Journal of Toxicology: Clinical Toxicology
`
`ISSN: 0731-3810 (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ictx19
`
`Naloxone–For Intoxications with Intravenous
`Heroin and Heroin Mixtures-Harmless or
`Hazardous? A Prospective Clinical Study
`
`Joseph J. Osterwalder
`
`To cite this article: Joseph J. Osterwalder (1996) Naloxone–For Intoxications with Intravenous
`Heroin and Heroin Mixtures-Harmless or Hazardous? A Prospective Clinical Study, Journal of
`Toxicology: Clinical Toxicology, 34:4, 409-416, DOI: 10.3109/15563659609013811
`To link to this article: https://doi.org/10.3109/15563659609013811
`
`Published online: 25 Sep 2008.
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`Clinical Toxicology, 34(4), 409-416 (1996)
`
`Naloxone-For Intoxications with
`Intravenous Heroin and Heroin Mixtures-
`Harmless or Hazardous? A Prospective
`Clinical Study
`
`Joseph J. Osterwalder, MD, MPH
`
`Department of Emergency Medicine and Surgery, Kantonsspital,
`St. Gallen, Sw'tzerland
`
`ABSTRACT
`
`Backaround: Naloxone is standard medication for the treatment of heroin
`intoxications. No large-scale studies have yet been carried out to determine its
`toxicity in heroin intoxications. M e t h d : We have undertaken an investigation as
`to the frequency, type and &pee of seventy of complications attributable to
`naloxone administration. Subjects treated between 1991 and I993 with naloxone
`for intravenous drug intoxications were prospectively evaluated. Main Outcome
`Measurements: Development of ventricular tachycardia or fibrillation; atrial
`fibrillation; asystok; pulmonary edema; convulrions; vomiting; and vioknt
`behavior within ten minutes afrer parenteral administration of naloxone. Results:
`Six of 453 intoxicated subjects (I. 3 4% ; 95 4% confidence interval 0.4 4% -3 4%) suflered
`severe adverse elprects within ten minutes after naloxone administration (one
`asystole; three generalized convulsions; one pulmonary edema; and one violent
`behavior). @er the ten minute period, no further complications were observed.
`Conclusions: 7he short time between naloxone administration and the occurrence
`of complications, as well as the type of complications, are strong evidence of a
`In IOIO clinically diagnosed intoxications with heroin or heroin
`causal link.
`mixtures, @om 4 to 30 sm'ous complications can be expected. Such a high
`incidence of complications is unacceptable and could theoretically be reduced by
`artijkial respiration with a bag valve device (hyperventilation) as well as by
`administering pzloxone in minimal divided doses, injected slowly.
`
`Correspondence: Dr. Joseph Osterwalder, Leitender Arzt ZNF, Kantonsspital, 9007 St. Gallen, Switzerland. Tel: 41/71-
`494-1111; Fax: 41/71494-2870.
`
`Copyright cD 1996 by Marcel Dekker, Inc.
`
`409
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`410
`
`INTRODUCTION
`
`Naloxone, a pure, semisynthetic opioid antagonist,
`is today one of the standard emergency medications,
`promptly alleviating coma and respiratory depression
`caused by overdoses of heroin or other opioid
`agonists. The first published report on naloxone
`appeared in 1961. Thereafter, it was described as a
`safe drug, based on the fact that pharmacologic
`studies with high doses, in the absence of opioids,
`
`had revealed no essential pharmacologic changes. '
`
`reports have appeared
`Since 1974, however,
`repeatedly in the anesthesiology literature, describing
`isolated cases of severe cardiovascular complications,
`thus questioning the unequivocal safety of naloxone.2
`Similar observations were reported in the 1980s,
`following treatment of subjects with opioid intoxi-
`cations. A Medline search disclosed six reports in a
`total of only seven patient^,^-^ as well as one retro-
`spective case series, describing five com lications
`following 8 13 treatments with naloxone.'
`These
`complications consisted of atrial fibrillation and
`ventricular arrhythmias, pulmonary edema, convul-
`sions, vomiting, violent behavior as well as
`hypotonia and hypertonia. Furthermore, naloxone
`was reported to potentiate the effects of
`The reason for this surprisingly small number of
`reported complications attributed to naloxone may be
`that these adverse effects are difficult to differentiate
`from those due to opioid overdoses or cocaine. In
`most cases any complications are probably attributed
`to the effects of the intoxication itself.
