Codeine
| 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 |
| 1.7 Presentation, Formulation |
| 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. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical Properties |
| 3.3.1 Properties of the substance |
| 3.3.1.1 Colour |
| 3.3.1.2 State/Form |
| 3.3.1.3 Description |
| 3.3.2 Properties of the locally available formulation |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Shelf-life of the locally available formulation |
| 3.4.3 Storage conditions |
| 3.4.4 Bioavailability |
| 3.4.5 Specific properties and composition |
| 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 ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Other |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination and excretion |
| 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 |
| 8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Sample |
| 8.1.1 Collection |
| 8.1.2 Storage |
| 8.1.3 Transport |
| 8.2 Toxicological analytical methods |
| 8.2.1 Test for active ingredient |
| 8.2.2 Test for biological sample |
| 8.3 Other laboratory analyses |
| 8.3.1 Haemotological investigations |
| 8.3.2 Biochemical investigations |
| 8.3.3 Arterial blood gas analysis |
| 8.3.4 Other relevant biomedical analyses |
| 8.4 Interpretation |
| 8.5 References |
| 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(CNS) |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Others |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ears, nose, throat: local effects |
| 9 4.10 Hematological |
| 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 |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other investigations |
| 10.3 Life supportive procedures and symptomatic/specific treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases |
| 12. ADDITIONAL INFORMATION |
| 12.1 Availability of antidotes |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
1. NAME
1.1 Substance
Codeine (USAN)
(Fleeger, 1993)
1.2 Group
ATC classification index
Cough and cold preparations(R05)/Antitussives excl.
combinations with expectorants (R05D)/Opium alkaloids and
derivatives (R05DA)
(WHO, 1992)
1.3 Synonyms
Codeinum; codeina; methylmorphine; morphine 3-methylether;
morphine monomethyl ether.
1.4 Identification numbers
1.4.1 CAS number
Codeine base (anhydrous) 76-57-3
Codeine base (monohydrate) 6059-47-8
Codeine hydrochloride 1422-07-7
Codeine phosphate (anhydrous) 52-28-8
Codeine phosphate (hemihydrate) 41444-62-6
Codeine phosphate (sesquihydrate) 5913-76-8
Codeine sulfate (anhydrous) 1420-53-7
Codeine sulfate (trihydrate) 6854-40-6
1.4.2 Other numbers
RTECS
Codeine base (anhydrous) QD0893000
1.5 Brand names, Trade names
Monocomponent products
Actacode (Sigma, Australia)
Codate (USV, Australia)
Codinfos (Spain)
Codelix (Drug Houses Australia, Australia)
Codicept (Sanol, Germany)
Codicompren (Cascan, Germany)
Codipertussin (Fink, Germany and Switzerland)
Codlin (Nelson, Australia)
Codyl (Boehringer Ingelheim, Germany)
Galcodine (Galen, UK)
Paveral (Desbergers, Canada)
Perduretas Codeina (Medea, Spain)
Solcodein (Inibsa, Spain)
Tricodein (Zyma, Germany; Solco, Switzerland)
Fosfato de codeina; Dipirona con codeina; Espasmo Cibalena;
Trigésico con codeina
(Squibb, Uruguay)
Other numerous combination products containing codeine or its
salts are available.
(To be completed by each Centre using local data).
1.6 Manufacturers, Importers
Ciba Geigy, Gramon, Farmaco Uruguayo, Coro, Roussel Fisher,
and many others.
(To be completed by each Centre using local data).
1.7 Presentation, Formulation
Various formulations are available, e.g. codeine syrup
5 mg/ml; codeine phosphate syrup 5 mg/ml; codeine tablets 15,
30 and 60 mg; codeine phosphate injection 15, 30 and 60 mg/ml
(Reynolds, 1989, McEvoy, 1989).
(To be completed by each Centre using local data).
2. SUMMARY
2.1 Main risks and target organs
Respiratory depression is the main risk. The characteristic
triad of opiate poisoning is coma, pin-point pupils and
respiratory depression which are found in severe codeine
poisoning.
Most fatalities occur after intravenous administration in
drug abusers who have taken codeine in association with other
depressant drugs or alcohol.
Deaths can also occur after oral overdosage.
