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Diamorphine

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names/Trade names
   1.6 Manufacturers/Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICOCHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelflife of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscles
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. TREATMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Treatment discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATIONS
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWERS, DATES, ADRESSES
    DIAMORPHINE

    International Programme on Chemical Safety
    Poisons Information Monograph 261
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Diamorphine

        1.2  Group

             Nervous system (N) / Analgesics opioids
             (N02) / Natural opium alkaloids (N02AA).

        1.3  Synonyms

             Acetomorphine; Acetomorfine;
             Aspron; Diacephin;
             Diacetylmorfin; 3-6 Diacetylmorphine;
             Diacetylmorphine; Diamorfina;
             Diaphorm; Diasetielmorfien;
             Diasetilmorfin; Diasetylmorfiimi;
             Diazetylmorphine;
             ;7,8-Dihydro-4,5-a-epoxy-17-methylmorphinan-3,6-a-diol acetate;
             Eroina; Heroiin; Heroïne;
             Herolan; Ieroin; Iroini;
             Morphacetin; Morphine diacetate;
             Amsterdam Marble; Black tar;
             Boy; Brown Sugar (strychnine + heroin);
             China white (also used for fentanyl);
             Crap; Dava; Dooje; Dujie;
             Edorion; H; Hairy;
             Harry; Horse; Indian Pink;
             Joy powder; Junk; 
             Malaysian Pink; Mexican brown;
             Mexican Tar; Noise; 
             Penang Pink; Persian; 
             Persian brown; Preza; 
             Rufus; Scot; Smack;
             Snow; Speedball (heroin + cocaine);
             Stuff; TNT; White junk;
             White Stuff

        1.4  Identification numbers

             1.4.1  CAS number

                    561-27-3 (heroin base)

             1.4.2  Other numbers

                    CAS: 1502-95-0 (heroin hydrochloride)
                    NIOSH: QC 8050000
                    ATC: N02AA09

                    (Sax, 1984; Clarke, 1986; Lewis, 1990)

        1.5  Brand names/Trade names

             Heroïne(R)
             Diagesil (U.K.)

        1.6  Manufacturers/Importers

             Medicinal diamorphine: Bayer; Berk (U.K.)

    2.  SUMMARY

        2.1  Main risks and target organs

             -  Respiratory depression: sudden respiratory arrest
             -  CNS depression: impaired consciousness
             -  Risk of psychological or/and physical dependence

        2.2  Summary of clinical effects

             Desired effects
             Addicts use the drug for the excitement, euphoria, sensation
             of wellbeing and alteration of mood that it produces. The
             rapid onset of these effects with an IV bolus is called a
             "flash" or "rush".
    
             Overdosage
             The characteristic syndrome consists of:
             -  respiratory depression, reduced respiratory rate,
                cyanosis;
             -  impaired consciousness, sedation and coma;
             -  miosis with pinpoint pupils.
             This triad can be accompanied by:
             bradycardia, hypertension, cardiovacular collapse; evidence
             of intravenous injection (needle tracks).
    
             Complications of overdosage
             Inhalation pneumonia
             Acute pulmonary oedema
             Hypothermia
             Rhabdomyolysis.
    
             Late complications
             These include bacterial sepsis and a high risk of viral
             hepatitis and HIV contamination.
             Withdrawal syndrome in dependent addicts. 

        2.3  Diagnosis

             -  The triad of respiratory depression, cyanosis,
                impaired consciousness (stupor, coma) and pinpoint pupils
                is very suggestive of opioid overdosage.
             -  Urine screening for opioids.
             -  Rapid improvement in clinical state (increase in
                respiratory rate, return in consciousness) with the
                administration of naloxone is strongly in favour of a
                diagnosis of opioid intoxication.
             -  Chest X-ray, arterial blood gases and biological tests as
                indicated.

        2.4  First aid measures and management principles

             -  Maintain the airway and oxygenation, treat
                respiratory depression.
             -  Assisted ventilation.
             -  Administration of the specific antagonist naloxone.

    3.  PHYSICOCHEMICAL PROPERTIES

        3.1  Origin of the substance

        3.2  Chemical structure

             Chemical name: 
             morphinan-3,6-diol,7,8-didehydro-4,5-epoxy-17-methyl
             (5a-6a)-, diacetate (ester) 
             (Index Nominum, 1990)
    
             Molecular formula: C21 H23 N O5
             Molecular weight: 369.4
             (Sax, 1984; Clarke, 1986; Budavari, 1989)

        3.3  Physical properties

             3.3.1  Colour

                    White (pure heroin)
    
                    11 different colours have been reported for illegal
                    heroin
                    (Chaudron-Thozet et coll., 1990).

             3.3.2  State/Form

                    Solid-crystals
                    Solid-powder

             3.3.3  Description

        3.4  Other characteristics

             3.4.1  Shelflife of the substance

             3.4.2  Storage conditions

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

                    Heroin behaves as a pro-drug of morphine, but
                    shows certain pharmacokinetic and clinical differences
                    (Lacomblez & Puech, 1987). In the brain, heroin
                    undergoes deacetylation to 6-monoacetylmorphine
                    (6-MAM) and morphine.
                    Diamorphine hydrochloride is used as an analgesic: it
                    is a more potent analgesic than morphine but has a
                    shorter duration of action.
                    In those countries where diamorphine is used
                    therapeutically it is indicated for treating chronic
                    pain in terminal illness, the acute pain of myocardial
                    infarction and in obstetric epidural anaesthesia
                    (Reynolds, 1989; Smith et al. 1991).

        4.2  Therapeutic dosage

             4.2.1  Adults

                    Diamorphine hydrochloride is used in doses of 5
                    to 10 mg orally, intramuscularly, subcutaneously or
                    intravenously, repeated four hourly (Reynolds, 1989;
                    Clarke, 1986).
                    Addicts may tolerate up to 200 mg a day (Baselt &
                    Cravey, 1989).
                    5 mg diamorphine given epidurally for Caesarean
                    section was equivalent to 2 mg phenoperidine
                    (Reynolds, 1989).