`A treatment mode that may lead to life-threatening
`complications is contrary to current tenets of medical
`practice and requires a critical examination. Most
`overdoses involve young healthy people with a
`favorable prognosis for spontaneous recovery with-
`out medical treatment. Nevertheless, here as well,
`appropriate investigations are lacking. The pre-
`vailing uncertainty is reflected in two different
`treatment recommendations: 1) administer 0.04 mg
`IV, to be repeated at 1-2 min intervals until the
`
`desired effect has been attained; '' 2) administer 0.4
`
`mg IV, to be repeated at 2-3 min intervals until the
`desired effects have been attained.12 There is a
`tenfold difference of the two doses.
`Several fundamental questions, concerning the
`treatment with naloxone for intoxications with
`opioids or opioid mixtures, remain unanswered:
`
`Osterwalder
`
`life-threatening
`
`the potentially
`1) What are
`complications of opioid poisoning?
`2) What are the therapeutic effects of naloxone?
`3) Does naloxone have any toxic effects?
`4) Are there drug interactions between naloxone
`and opioids?
`5 ) Has naloxone the potential for causing life-
`threatening complications? If the answer is yes, how
`often?
`6) Are these complications caused by an intrinsic
`property of naloxone or by an acute withdrawal
`reaction?
`7) What is the safest administration route and
`dosage regimen?
`We undertook a prospective investigation of the
`frequency, type, severity and magnitude of compli-
`cations encountered with IV opioid intoxication and
`subsequent naloxone treatment. We limited our
`study to intoxications with heroin or heroin mixtures
`because they are the most common opioid intoxi-
`cation seen in our Emergency Department (ED)
`(Table 1). Furthermore, we theorize the mechanism
`of complications and their prevention. We did not
`try to answer questions 2 and 4.
`
`METHODS
`
`Setting
`The Canton Hospital St. Gallen is a 900-bed
`municipal hospital, serving 150,000 people as the
`sole primary care institution, and serving a further
`800,000 people as a general hospital. All emergency
`cases are admitted into an interdisciplinary emer-
`gency unit.
`Patients and Procedures
`From January 1, 1991 until December 31, 1992,
`all emergency cases admitted for acute intoxications
`with heroin or heroin mixtures were prospectively
`included in our study. Moreover, we also investi-
`gated the occurrence of delayed comFlications. The
`indications for opioid antagonism were: 1) a
`Glasgow Coma Scale (GCS) score C 14; 2) hypo-
`tension; and 3) clinically significant hypoventilation
`after a trial with mechanical ventilation.
`Inclusion
`criteria were GCS score C 14; respiratory rate <
`12/min; and improvement of consciousness and
`respiration after naloxone administration;
`new
`injection sites on the body as well as obligatory
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`Naloxone
`
`Table 1
`Substances Used by Drug Addicts
`(538 visits to the ED)
`
`Substance
`
`Single
`(96)
`
`Combinations Total
`(%I
`(%I
`
`Heroin IV
`
`Cocaine IV
`
`Others
`No data
`
`357
`(66.4%)
`4
`(0.7%)
`-
`-
`
`127’
`(23.6%)
`39t
`(7.3%)
`6*
`(1.1%)
`-
`
`484
`(90%)
`43
`(8%)
`6
`(1.1%)
`5
`(0.9%)
`
`*Alcohol, benzodiazepine, cannabis, methadone.
`tHeroin IV. *Methadone IV with cannabis, LSD,
`alcohol.
`
`confirmation of the clinical observations based on the
`patient’s own or an external source’s patient history.
`We chose the GCS score because it is reproducible,
`simply applied,
`and also accepted
`for
`the
`classification
`of
`nontraumatic
`disorders
`of
`consciousness.
`Excluded were patients who
`recovered spontaneously (after mechanical ven-
`tilation) without requiring naloxone administration.
`Since the presence of an opioid or other drugs is not
`definitive evidence of clouding of consciousness or
`respiratory depression, and for logistic reasons,
`toxicochemical screening tests were carried out only
`in serious or doubtful conditions.
