The observation time
`was, however, recorded in only 104 of the episodes (9%;
`mean observation time was 8 min with a range of
`1–30 min).
`
`Adverse events were reported in 538 of the 1192 episodes
`(45%), presenting a total of 726 events. Adverse events
`were significantly more often seen in cases of severe
`poisoning than in episodes with mild to moderate
`poisoning (49 versus 22%, P < 0.00006; Table 2).
`
`Table 3 lists the most frequent adverse events, of
`which confusion/restlessness and headache dominated.
`Other events were aggressiveness, gastrointestinal com-
`plaints, tachycardia (range 80–180 beats per minute),
`shivering, seizures, sweating and tremor. These features
`were independent of whether the toxic agent(s) were
`heroin only or heroin in combination with other drugs or
`alcohol, and whether the poisoning was severe or not.
`Most events were considered to be non-serious, but were
`experienced as unpleasant for the patient. The episodes
`of tachycardia and seizures may be characterized as high-
`risk clinical conditions. Adverse events led to hospitaliza-
`tion in three episodes (0.3%), and they were therefore
`considered serious. These were one episode of confusion,
`headache and vision disorder, one episode of nausea and
`vomiting and one episode of confusion, tremor and
`‘feeling bad’.
`
`Discussion
`The present study was designed to investigate the safety
`of treating heroin overdoses in an out-of-hospital setting
`without further hospitalization. The paramedics based
`the recording of adverse events on observations of
`patients’ complaints immediately after recovering from
`an opioid overdose. Others have earlier reported that data
`collected by ambulance personnel on non-fatal overdoses
`are an underutilized source of information [6].
`
`The frequency of adverse events in the present study was
`higher
`than previously reported [4,7,11,12]. To our
`knowledge, only Yealy et al. [4] have systematically
`investigated the adverse events of naloxone treatment
`based on observations by paramedics on site, describing
`only six adverse events in the 813 patients studied. Their
`data were based on reviewing the charts of all patients
`who received out-of-hospital treatment with naloxone.
`The much higher frequency seen in our study is probably
`related to our method of prospectively observing the
`patients by using a reporting chart with a predefined list
`of expected events. The reporting of events is considered
`more complete when the patients are interviewed
`according to predefined lists of possible events, than
`when relying on spontaneous reporting [15,16].
`
`Another reason for the high frequency of events seen in
`our study may be related to the rapid injection of
`naloxone, which is assumed to be necessary to avoid
`problems with patients resisting treatment when regain-
`ing consciousness. An unknown number of the adverse
`events may be related to the speed of the naloxone
`injection. A slower titration of naloxone according to the
`patient’s needs might have led to fewer and less
`pronounced adverse events [12].
`
`Osterwalder [11] suggested that complications can be
`reduced by using artificial respiration with a bag valve
`device as well as by administering naloxone in minimal
`divided doses, injected slowly. It could be argued that it
`would be safer to bring the unconscious patient to
`hospital intubated and with controlled ventilation or with
`ongoing bag–mask ventilation, than treating them outside
`hospital and leaving them without
`further contact.
`Ongoing bag–mask ventilation or
`intubation under
`
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`

`22 European Journal of Emergency Medicine 2004, Vol 11 No 1
`
`unstable conditions outside hospital is always a threat to a
`patient’s airways and oxygenation. As there is no legal way
`to keep a patient in hospital after recovery, it would not
`be safer to transport a patient to hospital before treating
`them. Leaving the treated patient together with a
`specialized team or friends and relatives outside the
`hospital seems a much safer procedure.
`
`The events reported were mainly classified as non-
`serious, which is in agreement with observations by Yearly
`et al. [4]. However, serious events were observed in 0.3%
`of the episodes in addition to some events of high-risk
`clinical conditions such as tachycardia and seizures.
`Osterwalder [11], who studied naloxone treatment in
`overdosed patients after hospital admission, reported a
`frequency of 1.3% of severe adverse effects such as
`asystole, convulsions, pulmonary oedema and violent
`behaviour. These were all observed within 10 min after
`naloxone administration. He did not report on non-
`serious events, and therefore a comparison with our study
`is not possible.
`
`In our study the majority of patients were severely cyanotic
`and hypoxic before the naloxone treatment. This may
`explain the high frequency of severe headache and seizures
`reported. The mechanisms by which naloxone may induce
`seizures is uncertain. Mariani et al. [17] reported experi-
`mental studies that gave evidence of a receptor-indepen-
`dent g-aminobutyric acid antagonism as the most likely
`mechanism. Seizures may therefore be a symptom of the
`opioid withdrawal syndrome. However, seizures are also
`well-known complications after severe cerebral hypoxia, as
`might have been the case in comatose patients. Other
`events are probably related to opioid withdrawal effects,
`which are characterized by agitation, nausea, vomiting,
`diarrhoea, piloerection, yawning, lacrimation and rhinor-
`rhea, mild shivering and restlessness. Opioid abstinence
`may also be characterized by sweating,
`light tremor,
`cardiovascular symptoms and signs, muscle pain, bone
`pain, sleep disorders, abdominal pain and seizures.