             4.2.2  Children

                    Oral dose: 0.6 mg/kg/day
                    Intravenous: 0.01 mg/kg/hour

        4.3  Contraindications

             Respiratory depression.
             Substantial risk of addiction with continued use.

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Used therapeutically (Reynolds, 1989). Oral and
             sublingual resorption is sufficient to cause poisoning
             (Duberstein & Myland Kaufman, 1971; Ellenhorn & Barceloux,
             1988).

        5.2  Inhalation

             Absorption after sniffing the powder ("snorting") is
             sufficient to cause poisoning. Heroin vapor can also be
             inhaled ("chasing the dragon") (Duberstein & Myland Kaufman,
             1971; Ellenhorn & Barceloux, 1988).

        5.3  Dermal

             Diamorphine is not absorbed through the intact skin.

        5.4  Eye

             No data available.

        5.5  Parenteral

             Subcutaneous, intramuscular, intravenous and intrathecal
             routes are used therapeutically (Reynolds, 1989). Addicts
             most commonly use the intravenous route.

        5.6  Other

             Absorption is possible by the rectal route (Ellenhorn &
             Barceloux, 1988).

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    Addicts use the drug for the excitement,
                    euphoria, sensation of wellbeing and alteration of
                    mood that it produces. The rapid onset of these
                    effects with an intravenous bolus is called a "flash"
                    or "rush".
                    The acute toxic effects are an accentuation of the
                    pharmacodynamic effects.
    
                    Chronic effects:
                    -  respiratory. Acute pulmonary oedema may be due to a
                       direct toxic effect (Conti et al., 1990), as may be
                       acute bronchospasm (Del Los Santos-Sastre et al.,
                       1986; Oliver, 1986).

                    -  rhabdomyolysis. A direct effect has been suggested
                       (D'Agostino & Ernest, 1979; Conti et al., 1990).
                       The commonly accepted explanation is that it is due
                       to compression of muscle during prolonged coma
                       aggravated by hypoxia, acidosis and hypovolemia
                       (Pearce & Cox, 1980; Ellenhorn & Barceloux,
                       1988).
                    -  renal (Vassals & Pezzano, 1987; Uzan et al., 1988).
                       Renal damage may progress to terminal renal
                       insufficiency (Cunningham et al., 1980). Genetic
                       factors (African Carribean), and impurities in the
                       heroin (direct toxicity, or immunogenicity) have
                       been suggested as causes (Cunningham et al., 1980).
                       There is no experimental evidence concerning the
                       effects of repeated injection of unsterile heroin
                       on renal function. In humans, such injections
                       generally introduce a variety of antigens, and can
                       lead to circulating immune complexes (Uzan et al.,
                       1988).
                    -  cutaneous. The effects may be systemic or local.
                       They may depend on adulterants, bacterial
                       contamination or direct effects of heroin (Louria
                       et al., 1967; Ellenhorn & Barceloux, 1988).
                    -  immunological. Heroin addiction leads to reduced
                       resistance to cutaneous and respiratory infections
                       (Ellenhorn & Barceloux, 1988). Immune deficiency
                       observed in humans and animals is supported by
                       experiments in rats which show reduction in
                       lymphocyte proliferation, spontaneous cytolytic
                       activity, phagocytosis, and interferon production
                       during chronic morphine administration (Hamon,
                       1991). Naloxone and naltrexone reverse these
                       effects, perhaps by a central action.
                    -  splenomegaly due to antigenic stimulation has been
                       described (Vassals & Pezzano, 1987).

             7.1.2  Pharmacodynamics

                    Effects of diamorphine are very similar to
                    those of morphine. They vary according to the dose,
                    the route of administration and the tolerance of the
                    subject. Diamorphine behaves as a highly lipophilic
                    transporter of morphine and induces more rapid and
                    more intense CNS effects (Lacomblez & Puech, 1987).
                    However heroin and 6-acetylmorphine (6-MAM) have lower
                    affinities than morphine for brain opioids receptors
                    (Ellenhorn & Barceloux, 1988).
                    The absorption of diamorphine is one and a half times
                    better than that of morphine, and it is two and a half
                    times more potent, and 200 times more soluble. The
                    onset and duration of action are shorter and it causes
                    less nausea and vomiting but more sedation (Mondzac,
                    1984). 3 mg of diamorphine by intramuscular,

                    intravenous or subcutaneous injection have the same
                    analgesic effect as 10 mg of morphine intravenously or
                    60 mg orally (Ellenhorn & Barceloux, 1988).
    
                    The main CNS and gastrointestinal effects are due to
                    an agonist action at opioid mu receptors, and to a
                    lesser extent at opioid delta and kappa receptors.
    
                    -  at CNS receptors (spinal and supra spinal mu
                       receptors) (Lacomblez & Puech, 1987; Goodman &
                       Gilman, 1990):
                    -  analgesia without alteration of consciousness,
                       somnolence, dysphoria, and respiratory depression
                       are manifest as a reduction in respiratory rate and
                       reduced sensitivity of respiratory centres to CO2.
                       Effects on the area postrema cause nausea and
                       vomiting. Repeated doses lead to tolerance and
                       physical dependence. Morphine and 6-MAM are
                       responsible for the pharmacological effects of
                       diamorphine,
                    -  dysphoria occurs, with excitation, euphoria, a
                       feeling of wellbeing and alteration of mood (more
                       obvious after an intravenous bolus),
                    -  addiction is manifest as: tolerance, physical and
                       psychological dependence which is more marked with
                       heroin than with morphine
    
                    By the intrathecal route the analgesia is very
                    localised because diamorphine binds rapidly to nerve
                    tissue (Lacomblez & Puech, 1987).
    
                    -  on the autonomic nervous system (mu and kappa
                       receptors) heroin leads to pinpoint pupils and
                       peripheral vasodilation.
    