`Measurements
`We collected the following demographic and
`clinical data: date; time of admission; time of
`discharge; age; sex; number of intoxications in the
`current year; substances involved (questioning the
`patients); discharge modality (ambulatory; hospi-
`talized;
`intensive care); medication and dosage
`regimen (naloxone and flumazenil); development of
`ventricular
`tachycardia or
`fibrillation;
`atrial
`fibrillation; asystole, pulmonary edema; convulsions;
`vomiting; and violent behavior following administra-
`tion of naloxone. Naloxone doses or divided dose
`intervals were not stipulated.
`Further details
`
`411
`
`concerning the patients could be ascertained from the
`respective patient histories. Autopsy protocols are
`available for all deaths.
`Statistical Analysis
`Calculations were made by means of the SystaP
`version 5, 1992. The complication rate for naloxone
`was defined as the number of patients who had
`developed cardiovascular arrest, pulmonary edema,
`convulsions, vomiting, or violent behavior within 10
`min after naloxone administration relative to the
`number of
`intoxications treated with naloxone
`parenterally. In our experience, a 10 min interval is
`essential because we give an IV injection slowly;
`therefore, a dose of 0.4 mg of naloxone reaches
`effective blood levels only after 5-10 min, thus
`delaying its action.
`To calculate the incidence rate, we projected the
`number of complications to loo0 intoxications and
`expressed the results as an absolute 95% confidence
`interval.
`
`RESULTS
`Patients and Clinical Course
`Four hundred and eighty-five patients visited the
`Emergency Department 538 times (92 women; 393
`men) with acute IV drug intoxications. Several
`patients visited the ED on more than one occasion.
`The median age was 24 years old (range 15-47
`years old), of whom 67% reported to have taken
`heroin alone, and 31 % heroin combined with other
`substances (Table 1).
`Forty-six complications occurred, before or after
`treatment, in 30 patients (5.6%), i.e., 1.5 complica-
`tions per patient (Table 2). Seven men and one
`woman died (1.5%): five due to cardiocirculatory
`arrest, two due to pneumonia, and one due to
`pulmonary edema.
`Treatment Procedures (Table 3)
`No treatment with naloxone was required for 85
`remaining 453
`intoxicated
`subjects.
`In
`the
`intoxicated subjects, naloxone was given IV 51
`times, IM 49 times, and IV plus IM 350 times. No
`information is available for three patients. The
`median IV dose was 0.2 mg of naloxone (range 0.1
`mg-2.8 mg); the median IM dose was 0.2 mg (range
`0.1 mg-0.9 mg).
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`412
`
`~ TY Pe
`
`Table 2
`Complications (30 patients)
`
`No. of Complications
`
`~
`
`Cardiocirculatory arrest
`Delayed onset of consciousness
`and normal respiration
`Pulmonary edema
`Aspiration
`H yperthermia
`Generalized seizures
`Rhabdom yo1 ysis
`Pneumonia
`Hypoglycemia
`Hypothermia
`Total
`
`9
`
`8
`8
`5
`4
`3
`3
`2
`2
`2
`46
`
`Table 3
`Pharmaologic Treatment (538 Interventions)
`
`~~
`
`Drug
`
`No. of Interventions
`
`%I
`
`None*
`Naloxone
`Naloxone and flumazenil?
`Flumazenil
`Unknown
`Total
`
`69
`414
`39
`1
`15
`538
`
`12.8%
`77.0%
`7.2%
`0.2%
`2.8%
`100.0%
`
`*Patients with a GCS score of 2 13 and respiratory
`frequency of 2 12 min after mechanical respiration
`with a bag valve device did not receive naloxone.
`?Flumazenil was administered if additional benzo-
`diazepine intoxication was suspected.
`
`Complications
`Six patients out of 453 treated with naloxone
`(1.3%; 95% confidence interval 0.4%-3%), devel-
`oped severe complications within 5 min after a
`parenteral injection. Three patients had severe
`disorders before naloxone administration in addition
`to their intoxication (Table 4). Despite response to
`
`Osterwalder
`
`treatment (except Case 1) their conditions rapidly
`deteriorated further. After this time period, no
`further complications were encountered. Full details
`are shown in Table 4 and the following case reports.