`
`Extreme agitation and combative behaviour have also
`been reported after administering naloxone [18,19].
`According to Gaddis and Watson [19] the mechanisms
`involved may be related to the physical discomfort of
`withdrawal, the confusion of awakening in an unexpected
`setting, anger at losing the altered mental status ‘high’,
`the effects of other concomitantly ingested medications
`no longer opposed by narcotics, underlying personality
`disorders or other causes. Osterwalder [11] suggested
`that violent behaviour might be explained as an acute
`withdrawal syndrome. Cuss et al. [20] suggested that
`naloxone antagonizes opioid suppression of the sym-
`pathomimetic system, resulting in a sudden increase in
`its activity, which may be the mechanism for
`the
`occurrence of tachycardia.
`
`The most important limitation of the present study was
`the short time of observing the patients. The effect of
`naloxone is expected within one minute after intravenous
`administration and within 5–10 min after intramuscular
`administration. Accordingly, most adverse events should
`occur within few minutes after naloxone administration.
`This is also demonstrated in the study by Osterwalder
`[11], in which no further complications were observed
`after a 10 min period following naloxone administration.
`We therefore assume that most events were captured
`within the reported observation time. Watson et al. [21]
`suggested that the frequency of relapse of opioid toxicity
`is approximately 20–45% after the initial response to
`naloxone, most frequently with long-acting opioids, but
`also occurring with short-acting opioids such as heroin. To
`capture cases of reintoxication, Osterwalder [12] con-
`cluded that patients should be monitored for a period of
`at least 8 h, far longer than in our study. We may thus have
`lost cases with relapse of heroin intoxication.
`
`The police investigate all sudden unexpected deaths
`outside hospital, therefore all overdoses that result in
`deaths are investigated. Previous contact with the
`ambulance service a short time before the patient dies
`will be discovered and investigated. We have not received
`any information that relapses are a problem. All overdose
`patients are registered in a patient database archive at the
`dispatch centre, and relapses in which the patient was
`unconscious would be discovered. We do from time to
`time see the same patient with a new overdose as a result
`of the injection of a new heroine dose, but this is not a
`major problem.
`
`Another limitation in our study is that data concerning
`overdose agents were based on observations and informa-
`tion from bystanders or patients. It could be argued that
`ambulance personnel cannot trust information about the
`intoxication given by the patient or lay individuals. The
`drug abuser milieu in Oslo is well known to ambulance
`service personnel. The ambulance service has organized
`courses in basic life support for drug addicts for some
`years. Drug addicts know that they are treated with
`respect and that all
`information on drugs is kept
`confidential. Therefore we have no reason to believe
`that they do not cooperate or give false information about
`their intoxication. It is also well known that drug addicts
`usually combine opioids with other central nervous
`system depressants, particularly benzodiazepines or
`stimulants such as amphetamines [9,22–25], and exact
`information in each case is not to be expected at the time
`of antidote administration.
`
`Media focus in Norway is still strongly directed towards
`the fact that the number of overdoses resulting in death
`has not been reduced on a nationwide basis, and towards
`the lack of better life-saving measures for the individual.
`
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`

`More use of compulsory treatment is debated [14] as the
`legal framework very much prohibits the use of treatment
`and rehabilitation against the patient’s will. New and
`debated methods
`such as low-threshold methadone
`distribution and public injection rooms are being used
`and tested. The nationwide number of clients receiving
`substitution treatment has increased dramatically. In
`spite of the large number of overdose-related deaths, it
`has been difficult to allocate resources for new applicants
`for treatment, particularly in Oslo.
`
`Conclusion
`A high incidence (45%) of adverse events was reported
`during out-of-hospital naloxone administration. It is likely
`that the observed events mainly represented opioid
`withdrawal effects caused by naloxone. They could also
`be related to hypoxia and to the extensive use of heroin in
`combination with other agents. Most events were non-
`serious. Events such as tachycardia and seizures could
`represent high-risk conditions and should initiate the
`follow-up of patients. The present practice of treating
`acute opioid overdose out-of-hospital seems to save
`several lives a year. However, the risk of relapse should
`be studied further.
`
`Acknowledgements
`The authors would like to thank the ambulance
`personnel in the Oslo area, and Trond Boye Hansen in
`particular, for excellent recording of data during the study
`period. They would also like to thank their financial
`contributor: the Research Council of Norway.
`
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`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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