                    -  cardiovascular effects include venodilation,
                       reduced peripheral resistance (partly due to
                       histamine release), inhibition of baroreceptor
                       reflexes, and diminished vasoconstrictor response
                       to an increase in PaCO2.These effects cause a fall
                       in arterial blood pressure.
    
                    -  gastro-intestinal effects (mu and delta receptors):
                       there are variable effects on gastric secretion,
                       reduction on gastric motility, worsening of
                       oesophageal reflux. Gastric emptying may be delayed
                       as much as 12 hours. Biliary, pancreatic and
                       intestinal secretions are diminished. Tone in the
                       sphincter of Oddi, and biliary tract pressure are
                       increased, as are intraluminal pressures in small
                       and large bowel. A reduction in duodenum, small

                       bowel and colonic motility leads to nausea,
                       vomiting and constipation (Goodman & Gilman,
                       1990).
    
                    -  urinary tract effects include increased tone and
                       amplitude of contraction (Goodman & Gilman,
                       1990).
                    -  effects on the skin: cutaneous vasodilation
                       probably as a result of histamine liberation which
                       may also cause pruritus, sweating and urticaria
                       (Goodman & Gilman, 1990).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             The toxic and lethal doses depend
                             greatly on the individual's tolerance to the
                             drug, thus the usual dose for an addict may
                             be dangerous for the same addict after
                             several days of abstinence because of the
                             rapid diminution in tolerance.
                             A dose of 20 mg diamorphine may be lethal in
                             non tolerant subjects, whilst addicts may
                             tolerate doses ten times larger. Fatalities
                             have been observed after a dose of 10 mg
                             (Clarke, 1986).
                             Plasma concentration of morphine after lethal
                             overdosage of diamorphine have been in the
                             range 0.01 to 0.09 mg/l (Garriot, 1973,
                             quoted by Kintz et al., 1989).

                    7.2.1.2  Children

                             Diamorphine crosses the placenta and
                             is found in breast milk. Neonatal respiratory
                             depression can occur in babies born to
                             mothers addicted to heroin; it can be treated
                             with naloxone. Manifestations of withdrawal
                             in new-born infants can last for several
                             weeks. Some observed effects in the neonates
                             may be secondary to aspects of addictive
                             behaviour rather than to direct effects of
                             the drug.

             7.2.2  Relevant animal data

                    In the mouse:
                    - LD50 subcutaneous: 261,6 mg/kg
                    - LD50 intravenous: 21,8 mg/kg

                    In the dog:
                    - LDLo subcutaneous: 25 mg/kg
                    In the guinea pig:
                    - LDLo subcutaneous: 400 mg/kg
                    In the cat:
                    - LDLo oral: 20 mg/kg
                    In the rabbit:
                    - LDLo subcutaneous: 150 mg/kg
                    - LDLo intravenous: 9 mg/kg
    
                    (Sax, 1984; Budavari, 1989)

             7.2.3  Relevant in vitro data

                    No data available.

        7.3  Carcinogenicity

             Cancers are commoner in drug addicts, perhaps because of
             immunological disorders (Falek et al., 1991).

        7.4  Teratogenicity

             In the animal:
             CNS malformations were observed in 12 hamsters (Schardein,
             1985). Birth weight was reduced in rabbits, without evidence
             of malformation (Schardein, 1985; Briggs et al., 1986).
    
             In humans:
             A large study of approximately 500 births failed to show any
             increase in malformation rate (Schardein, 1985). Taking
             heroin during pregnancy has not been associated with any
             congenital malformation, and no characteristic group of
             malformations exists (Heinonen et al., 1982; Briggs et al.,
             1986; Shepard, 1989; Hutchings, 1991).

        7.5  Mutagenicity

             Cases of mutation have been reported (Lewis, 1990). One
             study found chromosomal aberration in a group of 16 children
             born to mothers who were heroin addicts (Schardein, 1985). In
             one case the chromosomal damage was linked to a malformation
             (Briggs et al., 1986).
             Heroin addicts have an increase in chromosomal damage with
             sister chromatid exchange and reduced DNA repair (Falek et
             al., 1991).

        7.6  Interactions

             Synergistic interactions with CNS depressants (Ellenhorn
             & Barceloux, 1988).

        7.7  Main adverse effects

             Respiratory depression
             Pruritus
             Nausea and vomiting
             Constipation

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Acute poisoning has been described after
                    ingestion (Conti et al., 1990). Acute poisoning may
                    occur in "body-packers" after leakage of
                    packaging.
                    The characteristic clinical presentation comprises
                    impaired consciousness, depressed respiration
                    (decrease rate of respiration leading to cyanosis) and
                    miosis with pinpoint pupils. Coma may be due to
                    cerebral hypoxia. Neurological signs are symmetrical;
                    focal neurological signs suggest a vascular traumatic
                    or infectious cause and may require cranial CT
                    scan.

             9.1.2  Inhalation

                    Acute poisoning has been described after
                    sniffing heroin ("chasing the dragon") (Duberstein &
                    Myland Kaufman, 1971; Conti et al., 1990).

             9.1.3  Skin exposure

                    Not relevant.

             9.1.4  Eye contact

                    Not relevant.

             9.1.5  Parenteral exposure

                    The intravenous route is the preferred route in
                    the addict.
                    Acute poisoning has also been reported after
                    subcutaneous administration (Conti et al., 1990).
                    Acute intoxication can occur after more concentrated
                    heroin than usual, injection of a large dose (usual
                    for tolerant users) in a non addict or after several
                    days of abstinence (tolerance is rapidly lost) (Louria
                    et al., 1967).