`
`Case Reports
`Case 1
`This 21-year-old man was admitted with a GCS
`score of 3. The patient’s carotid pulse was easily
`palpable, regular and fast. His respiration rate was
`< 12; arterial blood gas analysis (ABGA): PaOz
`49.5 mm Hg, SaO, 54.9%; PaCO, 106.6 mm Hg,
`(pH 6.95). An IV injection of 0.4 mg naloxone was
`administered, followed by an asystole (registered on
`the ECG monitor) within seconds. After mechanical
`resuscitation, intubation, and suction of stomach
`contents, administration of 1.8 mg of epinephrine
`and 1 mg of atropine, spontaneous circulation was
`restored. The patient awoke with a blood pressure
`of 100/65 and a pulse rate of 68/min. He required
`sedation.
`Laboratory values were as follows: Hgb 127g/L
`(normal 140-180 g/L); Wbc 14.6 x 109/L (normal 4-
`10 x 109/L); platelets 229 x 109/L (normal 150-300
`x 109/L); Na 140 mmol/L (normal 130-145
`mmol/L); K 5.1 mmol/L (normal 3.4-4.8 mmol/L);
`C1 93 mmol/L (normal 95-107 mmol/L); phosphate
`4.1 mmol/L (normal 0.8-1.5 mmol/L); creatinine
`186 pmol/L (normal 30-120 pmolll); CK 49,200
`U/L (normal 25-170 U/L); CK-MB 1,151 U/L
`(normal < 8% CK); glucose 10.1 mmol/L (normal
`3-6 mmol/L); E M I P test of serum for opioids,
`cocaine, and cannabis: positive; morphine blood
`levels 0.2 mg/L; ECG ST elevation in leads V3-V6
`as well as in all terminal limb leads. Chest X ray
`and CT scan of the head were both normal. Patient
`was discharged in full remission after 4 days.
`Case 2
`This man, 31 years of age, was vomiting on
`admission in the ED. He had a GCS score of 5;
`blood pressure 150/90 mm Hg; pulse 120 bpm and
`respiratory rate 4/min. After an unknown dose of
`naloxone IV, the patient woke up in a state of
`aggressive psychomotor agitation. His respiration
`was normal. Within 2-3 min, respiratory embar-
`rassment returned. The patient was intubated. Chest
`X ray showed right superior lobe infiltrates.
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`Naloxone
`
`413
`
`Table 4
`Cbmplications ajler Naloxone Adminktration
`
`Intoxication
`
`Naloxone Survival Status Pre-naloxone
`mg
`
`heroin/cocaine/
`cannabis*
`
`0.4
`
`Yes
`
`Case Events
`
`Sex
`
`1
`
`asystole
`
`2
`
`3
`
`4
`
`5
`
`violent
`behavior
`pulmonary
`edema
`
`generalized
`convulsion
`generalized
`convulsion
`
`M
`
`M
`
`M
`
`M
`
`M
`
`Age
`Y
`
`2 1
`
`3 1
`
`3 1
`
`19
`
`3 1
`
`heroin*
`
`heroin/
`flunitrazepam *
`
`heroin/
`flu nit razepam *
`heroidalcohol*
`
`?
`
`0.2
`
`1
`
`0.8
`
`0.3
`
`Yes
`
`Yes
`
`Yes
`
`no
`
`Yes
`
`6
`
`M
`
`generalized
`convulsion
`*Proved toxicochemically .
`
`3 1
`
`heroin
`
`rhabdom yo1 y sis
`CK 49,200 mmol/L
`K 5.1 mmol/L
`aspiration
`Graves' disease
`
`hypothermia 30" C
`K 6.0 mmol/L
`glucose 27.9 mmol/L
`rhabdomyolysis, mild
`suicidal attempt
`
`asystole in ED; hypoxemic
`encephalopath y ;
`hyperthennia 40°C
`epilepsy
`
`His laboratory values included the following apart
`from positive EMIT serum test for opioids and
`thyroid-stimulating hormone (TSH) 0.01 mU/L
`(normal 0.25-0.4 mU/L), TSH-receptor-antibody 21
`U/L (normal C 9 U/L). No other abnormal labora-
`tory values were identified. The patient was
`discharged in good condition after 10 days.