2.2 Summary of clinical effects
Toxic doses of codeine produce unconsciousness, pinpoint
pupils, slow and shallow respiration, cyanosis, weak pulse,
hypotension and in some cases pulmonary oedema, spasticity
and twitching of the muscles. The main and most dangerous
effect is respiratory depression. Death from respiratory
failure may occur within 2 to 4 hours after oral dose.
Convulsions may occur, especially in children.
Hallucinations, trembling, uncontrolled muscle movements,
mental depression and skin rash may be observed.
Chronic ingestion or injection leads to addiction. In this
case pinpoint pupils and changes in mood may be observed (or
no evident signs of use).
The withdrawal syndrome is characterized by yawning,
lacrimation, pilomotor reactions, severe gastrointestinal
disturbances with cramps, vomiting, diarrhoea or
constipation, sweating, fever, chills, increase respiratory
rate, insomnia, tremor, mydriasis and myalgia.
2.3 Diagnosis
Coma, pin-point pupils and respiratory depression is the
typical clinical triad of opiate poisoning. In codeine
poisoning, skin rash with urticaria are often associated.
Urine and blood should be collected for biomedical and
toxicological analyses.
2.4 First aid measures and management principles
In case of severe, acute poisoning, establish clear airway,
provide artificial ventilation, oxygen and monitor
haemodynamic status.
In the fully conscious patient, consider gastric lavage if
patient seen within one or two hours after ingestion.
Activated charcoal should be given afterwards. The use of a
cathartic is no longer recommended.
The recommended antidote is naloxone, given 0.4 mg
intravenously and repeated as necessary every two to three
minutes, until recovery.
Intravenous fluids, vasopressors and other supportive
measures as needed in shock.
Maintain body warmth.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Codeine is obtained either naturally, from opium (extracted
from Papaver somnifera) or by methylation of morphine.
It is a phenanthrenic alkaloid and constitutes 0.5% of raw
opium.
3.2 Chemical structure
Molecular formula
C18H21NO3
Molecular weight
Codeine base (anhydrous) 299.36
Codeine base (monohydrate) 317.4
Structural names
7,8-Didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol.
(5alpha,6alpha)-7,8-Didehydro-4,5-epoxy-3-methoxy-17-
methylmorphinan-6-ol.
3.3 Physical Properties
3.3.1 Properties of the substance
3.3.1.1 Colour
Codeine base
Colourless (crystals) or white (powder)
3.3.1.2 State/Form
Codeine base
Crystals or a crystalline powder
3.3.1.3 Description
Codeine base
Odourless
Bitter taste
Melting point is 154°C to 158°C
Effloresces slowly in dry air
Affected by light
Soluble 1 in 120 of water in 15 of boiling
water, in 2 of alcohol, in 0.5 of chloroform,
in 50 of ether.
Soluble in aryl-alcohol and methyl alcohol.
Very soluble in dilute acids, slightly soluble
in a excess of potassium hydroxide solution.
pH of more than 9 in a 0.5% solution of codeine
in water. pKa 8.2 (Casarett & Doull, 1980).
3.3.2 Properties of the locally available formulation
To be completed by each Centre using local data.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
No data available.
3.4.2 Shelf-life of the locally available formulation
Codeine formulations are generally considered to be
stable.
3.4.3 Storage conditions
Store in airtight containers, protected from light.
3.4.4 Bioavailability
To be completed by each Centre using local data.
3.4.5 Specific properties and composition
Codeine is commercially available as water soluble
hydrochloride, sulfate or phosphate and is administered
orally in the form of linctuses for the relief of
coughs, and as tablets for the relief of pain. Codeine
phosphate is also given parenterally for the relief of
pain.
Codeine, usually as the phosphate, is often
administered by mouth together with acetylsalicylic
acid or paracetamol.
The equivalence of the analgesic effects is 120 mg of
codeine corresponds to 10 mg of morphine. and 30 mg of
codeine to 325 to 600 mg of aspirin (Gilman et al.,
1990).
Codeine is less potent than morphine as an analgesic.
(To be completed by each Centre using local data).
4. USES
4.1 Indications
4.1.1 Indications
Analgesic for relief of moderate pain, and an
antitussive (principal uses).
Antidiarrhoeal.