                    The characteristic clinical presentation comprises
                    impaired consciousness, depressed respiration
                    (decrease rate of respiration leading to cyanosis) and
                    miosis with pinpoint pupils. Coma may be due to
                    cerebral hypoxia. Neurological signs are symetrical;
                    focal neurological signs suggest a vascular traumatic
                    or infectious cause and may require cranial CT scan.
                    Presence of puncture tracks is suggestive of
                    intravenous drug abuse.
                    Other symptoms include:
                    aspiration pneumonia, haemodynamic disturbances
                    (bradycardia, hypotension and vasovagal collapse),
                    hypothermia, rhabdomyolysis, noncardiac pulmonary
                    oedema, convulsions (due to impurities).

             9.1.6  Other

                    Clinical effects can be due to heroin itself
                    but also to bacterial contamination, impurities or
                    substances used to "cut" the drug.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Dependence has been described.

             9.2.2  Inhalation

                    Dependence has been described. Spongiform
                    leuco-encephalitis may occur (Wolters et al., 1982;
                    Sempere et al., 1991).

             9.2.3  Skin exposure

                    Not relevant.

             9.2.4  Eye contact

                    Not relevant.

             9.2.5  Parenteral exposure

                    The primary risks of chronic intoxication are
                    physical and psychological dependence, systemic
                    complications due to heroin, adulterants and multiple
                    drug abuse, and infectious complications, particularly
                    AIDS and hepatitis B and C.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             If treatment is rapidly instituted, the outcome is
             generally good (Conti et al., 1990; Larpin et al., 1990).
             Complications occur in about a quarter of cases (Larpin et
             al., 1990); these include:
             -  aspiration pneumonia which may be severe,
             -  haemodynamic disturbances (bradycardia, hypotension and
                vasovagal collapse), hypothermia,
             -  rhabdomyolysis (either from prolonged coma or a direct
                effect of heroin),
             -  non cardiac pulmonary oedema,
             -  convulsions (due to impurities).
             Death can result from prolonged apnoea, hypersensitivity
             reaction (to heroin or an adulterant such as quinine),
             complication of overdose itself or to drug addiction.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Arterial hypotension and collapse are
                    characteristic features of heroin overdose.
                    Complications of overdose include:
                    Cardiac arrest is secondary to anoxia, respiratory
                    arrest or secondary to hyperkalemia (Ellenhorn &
                    Barceloux, 1988). ECG disturbances may be seen,
                    usually as a result of quinine mixed with the heroin,
                    or other cardiotoxic drugs, or hyperkalemia (Ellenhorn
                    & Barceloux, 1988; Goldfrank & Bresnitz, 1990). They
                    can include bradycardia, tachycardia, atrial
                    fibrillation, QT segment prolongation, widening of the
                    QRS complex, and peaked T-waves (Pearce & Cox,
                    1980).
    
                    Complications of intravenous drug addiction:
                    injection of infected material can cause cardiac or
                    vascular damage, including infective endocarditis,
                    whether or not there are preexisting valvular lesions,
                    cerebral or pulmonary embolism, mycotic aneurysm.
                    Bacterial endocarditis can be complicated by septic
                    emboli (Louria et al., 1967). Tricuspid valve damage
                    with or without other valvular involvement is common
                    and leads to septic pulmonary emboli (Louria et al.,
                    1967; Ellenhorn & Barceloux, 1988).

             9.4.2  Respiratory

                    Respiratory depression (reduced respiratory
                    rate, apnoea, cyanosis) is one of the characteristic
                    features of heroin overdosage, with CNS depression and
                    miosis.
    

                    Complications of overdosage:
                    The lungs are the commonest site of complications, 21%
                    in a series reported by Louria et al. (1967):
                    -  respiratory arrest
                    -  inhalation pneumonia in 30% of cases (Duberstein &
                       Myland Kaufman, 1971)
                    -  acute pulmonary oedema (Sauder et al., 1983; Conti
                       et al. 1990), occurred in 48% of a series of 149
                       (Duberstein & Myland Kaufman, 1971). It is manifest
                       as hypoxemia, increased CO2, acidosis, and
                       pulmonary hypertension. And it can be associated
                       with anoxia, cardiac arrhythmia (atrial
                       fibrillation), functional respiratory impairment
                       and lung damage. Pneumonia or death occur in a
                       third of cases. The diffusing capacity for CO may
                       remain low for up to 3 months (Conti et al.,
                       1990).
                    The pulmonary oedema is non cardiogenic (Conti et al.,
                    1990). Several mechanisms have been proposed:
                    -  arterial hypoxia (although hypoxia due to other
                       poisons does not usually cause pulmonary
                       oedema).
                    -  individual hypersensitivity to heroin or to the
                       adulterants (although pulmonary oedema has been
                       described after the first dose of pharmaceutically
                       pure diamorphine). Anaphylactoid reactions may be
                       relevant (Goodman & Gilman, 1990).
                    -  similarity with altitude sickness (hypoxia,
                       increased capillary permeability and oedema, and a
                       vicious circle of hypoxia and oedema).
                    -  direct effect of the drug (Conti et al., 1990).
    
                    Complications of intravenous drug abuse:
                    pulmonary abcess, atelectasis, multiple infiltrates
                    with abcess formation due to tricuspid endocarditis
                    (Louria et al., 1967; Ellenhorn & Barceloux, 1988).
                    Opportunist infection affecting the lungs can occur in
                    AIDS patients.
    
                    Chronic effects:
                    Asthma attacks have been reported after inhalation of
                    heroin vapour (Del Los Santos-Sastre et al., 1986;
                    Oliver, 1986), and intravenous injection (Anderson,
                    1986). It is unclear whether it is due to heroin
                    itself, or adulterants. Other features described in
                    literature include: pulmonary arteritis due to cotton
                    wool, pulmonary hypertension and thrombosis from talc,
                    pulmonary granulomatosis and fibrosis, reduced vital
                    capacity and total lung volume (Louria et al., 1967;
                    Duberstein & Myland Kaufman, 1971; Ellenhorn &
                    Barceloux, 1988; Magnan et al., 1990).