`Case 3
`The patient, a 31-year-old man, was admitted with
`a GCS score of 3. His blood pressure was 1 17/64
`mm Hg and pulse rate 84 bpm. The rectal tempera-
`ture was 29.8"C. Hypoventilation (respiratory rate
`not available) showed the following PaO, 56.2 mm
`Hg, Sa02 69.946, PaC02 66.2 mm Hg, pH 7.05.
`Following administration of naloxone 0.2 mg IV, the
`patient awoke but respiratory depression returned
`after 5 min (blood gas post naloxone: PaO, 5 1.7 mm
`Hg, Sa02 67.1 %, PaCO, 51.7 mm Hg, pH 7.124).
`His chest X ray showed pulmonary edema.
`
`The laboratory values were as follows: blood
`profile normal; Na 137 mmol/L (normal 130-145
`mmol/L); K 6.0 mmol/L (normal 3.4-4.8 mmol/L);
`phosphate 2.1 mmol/L (normal 0.8-1.5 mmol/L);
`creatinine 135 pmol/L (normal 30-120 pmol/L); CK
`1977 mmol/L (normal 25-170 mmol/L); glucose 27.9
`mmol/L (normal 3-6.5 mmol/L); serum EMIT for
`opioids was positive. After three days, the patient
`was discharged in good condition.
`Case 4
`This man, 19 years of age, presumably attempted
`suicide with an IV injection of 6 mg of flunitrazepam
`and 0.5 g heroin. He was comatose when admitted
`to the ED several hours later. His GCS score was 3;
`blood pressure 118154 mm Hg, pulse rate 106/min;
`hypoventilation was present but the respiratory rate
`is unknown. After administration of a total dose of
`0.8 mg naloxone IV and 0.2 mg naloxode IM, his
`respiration improved, followed immediately, how-
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`414
`
`ever, by a generalized convulsion lasting 10 min,
`ending finally after an injection of 2 mg of
`clonazepam, and recurring only when reacting to
`pain stimulation. The patient was transferred to the
`Intensive Care Unit because of repeated hypoventi-
`lation. The laboratory values were normal. Free
`morphine serum levels were 0.2 mg/L and total
`morphine levels were 1.1 mg/L. The ratio of free to
`bound morphine indicates a massive consumption
`several hours earlier, or a recent new drug intake.
`This may be the reason the patient responded only to
`a higher dose of naloxone. The patient was
`discharged the following day in good condition. An
`electroencephalogram a week later was normal.
`Case 5
`This man, 31 years of age, was admitted in
`cardiocirculatory arrest (asystole on the monitor).
`His pupils were fixed and dilated. After 15 min of
`cardiopulmonary resuscitation and advanced cardiac
`life support his spontaneous circulation was restored.
`He was intubated and given both epinephrine 0.8 mg
`IV and naloxone 0.8 mg IV. His blood pressure was
`restored to 80/40 mm Hg and his pulse rate was 130
`beatdmin. Generalized convulsions developed about
`3 min after the last naloxone injection. Status
`epilepticus could only be controlled after adminis-
`tration of diazepam, clonazepam, and phenytoin.
`The laboratory values were as follows: Hgb 13 1 g/L
`(normal 140-18OglL); Wbc 19.4 x 109/L (normal 4-
`10 x 109/L); platelets 310 x 109/L (normal 150-300
`x lO'/L); whole blood: total morphine 0.14 mg/L;
`ethanol 3.03 % . The patient died two days later due
`to hypoxemic encephalopath y .
`Case 6
`This patient, 31 years of age, an epileptic, was
`admitted to the ED with GCS score 3, blood
`pressure 156181, pulse rate 147 beats/min, and
`hypoventilation (respiratory rate not available). His
`blood gas analysis revealed a PaO, 34 mm Hg; SaOZ
`40.7%; PaC0, 60.5 mm Hg; pH 7.09.