Used frequently in association with other analgesics
or antihistamines, sedatives and stimulants in some
pharmaceutical preparations. (This represents a higher
risk of poisoning and fatality [Ellenhorn & Barceloux,
1988]).
Codeine is used as a drug of abuse, and it may produce
dependence and withdrawal syndromes.
4.1.2 Description
Not relevant.
4.2 Therapeutic dosage
4.2.1 Adults
Analgesic
Codeine and its salts (sulfate or phosphate) are
administered in doses of 15 to 60 mg, four to six times
a day. (Note: Orally, a dose of 30 mg of codeine is
equivalent to 325 to 600 mg of aspirin [Gilman et al.,
1990]).
The maximum daily dose for the relief of pain is 360 mg
(Reynolds, 1993).
Antitussive
15 mg to 30 mg of codeine phosphate 3 to 4 times a day
(Reynolds, 1993). Not more than 120 mg/day is
recommended.
Parenteral
A dose of 120 mg of codeine given subcutaneously
produces analgesia equivalent to that resulting from 10
mg of morphine.
Doses given by intramuscular or subcutaneous routes are
similar to those given orally (Reynolds, 1993).
4.2.2 Children
Analgesic
0.5 mg/kg body weight (codeine phosphate) divided into
four to six doses a day (Reynolds, 1993).
Antitussive
The dose should not exceed 0.25 mg/kg/day divided into
three or four doses.
5 to 12 years
7.5 to 15 mg (codeine phosphate) three to four times a
day (Reynolds, 1993).
1 to 5 years
3 mg (codeine phosphate) three to four times a day
(Reynolds, 1993).
Under one year
Not generally recommended, but 1 mg/kg by mouth or
intramuscular injection as a single dose presented a
relatively small risk of respiratory depression and the
patient should be observed closely (Reynolds, 1993).
4.3 Contraindications
Codeine is contraindicated during pregnancy.
Paediatric and geriatric patients may be more susceptible to
the effects of codeine, especially to respiratory depression.
Lower doses may be required for this kind of patient, as well
as for those who suffer from some type of respiratory
insufficiency.
When prescribing for infants, prematurity should be taken
into account. Administration of cough suppressants containing
codeine should be avoided in children less than 12 months
(Reynolds, 1982).
5. ROUTES OF ENTRY
5.1 Oral
This is the most common route of entry.
5.2 Inhalation
No data available.
5.3 Dermal
No data available.
5.4 Eye
No data available.
5.5 Parenteral
Intramuscular administration of the phosphate derivative is
sometimes indicated.
The intravenous route may be used by drug abusers.
5.6 Other
No data available.
6. KINETICS
6.1 Absorption by route of exposure
Codeine and its salts are well absorbed from the
gastrointestinal tract. After ingestion, the peak plasma
level is attained in one hour (Reynolds, 1989).
Bioavailability is about 50% (Moffat, 1986)
Codeine, in contrast to morphine, is two-thirds as effective
orally as parenterally, both as an analgesic and as a
respiratory depressant. It has therefore a highly oral-
parenteral potency ratio (due to lower first-pass metabolism
in the liver) (Goodman & Gilman, 1985).
6.2 Distribution by route of exposure
The volume of distribution is 3.5 L/kg (Baselt & Cravey,
1989; Moffat, 1986) after oral administration and 2.6 L/kg
after intramuscular injection (Vivian, 1979).
Protein binding of codeine is about 25% in human serum
(Reynolds, 1989). Moffat (1986) states that plasma protein
binding is about 7 to 25%.
6.3 Biological half-life by route of exposure
The half-life of codeine in plasma is 2.5 to 4 hours (Gilman
et al.,1985; Reynolds, 1989).
6.4 Metabolism
Codeine is metabolized mainly in the liver where it undergoes
0-demethylation to form morphine, N-demethylation to form
norcodeine , and partial conjugation to form glucuronides and
sulphates of both the unchanged drug and its metabolites
(Moffat, 1986).
The rate of metabolism of codeine is 30 mg/hour (Nomof et
al., 1977).
6.5 Elimination and excretion
Total systemic clearance of codeine from the plasma is 10 to
15 mL/min/kg (Moffat, 1986).