             9.4.3  Neurological

                    9.4.3.1  Central nervous system

                             Desired effects:
                             Addicts use the drug for the excitement,
                             euphoria, sensation of wellbeing and
                             alteration of mood that it produces. The
                             rapid onset of these effects with an
                             intravenous bolus is called a "flash" or
                             "rush".
                             
                             Acute effects:
                             CNS depression is one of the characteristic
                             features of heroin overdose, along with
                             respiratory depression and miosis. Impairment
                             of consciousness invariably occurs. The
                             presence of coma ought nonetheless to suggest
                             the concommitent administration of other
                             psychotropics, or severe cerebral anoxia
                             (Baud & Bismuth, 1987).
    
                             Complications of heroin overdose:
                             Convulsions may occur, primarily due to
                             adulterants such as strychnine, cocaine, and
                             dextropropoxyphene (Conti et al., 1990).
                             Infectious complications include: bacterial
                             meningitis, mycotic aneurysm, cerebral,
                             subdural or epidural abcess, ventriculitis.
                             They may be caused by opportunistic infection
                             in patients with AIDS.
    
                             Chronic effects:
                             These include: spongiform leuco-encephalitis
                             (after inhalation) (Wolters et al., 1982;
                             Sempere et al., 1991), myelopathy (Estorc et
                             al., 1982), stroke (Bartolomei et al., 1992),
                             intracranial hypertension, acute toxic
                             confusion, abnormal movements (Ellenhorn &
                             Barceloux, 1988).

                    9.4.3.2  Peripheral nervous system

                             In overdosage, nerve damage from
                             compression (compartment syndrome) is
                             possible.
    
                             Chronic effects:
                             These include: acute polyneuropathy,
                             mono-neuritis multiplex, damage to the
                             brachial or lumbosacral plexus (Ellenhorn &
                             Barceloux, 1988); polyneuropathy may

                             sometimes be caused by adulterants such as
                             lead (Antonini et al., 1989).

                    9.4.3.3  Autonomic nervous system

                             Pinpoint pupils, impairment of
                             consciousness, and cyanosis are the
                             characteristic features of opioid overdose.
                             Moderate arterial hypotension is usually
                             seen. Hypothermia is a result of coma
                             (Durbenstein, 1971).

                    9.4.3.4  Skeletal and smooth muscles

                             Acute effects:
                             Acute rhabdomyolysis with myoglobinuria,
                             increased CK, hyperkalaemia and acute renal
                             failure have been described. It may be
                             worsened by hypoxia, acidosis and hypovolemia
                             (Ellenhorn & Barceloux, 1988; Pearce & Cox,
                             1980).
    
                             Chronic effects:
                             A musculo-skeletal syndrome of unknown
                             aetiology, with paravertebral myalgia,
                             periarthritis, lymphadenopathy and fever has
                             been described after parenteral use of "brown
                             heroin" (Pastan et al., 1977). A chronic
                             myositis appears to be multifactoral (Corcos
                             & Auzepy, 1982).

             9.4.4  Gastrointestinal

                    Acute effects:
                    nausea and vomiting are usual and are the cause of
                    pulmonary aspiration in overdose.
    
                    Chronic effects:
                    nausea, constipation proceeding to functional
                    obstruction. Splenomegaly, bacterial peritonitis,
                    visceral abcesses (Corcos & Auzepy, 1982; Vassals &
                    Pezzano, 1987).

             9.4.5  Hepatic

                    Hepatic damage reflects intravenous drug abuse.
                    Viral antigens are frequently positive (Vassals &
                    Pezzano, 1987).
                    Damage can be biochemical, (elevation of transaminases
                    and bilirubin), histological (e.g. chronic hepatitis,
                    and fibrosis) and clinical (acute hepatic necrosis,
                    liver failure) (Louria et al., 1967; Ellenhorn &
                    Barceloux, 1988).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Acute effects:
                             Oliguria is common (Goodman & Gilman, 1990).
                             Acute renal failure is a consequence of coma
                             and its complications.
    
                             Chronic effects:
                             they include:
                             -  glomerulonephritis of immunological
                                origin,
                             -  chronic glomerulonephritis with segmental,
                                then focal and diffuse,
                                glomerulosclerosis, leading to terminal
                                renal failure in one to four years
                                (Cunningham et al., 1980),
                             -  segmental hyalinosis,
                             -  nephrotic syndrome and renal amyloid,
                             -  glomerulonephritis which may be
                                membranous, proliferative or
                                membrano-proliferative
                             -  Goodpasture syndrome (Uzan et al., 1988;
                                Vassals & Pezzano, 1987).
    
                             Venereal infections are frequently present.
                             Renal abcesses occur with septicaemia.

                    9.4.6.2  Other

                             Pyuria and proteinuria are frequent
                             (Duberstein & Myland Kaufman, 1971).

             9.4.7  Endocrine and reproductive systems

                    Heroin reduces female fertility (Vassals &
                    Pezzano, 1987). Morphine reduces gonadotrophin
                    releasing hormone, and corticotrophin releasing
                    factor, with secondary reduction in levels of LH, FSH,
                    ACTH and beta-endorphin, and a fall in plasma
                    testosterone and cortisol concentrations. Prolactin
                    and ADH concentrations are increased. Tolerance can
                    occur (Goodman & Gilman, 1990).

             9.4.8  Dermatological

                    Dermatological effects can be generalised:
                    pruritus, urticaria, exanthema, or a pigmented or
                    bullous rash; or local and related to the route of
                    administration: injection tracks, cutaneous abcess,
                    folliculitis, cellulitis, lymphangitis, lymphadenitis,
                    hyperpigmentation of veins, thrombophlebitis, venous
                    thrombosis, scars and cutaneous ulcerations.

             9.4.9  Eye, ear, nose, throat: local effects

                    Chronic effects:
                    Nose: sniffing or "snorting" can cause ulceration or
                    perforation of the nasal septum (Ellenhorn &
                    Barceloux, 1988).
    
