Diamorphine
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)