Eighty six per cent of the drug is excreted within 24 hours,
(Gilman et al., 1985; Moffat, 1986) mainly in urine as
norcodeine and free and conjugated morphine. Negligible
amounts of codeine and its metabolites are found in faeces
(McEvoy, 1989).
Of the 86% excreted after an oral dose 40 to 70% is free or
conjugated codeine, 5 to 15% free or conjugated morphine, 10
to 20% is free or conjugated norcodeine; unchanged drug
accounts for 6 to 8% of the dose excreted in urine within 24
hours but this can increase to 10% if the urinary pH is
decreased. (Moffat, 1986).
After intramuscular administration, 15 to 20% is excreted
unchanged in acid urine within 24 hours (Moffat, 1986).
Codeine passes into the breast milk in very small amounts,
probably insignificant, which is compatible with breast-
feeding (Committee on Drugs, AAP, 1983), and small amounts
are excreted in the bile (Moffat, 1986).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Codeine is a mu receptor agonist. Overdose produces CNS
depression, respiratory depression, pinpoint pupils and
coma, but to a lesser degree than morphine.
In overdose, codeine may cause pulmonary oedema within
2 or 3 hours (Sklar & Timms, 1977).
7.1.2 Pharmacodynamics
Codeine binds with stereospecific receptors at many
sites within the CNS to alter processes affecting both
the perception of pain and the emotional response to
pain. Precise sites and mechanisms of action have not
been fully determined. It has been proposed that there
are multiple subtypes of opioid receptors, each
mediating various therapeutic and/or side effects of
opioid drugs. Codeine has a very low affinity for
opioid receptors and the analgesic effect of codeine
may be due to its conversion to morphine (Gilman et
al., 1985).
The actions of an opioid analgesic may therefore depend
upon its binding affinity for each type of receptor and
whether it acts as a full agonist or a partial agonist
or is inactive at each type of receptor. At least two
of these types of receptors (mu and kappa) mediate
analgesia. Codeine probably produces its effects via
agonist actions at the mu receptors.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
The adult lethal dose is 0.5 to 1.0 g (Gosselin
et al., 1984). This dose may cause convulsions
and unconsciousness, and death from respiratory
failure may result within 4 hours. Moffat
(1986) estimated the minimum lethal adult dose
at 800 mg.
Serum concentrations over 5 mg/L were detected
in an adult who had self-administered 900 mg of
codeine intravenously; he regained
consciousness only after 3 days when serum
levels reached 1.3 mg/L (Huffman & Ferguson,
1975).
Drug concentrations in codeine fatalities are
approximately 2.8 mg/L in blood and 103.8 mg/L
in urine (Baselt & Cravey, 1989).
The development of tolerance increases the
potentially toxic doses. In volunteer studies
individuals could tolerate up to 240 mg by
mouth, 4 times daily (Reynolds, 1982).
7.2.1.2 Children
Doses over 5 mg/kg may cause serious
respiratory depression.
Children may display signs of toxicity at
1/20 th of the minimum lethal dose of 800 mg
(Moffat, 1986).
A cough syrup which contained 10 mg of
codeine/5 mL, produced severe poisoning after
two 5 mL doses in a prematurely born 3 month
old baby (Wilkes et al., 1981).
7.2.2 Relevant animal data
Codeine
LD50 (oral) rat 427 mg/kg
LD50 (intravenous) rat 75 mg/kg
LD50 (subcutaneous) rat 229 mg/kg
Codeine phosphate
LD50 (oral) rat 266 mg/kg
LD50 (intravenous) rat 54 mg/kg
LD50 (subcutaneous) rat 365 mg/kg
LD50 (intramuscular) rat 208 mg/kg
(Sax & Lewis, 1989)
7.2.3 Relevant in vitro data
No relevant data available.
7.3 Carcinogenicity
No data available.
7.4 Teratogenicity
Briggs et al. (1986) examined the results of five studies
covering the maternal use of codeine during the first
trimester of pregnancy. While there was no evidence found to
suggest a relationship to large categories of major or minor
malformations, possible associations were found with
respiratory malformations, hydrocephaly, pyloric stenosis,
cardiac and circulatory system defects, cleft lip and palate,
umbilical hernia and inguinal hernia, dislocated hip and
other musculoskeletal defects. The association of codeine and
respiratory and heart malformation was statistically
significant. Data on inguinal hernias, circulatory system
defects, cleft lip and palate, dislocated hips and
musculoskeletal defects and alimentary tract defects were
inconclusive . But all the data serves as a clear warning
that indiscriminate use of codeine represents a risk to the
foetus.