                    Eye: miosis is a characteristic of opioid overdose
                    along with respiratory and CNS depression.
                    Ocular damage can arise from embolisation of small
                    vessels of the macula by crystalline material used to
                    "cut" (dilute) heroin. This causes macular oedema,
                    venous engorgement, central scotoma, reduced visual
                    accuity and retinal haemorrhage (Ellenhorn &
                    Barceloux, 1988). Chorio-retinitis, and anterior
                    uveitis can cause blindness.

             9.4.10 Haematological

                    A raised haematocrit and lymphocytosis have
                    been described. Leucocytosis reflects the stress of
                    overdose, or is a consequence of infection (Duberstein
                    & Myland Kaufman, 1971).

             9.4.11 Immunological

                    Chronic effects have been described in humans
                    (Corcos & Auzepy, 1982; Ellenhorn & Barceloux, 1988);
                    these include:
                    -  increased gammaglobulins, and immunoglobulins G and
                       M,
                    -  lymphocytosis,
                    -  functional alteration in T lymphocytes (Falek et
                       al., 1991),
                    -  impaired cellular immunity, auto-immune disease,
                       and circulating immune complexes (Uzan et al.,
                       1988).

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Hypoxaemia, and hypercapnia
                             indicate alveolar hypoventilation. It may be
                             severe with a lactic acidosis (Baud &
                             Bismuth, 1987).

                    9.4.12.2 Fluid and electrolyte disturbances

                             They are secondary to
                             rhabdomyolysis: hyperkalemia.

                    9.4.12.3 Others

                             Hypoglycemia has been reported in
                             the context of concommitent alcohol
                             intoxication (Duberstein & Myland Kaufman,
                             1971). Hypothermia is a consequence of coma
                             (Durberstein & Myland Kaufman, 1971).

             9.4.13 Allergic reactions

                    Anaphylactoid reactions are observed after an
                    injection of heroin and implicate allergy in sudden
                    death and pulmonary oedema with heroin (Ellenhorn &
                    Barceloux, 1988; Goodman & Gilman, 1990).
                    Hypersensitivity reactions can be due to the heroin or
                    to adulterants.

             9.4.14 Other clinical effects

                    Infections.
                    Fever may indicate a complication of overdose,
                    particularly aspiration pneumonia, and blood cultures
                    and chest X-ray should be performed.
                    Musculoskeletal complications: osteomyelitis,
                    spondylitis, sacro-ileitis, septic arthritis,
                    arthralgia, and myalgia (Ellenhorn & Barceloux, 1988).
                    The site may be atypical, involving the cervical and
                    lumbosacral cord, the sternum or the sternoclavicular
                    joint.
                    The prevalence of infections is increased due to
                    immunological disorders (Ellenhorn & Barceloux, 1988).
                    AIDS and its complications, septicaemia, tetanus,
                    tuberculosis, malaria, hepatitis, and systemic
                    candidosis are seen (Louria et al., 1967; Vassals &
                    Pezzano, 1987; Ellenhorn & Barceloux, 1988).
    
                    The toxicity of potentially addictive substances like
                    sedatives, alcohol, cocaine, cannabis, amphetamines
                    and, adulterants may modify the clinical picture and
                    alter the course of the poisoning.

             9.4.15 Special risks

                    In the neonate, two complications may require
                    urgent treatment: the withdrawal syndrome, and
                    neonatal respiratory distress (Naeye et al.,
                    1973).
    
                    The use of heroin can reduce female fertility (Vassals
                    & Pezzano, 1987).
                    Heroin use during pregnancy causes a greatly increased
                    frequency of:

                    -  spontaneous abortion (Ellenhorn & Barceloux, 1988)
                    -  intra-uterine growth retardation, low birth weight,
                       which is partly explained by malnutrition in about
                       50% of cases
                    -  prematurity (malnutrition, anemia, infection)
                    -  maternal infection (urinary, placental, chorionic)
                    -  still birth
                    -  increase in neonatal mortality 
                    -  obstetric complications  (premature rupture of the
                       membranes, sepsis, pre-eclampsia, placenta praevia,
                       haemorrhage)
                    -  neonatal infection: AIDS, hepatitis, syphilis
                    (Naeye et al., 1973; Pelosi et al., 1975; Schardein,
                    1985; Briggs et al., 1986; Ellenhorn & Barceloux,
                    1988; Shepard 1989).
    
                    The maturation of the lungs and the liver is by
                    contrast accelerated with a reduced frequency of
                    neonatal jaundice and hyaline membrane disease (Briggs
                    et al., 1986).
    
                    Long term effects on height, weight and behaviour have
                    been described in three to six year old children, but
                    this could be due in part to other factors (Wilson et
                    al., 1979 cited in Hutchings, 1991; Householder et
                    al., 1982).
    
                    Breast feeding:
                    Heroin enters breast milk in a quantity sufficient to
                    cause addiction in the neonate (Yafee, 1978; Briggs et
                    al., 1986; Ellenhorn & Barceloux, 1988).

        9.5  Other

             Withdrawal syndrome:
             Adults: (Ellenhorn & Barceloux, 1988).
             Psychological signs are apparent 6 to 8 hours after the last
             injection, peaking at 36 to 72 hours. They are characterized
             by numerous functional complaints.
             Physical signs:
             -  rhinorrhoea, lachrymation, sweating and yawning, 8 to 12
                hours after the last  injection, increasing in intensity
                over 24 hours,
             -  between 12 to 24 hours: restless sleep, agitation,
                mydriasis, anorexia, irritability, tremor, goose
                pimples,
             -  the intensity of the symptoms is maximum between 36 and 72
                hours: insomnia, irritability, anorexia, intense
                agitation, uncontrollable yawning, sneezing, lachrymation,
                coryza, asthaenia, nausea, vomiting, intestinal cramp,
                diarrhoea, tachycardia and increased blood pressure,
                feeling of hot and cold, sweating, fleeting pain, muscle
                spasm, and involuntary movements coexist and alternate.