`After an administration of naloxone, 0.1 mg IV
`and 0.2 mg IM, the patient awoke immediately, but
`4 min later had a generalized epileptic seizure. This
`stopped spontaneously after 1 min. No laboratory
`studies were done. Several hours later, the patient
`left the hospital at his request. No follow-up was
`possible.
`
`Osterwalder
`
`DISCUSSION
`
`' Caution is articularly recom-ended
`
`In six of 453 patients treated with naloxone,
`severe, even life-threatening reactions occurred
`(1.3%; 95% confidence interval 0.4%-3%). Assump-
`tion of the drug's complete safety is therefore not
`justified. 193-5*1
`In our series, asystole
`in connection with cocaine!
`occurred in a patient intoxicated with a heroin and
`cocaine mixture.
`In a sample of 1,OOO subjects,
`clinically diagnosed as intoxicated with heroin or
`heroin mixtures, treated with naloxone, 4-30 compli-
`cations can be expected.
`Contrary to our experience, the authors of the
`only case series currently published do not consider
`the empirical treatment with naloxone dangerous.'
`In their study of 853 patients with blurred conscious-
`ness treated with naloxone, five incidents (0.6%)
`occurred: one case of generalized convulsions; two
`cases of vomiting; and one serious incident each of
`hypotonia and hypertonia. However, the reports of
`only 60 patients clearly indicated opioid intoxica-
`tions. The actual complication rate, therefore,may
`be markedly higher, i.e., closer to 8.3% (5160) than
`0.6%. These considerations cast serious doubts on
`the reliability of published statistics. They certainly
`do not prove the harmlessness of naloxone.
`As a result of our study, the question arises
`whether the complications we encountered were
`actually caused by the naloxone treatment itself. It
`is well-known that most investigative (even prospec-
`tive)
`studies are
`fraught with methodologic
`difficulties concerning
`the adverse effects of
`medications. Thus, the short interval between drug
`administration and onset of complications is no
`definitive causative proof. Other factors may play a
`role, and many signs incriminate the intoxication
`itself. Pulmonary edema and arrhythmias are well-
`known adverse effects of heroin and cocaine.'*'3
`Epileptic seizures and dangerously aggressive
`behavior, however, are reported only after cocaine
`consumption. The effects of other drugs and
`substances must also be considered along with some
`underlying
`diseases
`(i.e.,
`hyperthyroidism,
`hypoxemic encephalopathy, etc.) that were present in
`five of our six patients. An exact diagnosis would
`have required a repeat intoxication and treatment
`with naloxone, to which procedure we could not
`expose our patients for ethical reasons.
`
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`Naloxone
`
`the causal
`We support our statement on
`relationship between the encountered complications
`and naloxone administration with knowledge of the
`pathophysiologic processes. Models simulating
`pathophysiologic processes have demonstrated the
`following: naloxone liberates centrally, at the locus
`coeruleus , epinephrine secretions blocked by
`opioids. l4 Consequently, massive secretions of
`epinephrine flood the circulation, overstimulating the
`sympathetic nervous system. This may result in
`ventricular fibrillation or asystole.
`Similar to
`neurogenic pulmonary edema,
`the
`release of
`catecholamines in the presence of pulmonovenous
`hypertonia as well as increased vascular permeability
`In cases of
`may lead to pulmonary edema.”
`generalized convulsions, a receptor-independent y-
`amino-butyric acid antagonism may play a role;16 an
`acute withdrawal syndrome is another plausible
`explanation. These pathophysiologic considerations
`are strong evidence for an acute withdrawal
`syndrome and speak against a direct intrinsic effect
`of naloxone.
`Our observation of epileptic seizures occurring in
`Cases 4, 5, and 6, supports our contention. So far,
`no reports have been published of epileptic seizures
`following either heroin alone or after an abrupt
`withdrawal. A sudden antagonistic treatment is,
`however, capable of provoking such an effect
`according to the manufacturer’s drug monograph. l2
`None of these patients received flumazenil or any
`other medication with proconvulsant properties.