7.5 Mutagenicity
No data available.
7.6 Interactions
Incompatible with bromides, iodides and salts of heavy
metals.
Codeine phosphate for injection has been reported to be
physically or chemically incompatible with solutions
containing amylobarbital, aminophylline, ammonium chloride,
thiazides, sodium bicarbonate, pentobarbitone, thiopentone
and sodium heparin (McEvoy, 1989).
Antidiarrhoeal opioids given concurrently with codeine may
result in increased constipation, paralytic ileus, as well as
an increased risk of respiratory depression (Shee & Pounder,
1980). Given together with antihypertensive drugs codeine
may potentiate hypotension and increase the risk of
orthostatic hypotension.
Concurrent use with other analgesic opioids may result in
additive CNS depression, respiratory depression, and
hypotensive effects.
Atropine or antimuscarinic agents administered with codeine
may produce constipation, ileus, urinary retention.
With monoamine oxidase inhibitors fatal reactions may occur.
Symptoms and signs include excitation, sweating, hypertension
or hypotension, severe respiratory depression, seizures,
hyperpyrexia and coma.
Neuromuscular blocking agents may also increase the
depressant effects.
Codeine may antagonize the effects of metoclopramide on
gastrointestinal motility.
Naloxone antagonizes the analgesic effects and may
precipitate withdrawal symptoms in dependent patients. The
dosage of the antagonist should be carefully titrated when
used to treat codeine overdose in patients who are dependent
(USP,1985).
7.7 Main adverse effects
In acute asthma attack, codeine depresses the respiratory
centre and increases airway resistance.
Cardiac arrhythmias and seizures may be induced or
exacerbated.
Codeine abuse or dependency may produce emotional instability
or suicidal tendencies.
Codeine may cause biliary tract spasms in case of
cholelithiasis disease or gallstones.
In head trauma or raised intracranial pressure, the risk of
respiratory depression and further elevation of cerebrospinal
fluid pressure is increased by codeine, which also causes
sedation and pupillary changes (misleading diagnosis on the
clinical course of cerebral trauma).
Codeine may cause urinary retention in patients with
prostatic hypertrophy, obstruction, or urethral strictures.
Administration of codeine should be cautious in case of renal
function impairment as codeine is excreted primarily by the
kidneys.
Caution is also advised in administration to very young, ill
or debilitated patients who may be more sensitive to the
depressant effects, especially on the respiratory system.
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
8.1 Sample
8.1.1 Collection
8.1.2 Storage
8.1.3 Transport
8.2 Toxicological analytical methods
8.2.1 Test for active ingredient
8.2.2 Test for biological sample
8.3 Other laboratory analyses
8.3.1 Haemotological investigations
8.3.2 Biochemical investigations
8.3.3 Arterial blood gas analysis
8.3.4 Other relevant biomedical analyses
8.4 Interpretation
8.5 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Toxic doses of codeine will cause unconsciousness,
pinpoint pupils, slow shallow respiration, cyanosis,
hypotension, spasms of gastrointestinal and biliary
tracts, and in some cases pulmonary oedema, spasticity,
twitching of the muscles and convulsions. Death from
respiratory failure may occur within 4 hours after
large overdose.
Initial signs of overdose are cold and clammy skin,
skin rash, confusion, nervousness or restlessness,
dizziness, low blood pressure, respiratory distress,
bradycardia, weakness and miosis.
9.1.2 Inhalation
No data available.
9.1.3 Skin exposure
No data available.
9.1.4 Eye contact
No data available.
9.1.5 Parenteral exposure
In case of overdose, the symptoms are basically the
same as by ingestion but will develop more rapidly.
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
Clinical findings in case of chronic use or addiction
of codeine may not be evident. Pinpoint pupils and
rapid changes in the mood may be observed (Dreisbach,
1987).
Symptoms of withdrawal may be cramps, vomiting,
diarrhoea or constipation, sweating, fever, chills,
increase in respiratory rate, insomnia, tremor and
mydriasis. A narcotic antagonist such as nalorphine or
naloxone may precipitate the withdrawal reaction.