                Feature of an acute abdominal emergency may appear.
                Symptoms abate gradually over 5 to 10 days (Corcos &
                Auzepy, 1982).
    
             Neonates (Pelosi et al. ,1975; Briggs et al., 1983; Ellenhorn
             & Barceloux, 1988; Goldfrank & Bresnitz, 1990; Hutchings,
             1991):
             A neonatal withdrawal syndrome may occur in up to 85% of
             cases. Symptoms appear between 48 hours and 6 days after
             birth. They usually peak between 3 to 6 weeks then diminish
             progressively over as long as 6 months. They manifest as
             hyperactivity, tremor, myoclonus, hyperirritability,
             anorexia, poor weight gain, and scratching. Sweating,
             sneezing, mucous secretion, yawning, vomiting, diarrhea and
             hyperthermia may also be present. Convulsions appear in 5% of
             the children, and hypoglycemia, hypocalcemia, hypomagnesemia,
             or hyperthyroidy should be excluded.
             Withdrawal syndrome in the mother during pregnancy can cause
             an increase in fetal catecholamine concentration, an increase
             in fetal movement, a relative oxygen lack, acute fetal
             distress and an increase in interuterine death rate.

        9.6  Summary

    10. TREATMENT

        10.1 General principles

             Rapidly assess vital signs.
             Maintain an airway.
             Assure ventilation (there is a danger of underestimating the
             severity of respiratory depression).
             Administer oxygen by nasal cannulae, face mask, or
             endotracheal tube.
             Ensure intravenous access.
             Infuse isotonic glucose solution.
             Monitor the electrocardiogram.
             Overenthusiastic adminstration of the specific antidote
             naloxone can provoke acute withdrawal, which can complicate
             treatment.
             Careful titration of the dose of antidote administered should
             allow the treatment of respiratory depression (assuring a
             respiratory rate above 14 breaths per minute), without
             provoking acute withdrawal.
             Decontamination if indicated (for example, with
             body-packers).

        10.2 Life supportive procedures and symptomatic/specific treatment

             Standard treatment of opioid overdose is:
             -  artificial ventilation or mask ventilation
             -  use of naloxone

             Failure to regain consciousness requires consideration of
             prolonged cerebral anoxia or poisoning by other psychotropic
             drugs  (Baud & Bismuth, 1987).
    
             Treatment of a complicated opioid overdose may require:
             (Baud & Bismuth, 1987)
             -  infusion of plasma expanders for cardiovascular collapse
                unresponsive to naloxone. Pressor amines may also be used.
                If there is no response then measurement of CVP, and
                pulmonary artery catheterization allow more precise
                haemodynamic treatment. Hyperdynamic circulation and
                increased cardiac output and a fall in peripheral
                resistance and a slight increase in heart rate may appear
                if fluids are given to preserve renal function (Conti et
                al., 1990).
             -  mechanical ventilation with PEEP is the preferred
                treatment of non cardiac pulmonary oedema which usually
                responds rapidly. Ventilation may be stopped after 2 to 4
                days (Conti et al., 1990). It may also be required for
                hypoxaemia.
             -  diazepam is used to control convulsions.
             -  other measures may be required to treat inhalation
                pneumonia, rhabdomyolysis, hyperthermia.
    
             Treatment of withdrawal syndrome:
             In adults:
             -  substitution is possible with dextropropoxyphene,
                buprenorphine or methadone
             -  analgesics (paracetamol)
             -  antispasmodics
             -  sedatives: e.g. benzodiazepines
             The withdrawal syndrome after long use may require medical,
             psychological and social treatment. Substitution is preferred
             to drug withdrawal during pregnancy (Ellenhorn & Barceloux,
             1988, Goodman & Gilman, 1990).
    
             Acute withdrawal in the neonate can be treated with dilute
             morphine solution (Paregoric elixir- 400 micrograms morphine
             per milliliter), 0.2 mL every 3 to 4 hours as needed to
             relieve symptoms without causing sedation. If there is no
             response, the dose can be increased in steps of 0.1 mL (0.04
             mg morphine) (Goldfrank & Bresnitz, 1990).
             Diazepam, chlorpromazine, and phenobarbitone may be required
             as sedatives for several days or weeks.

        10.3 Decontamination

             If there is a suspicion that the patient is a body
             packer, then the following are required:
             rectal (and vaginal) examination, plain abdominal X-ray erect
             and supine, and examination of the colon with water soluble
             contrast medium, sigmoidoscopy, enema and stool examination
             for several days (Karhunen, 1987; Marc et al., 1989).
    

             Decontamination is only necessary in body packers. Packets in
             the stomach cannot be removed by gastric lavage. Ipecac can
             be used if the patient is fully conscious and ingestion is
             recent. Apomorphine should be avoided (Baud & Bismuth, 1987).
             Close monitoring is required because of the high risk of
             rupture of the packets.
    
             Foreign objects in the gastrointestinal tract may require
             sorbitol or mannitol administration with stool examination
             (PEG 4000 can be used ). Surgery is indicated for mechanical
             obstruction and if packets rupture (Marc et al.,
             1989).

        10.4 Elimination

             Haemodialysis, haemoperfusion and peritoneal dialysis
             are not recommended (Ellenhorn & Barceloux, 1988).

        10.5 Antidote treatment

             10.5.1 Adults

                    Naloxone is a specific antagonist. It can be
                    administered by intravenous bolus, intravenous
                    infusion, or intramuscular routes. Adverse effects and
                    problems include:
                    -  a short duration of action (10 to 45 minutes)
                    compared with that of opioids; symptoms of
                    poisoning can reappear after the initial injection,
                    with consequent risk of respiratory depression and
                    apnoea, necessitating maintainance treatment.
                    -  an acute withdrawal syndrome may appear a few
                       minutes after the injection, peaking at 30 minutes
                       (Goodman & Gilman, 1990).
                    -  there is a risk of rebound sympathetic activity,
                       with acute pulmonary oedema and cardiac arrhythmia
                       (Baud & Bismuth, 1987; Ellenhorn & Barceloux, 1988;
                       Goodman & Gilman, 1990).
    