`Neither could cocaine (a well-known epileptogenic)
`be identified in any of these patients. Furthermore,
`abrupt antagonism may also cause cardiac arrest
`(Case 1) and pulmonary edema (Case 3), according
`to the company’s drug monograph.12
`It is also
`known
`that
`naloxone
`can
`potentiate
`the
`cardiovascular side effects of cocaine. lo
`The
`development of violent behavior (Case 2) is not
`mentioned in the company’s drug rnonographl2 but
`might be explained as an acute withdrawal
`syndrome. Our studies and the reports in the
`literature support the following conclusions:
`1) Naloxone can cause an acute withdrawal
`syndrome.
`2) We were the first to report that doses of
`naloxone far below 0.8 mg can induce a dramatic
`withdrawal syndrome. We therefore assume that
`not only a high dose but also the speed of the
`
`415
`
`triggers
`
`the abrupt withdrawal
`
`administration
`reaction.
`3) Since withdrawal complications occur in more
`than 1 %I of naloxone treatments, caution against the
`indiscriminate use and high doses of naloxone is
`recommended. We believe it desirable that other
`medical centers consider this potential risk.
`4) Consequently, our naloxone dose is much
`lower than the one recommended by the pharma-
`ceutical company. It is implausible that a larger IV
`dose of naloxone, injected rapidly, would prevent the
`reactions we encountered since in all cases, except in
`Case 1, the antagonistic effect occurred before a
`It is pathophysiologically
`deterioration set in.
`unlikely that aggressive antagonistic treatment could
`have prevented the asystole in Case 1.
`Since we carried out toxicochemical analyses in
`exceptional cases only, doubt could be cast on our
`diagnoses made solely on the basis of clinical
`criteria. Strictly speaking, ours are mere assump-
`tions concerning self-inflicted intoxications with
`heroin or heroin mixtures.
`Identification of an
`opioid provides no definitive proof. The presence of
`a substance does not establish it as the cause of
`disturbed consciousness or a respiratory depression.
`Only extrapolation of quanitative results defining
`exact time of an injection can demonstrate a link
`between the injected drug dose and the onset of
`intoxication. Intoxicated drug addicts are rarely able
`to remember reliably the exact time of past events.
`A possible bias in this connection would most likely
`have led us to underestimate the complication rate.
`On the other hand, a higher
`incidence of
`complications would more strongly support a link
`with naloxone.
`What do these results mean to the ED physician?
`First of all, naloxone may cause life-threatening
`complications in over 1 % of heroin-overdosed
`subjects. This high complication rate has to be
`reduced. Naloxone must therefore be administered
`with great caution. Several measures can be taken.
`Animal experiments have shown that normal or
`hypocapnic dogs, pretreated with fentanyl and
`enflurane, had significantly lower pulse rates, lower
`blood pressures, and lower catecholamine serum
`levels when subsequently treated with naloxone. l7
`It is therefore advisable to hyperventilate patients
`with a bag valve device for 2-5 min before initiating
`treatment with an opioid antagonist.
`
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`

`

`Osterwalder
`
`416
`
`This method is safe and often obviates the need
`for naloxone as reported by Swiss investigators in a
`study of more than 1 ,OOO patients. l8
`As long as the question of the dosage for naloxone
`is still unresolved, naloxone should be administered
`slowly, at the lowest effective divided doses. A one-
`dose administration of 0.4 mg-2 mg as recommended
`by the manufacturer is not advisable. Theoretically,
`to prevent an abrupt withdrawal syndrome, naloxone
`0.4 mg (1 mL) should be diluted in 9 mL NaCl and
`injected IV in milliliter doses, at 30-60 sec intervals,
`until respiration and consciousness have become
`normal. In our experience, this dosage regimen has
`proved satisfactory in over 100 patients.
`In view of the serious complications associated
`with naloxone, new agents should be studied.
`Although physostigmine antagonizes the respiratory
`depression and coma due to opioid intoxications, its
`short duration of action, side effects and narrow
`therapeutic spectrum preclude its replacement of
`naloxone. l9 Whether nalmefene, a new opioid
`antagonist, with an ideally long half-life, has a
`similar complication potential as naloxone, has yet to
`be determined.*'
`
`ACKNOWLEDGEMENTS
`
`6.
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`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`My sincere thanks to the Institute of Forensic Medicine
`for their support in providing their data, and to the
`physicians in the Department of Emergency Medicine and
`Surgery for their collaboration in completing the study
`protocols.
`
`15.
`
`16.
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