9.2.2 Inhalation
No data available.
9.2.3 Skin exposure
No data available.
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
Chronic intravenous use is seen in addicts and causes
similar symptoms as oral but with an increased risk of
life threatening situations.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Within one hour of a large oral overdose the patient will
suffer increasing CNS depression, miosis, and a fall in body
temperature with hypotension. This may progress to coma with
respiratory depression within 4 hours.
Intravenous injection may cause these effects more rapidly.
Death from codeine overdose is relatively rare. An
association with alcohol or other CNS depressants increases
the risk of fatalities.
Death is due to respiratory arrest, which may occur within 4
hours after a toxic oral dose or subcutaneous administration,
or immediately after intravenous overdose
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Palpitations, hypotension.
9.4.2 Respiratory
Depression of the respiratory centre and increased
airway resistance leads to acute respiratory failure,
which may be enhanced by acute pulmonary oedema.
9.4.3 Neurological
9.4.3.1 Central nervous system(CNS)
Codeine causes less euphoria and sedation than
morphine, but CNS depression and coma occur in
case of overdose. Codeine has a weaker
depressive effect than other opiates to the
cortex and medullary centres, but is more
stimulating to the spinal cord. It may induce
unusual excitation and convulsions, especially
in children (Reynolds, 1989).
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
No data available.
9.4.4 Gastrointestinal
Spasm and ileus occur especially when codeine is
administered with spasmolytics.
9.4.5 Hepatic
Codeine may cause biliary tract spasm.
Increases in intrabiliary pressure may be observed
after administration of 10 to 20 mg of codeine
(Reynolds, 1982).
9.4.6 Urinary
9.4.6.1 Renal
No data available.
9.4.6.2 Others
Urinary retention may occur.
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatological
Rash, itching or swelling of face may occur.
9.4.9 Eye, ears, nose, throat: local effects
Miosis is a characteristic symptom in the overdosed
patient and in the chronic drug abuser.
9 4.10 Hematological
No data available.
9.4.11 Immunological
No data available.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No specific effect.
9.4.12.2 Fluid and electrolyte disturbances
No specific effect.
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
Rashes, bronchospasm and/or anaphylactic reaction have
been reported after codeine overdose (Reynolds, 1993).
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy
A possible association between cardiac and respiratory
malformations and codeine was reported (Reynolds,
1989; Briggs et al., 1986).Data on inguinal hernias,
circulatory system defects, cleft lip and palate,
dislocated hips and musculoskeletal defects and
alimentary tract defects were inconclusive (Briggs et
al, 1986). But all the data serves a clear warning
that indiscriminate use of codeine does represent a
risk to the foetus.
Codeine crosses the placenta and regular use during
pregnancy may result in addiction of the foetus
leading to withdrawal syndrome in the newborn
(irritability, excessive crying, tremors, hyperactive
reflexes, fever, vomiting, diarrhoea, yawning).
It may also produce respiratory depression in the
newborn whose mother has received codeine during
labour (Briggs et al., 1986).
Breast feeding
It is excreted in the breast milk in small amounts
that are probably insignificant, and is compatible
with breast feeding, after therapeutic doses
(Committee on Drugs, AAP, 1983).
Other
Patients with hypothyroidism are at higher risk of
respiratory depression.
9.5 Other
No data available.
10. MANAGEMENT
10.1 General principles
Respiratory depression should be treated through either
artificial ventilation and/or artificial ventilation and
intravenous naloxone. Cardio-circulatory function should be
monitored.
In case of ingestion, and in the conscious or intubated
patient, gastric aspiration and lavage should be considered
(provided the patient is seen early after the ingestion)
and activated charcoal should be administered in order to
reduce absorption.
In the drug user, codeine is rarely taken alone, therefore
symptomatology of overdose may not be clear-cut. It is
usually modified or enhanced by the other drugs.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Blood and urine.
10.2.2 Biomedical analysis
Routine blood, arterial gases and urinalysis are
required.
10.2.3 Toxicological analysis
10.2.4 Other investigations
Nothing specific.
10.3 Life supportive procedures and symptomatic/specific
treatment
Administration of the antidote naloxone may be required.