                    1) Slow administration of an initial intravenous dose
                       of 0.4 to 2 mg, titrated until the respiratory rate
                       is above 14 breaths per minutes, but sedation is
                       maintained œ this avoids acute withdrawal effects.
                       If the initial dose has no effect, it can be
                       repeated after 2 or 3 minutes (Ellenhorn &
                       Barceloux, 1988; Goodman & Gilman, 1990).
    
                    2) Maintenance treatment, needed because of the short
                       duration of action of naloxone, is given by
                       infusing 1.6 to 2.4 mg naloxone in isotonic (5%)
                       glucose solution, or by syringe pump, at a rate
                       sufficient to maintain the respiratory rate above
                       14 breaths per minute (usually 0.4 to 0.8 mg per

                       hour) (Ellenhorn & Barceloux, 1988). If artificial
                       ventilation is required because of respiratory
                       insufficiency or pulmonary oedema, then naloxone
                       should be stopped (Baud & Bismuth, 1987).

             10.5.2 Children

                    The initial dose in children is 0.01 to 0.03
                    mg per kg, followed by a dose of 0.1 mg per kilogram
                    if there is no response (Ellenhorn & Barceloux, 1988;
                    Goodman & Gilman, 1990). Infusion should be at a rate
                    of 0.03 mg per kg per hour.

        10.6 Treatment discussion

             Haemodialysis, haemoperfusion and peritoneal dialysis
             are not recommended (Ellenhorn & Barceloux, 1988).

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Werner A (1969) described a near-fatal hyperacute
             reaction to intravenously administered heroin:
             The patient, a 23 year-old man, was found unconscious and
             deeply cyanosed, lying over the steering wheel of his car,
             shortly after leaving a service station where he had just
             taken some heroin intravenously. On examination the patient
             was hypotonic, apnoeic, and pulseless, and heart sounds could
             not be heard above the traffic noise. There were miotic
             pupils; the breath did not smell of alcohol. Mouth-to-mouth
             resuscitation and cardiac massage were started, without any
             spontanous respiration after 3 minutes. After 5 minutes,
             cyanosis began to improve, a regular pulse at 140 per minute
             was felt, and a few irregular movements of the chest wall
             were seen.
             An emergency ambulance arrived after 10 minutes, the patient
             was given oxygen and the cyanosis disappeared. By the time
             the ambulance reached hospital, the patient was breathing
             spontaneously and had a strong, regular pulse rate of 120
             beats per minute. The pupils remained miotic and the lungs
             were clear. About 25 minutes after the episode begun, the man
             was awake, sitting up, had normal vital signs, and was
             responding to questions. At no time were there excess
             respiratory secretions, urticaria, or other physical signs of
             allergic response. The patient denied being a regular user
             and said he had taken the same amount before without
             difficulty.
    
             Popper et al. (1989) described a case of possible iatrogenic
             complications arising from the routine administration of
             opiate antagonists:

             A 35-year old woman was the belted driver in a head-on
             collision. She was immobilised on a back-board in the
             ambulance and was in a somewhat confused lethargic state on
             arrival at hospital. She had a forehead laceration, but it
             was unclear whether she had transiently lost consciousness.
             Blood pressure was 150/80 mm Hg, pulse 110/minute, and
             respiratory rate 12/minute. She was uncooperative. Needle
             track marks were noted in both antecubital fossae, and 2 mg
             naloxone was given intravenously. Within 3 minutes the
             patient became very agitated and combative, requiring
             physical restraint. It was difficult to maintain venous
             access and radiography was impossible. A total of 4 mg
             morphine sulphate and 2.5 mg droperidol was given
             intravenously without subsequent change in her agitation. A
             further 5 mg of droperidol also failed to have an effect.
             After 47 minutes the patient's state continued to hinder
             diagnostic evaluation and it was felt that her agitation
             could aggravate injuries she may have sustained. She was
             therefore intubated and ventilated following the
             administration of pancuronium (20 mg). It was then possible
             to examine the head, cervical spine, and abdomen by computed
             tomography (CT). CT scans, radiographs, arterial blood gases,
             haematocrit, serum electrolytes, and urinalysis were normal.
             Toxicological analysis revealed the presence of large
             quantities of opiates and cocaine. Her family later confirmed
             that she had used large amounts of heroin shortly before the
             accident. It is likely that the administration of naloxone
             either precipitated acute opiate withdrawal or allowed the
             effects of another drug to predominate.

    12. ADDITIONAL INFORMATIONS

        12.1 Specific preventive measures

             Those caring for drug addicts should take precautions
             against HIV and hepatitis (B and C) and should avoid all
             contact with blood or with contaminated needles.

        12.2 Other

             No data

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    14. AUTHOR(S), REVIEWERS, DATES, ADRESSES

        Author: Docteur Philippe Saviuc
        Toxicologie Clinique et Centre Anti-Poisons (Docteur V Danel)
        Service de Medecine Interne et Toxicologie (Pr JL Debru)
        Centre Hospitalier Universitaire. B.P. 217
        38043 Grenoble Cedex 09. France
        Tel. 33 4 76 76 56 46
        Fax 33 4 76 76 56 70
    
        Date: September, 1993
    
        Peer review:   C Alonzo, V Danel, J de Kom, R Ferner, A Furtado
                       Rahde, P Hodgson, Z Kolacinski, P Myrenfors
                       Cardiff, U.K.
    
        Date:          February, 1994
    
        Translation:   R Ferner, MO Rambourg Schepens
                       London, March, 1998
    
        Editor:        M.Ruse (IPCS, May, 1999)
    


    See Also:
       Toxicological Abbreviations