Establish and maintain adequate ventilation: endotracheal
intubation and assisted ventilation are needed in the
severely poisoned patient.
Administration of intravenous fluids, vasopressors and
other supportive measures may be required.
Maintain body warmth and fluid balance.
Monitor continuously: arterial blood gases (PaO2, PaCO2),
pH, respiration, blood pressure and consciousness.
10.4 Decontamination
In fully conscious patients gastric lavage followed by
charcoal should be considered if the patient is seen within
1 or 2 hours after the ingestion.
10.5 Elimination
Dialysis is not indicated.
10.6 Antidote treatment
10.6.1 Adults
Naloxone is a specific opioid antagonist.
The effect of naloxone may be of shorter duration
than that of the narcotic analgesic. (Reynolds,
1989).
Since naloxone is a competitive antagonist of opiate
poisoning, there can be no absolute guidelines on
dosage. Naloxone should be given intravenously, in
successive doses of 0.4 to 2.0 mg, until the desired
response has been obtained.
An alternative approach, which may be appropriate
for opiate addicts, is to give naloxone (0.8 to 1.2
mg) intramuscularly, before waking the patient with
an intravenous dose of 0.4 to 0.8 mg. Adequate
ventilatory support must be given. The patient then
has a "depot" of antidote in case he/she departs
soon after the initial treatment (as many addicts
do). (Meredith et al., 1993)
If an effective increase in pulmonary ventilation is
not achieved after the first dose, it may be
repeated every 2 or 3 minutes until respiration
returns to normal and the patient responds to
stimuli.
In an individual physically dependent on narcotics
(e.g. codeine), the administration of the usual dose
of narcotic antagonist may precipitate an acute
withdrawal syndrome (Barnhart, 1987). This may
require administration of intravenous diazepam.
In case of renal failure, it is not necessary to
reduce the dose of naloxone.
Naloxone also has a longer action than either
nalorphine or levorphan neither of which should be
used as antidotes, unless naloxone is not available.
10.6.2 Children
In children the usual initial dose is 10 mcg/kg body
weight given intravenously, followed, if necessary,
by a larger dose of 100 mcg/kg.
In newborns of addicted mothers the injection of
naloxone may precipitate acute severe withdrawal
syndrome.
10.7 Management discussion
Naloxone is the most effective antidote as yet, but it may
not be available in some countries. Levallorphan
(tartrate) or nalorphine (hydrochloride or hydrobromide)
antagonize the respiratory depression produced by narcotics
but may also have agonist effects and induce side-effects.
Naloxone is of diagnostic value in coma of unknown origin,
where narcotic overdose is suspected.
If the antidote is not available, the treatment relies on
the life-supportive measures, especially in maintaining
proper ventilation.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Case 1
A 31 month old baby was transferred to the hospital after
having ingested 6.6 mg/kg of codeine. On arrival he had
collapsed, and was cold and semi-comatose with pinpoint
pupils and Sheynes-stokes breathing. He was treated with
intravenous naloxone and was discharged after two days
without sequelae (Wilkes, et al, 1981).
Case 2
An evaluation of codeine intoxication in 430 children,
reported the following symptoms in decreasing order of
frequency: sedation, rash, miosis, vomiting, itching,
ataxia, and swelling of the skin (oedema). Respiratory
failure occurred in eight children, two of whom died; all
eight had taken 5 mg/kg body weight or more.
11.2 Internally extracted data on cases
Only a few uneventful cases have been registered, and
mostly involved children receiving cough medication.
11.3 Internal cases
To be completed by each Centre using local data.
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes
To be completed by the Centre.
12.2 Specific preventive measures
Caution is advised in administration of codeine to small
children, the elderly or very ill patients, who may be more
sensitive to the effects, especially to the respiratory
depression.
Caution is advised when administered with other medication
and during pregnancy and lactation.
12.3 Other
No data available.
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14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Author Dr M.S. Perrugia Paolino
CIAT 7 piso
Hospital de Clinicas
Av. Italia s/n
Montevideo
Uruguay
Tel 598-2-470300
Fax 598-2-470300
Date February 1990
Peer Newcastle, United Kingdom, January 1991
Review Cardiff, United Kingdom, February 1994
Berlin, Germany, October 1995