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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. 

    13. REFERENCES 

        Barnhart ER, ed. (1987) Physician's Desk Reference, 41st ed.  
        New Jersey,  Medical Economics Company Inc. 
          
        Baselt RC & Cravey RH (1989) Disposition of toxic drugs and 
        chemicals in man, 3rd Ed. Year Book Medical Publishers Inc, pp 
        214-218. 

        Briggs GG, Freeman RK, Sumner JY (1986) Drugs in pregnancy and 
        lactation, 2nd ed. Williams & Wilkins pp 102-103c. 

        Casaret & Doull's (1980) Toxicology, 2nd Ed. Macmillan 
        Publishing Co, Inc New York; 663, 678-691. 

        Committee on Drugs - American Academy of Pediatrics (1983) The 
        transfer of drugs and other chemicals into human breast milk. 
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        Dreisbach (1987) Handbook of poisoning, prevention. Appleton 
        Lange Norwalk, Connecticut, pp 324, 325-341. 

        Ellenhorn MJ & Barceloux DG (1988)  Medical toxicology, 
        diagnosis and treatment of human poisoning.  New York,  
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        Fleeger CA, ed. (1993) USAN 1994: USAN and the USP dictionary of 
        drug names. Rockville, MD, United States Pharmacopeial 
        Convention, Inc., p 171. 

        Gosselin RE, Hodge HC, Smith RP (1984) Clinical toxicology of 
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        Gilman AG, Rall TW, Nies AS & Taylor P, eds. (1990) Goodman and  
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        Gilman AG, Goodman LS, Rall TW & Murad F eds. (1985)  Goodman & 
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        Goodman et Gilman (1987) Editorial Medica Panamericana. pp 506, 
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        Huffman DH & Ferguson RL (1975) Acute codeine overdose: 
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        John Hopkins Med J, 136:183-186. 
        
        McEvoy GK, ed. (1989) American hospital formulary service, drug 
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        Meredith TJ, Jacobsen D, Haines JA, & Berger JC eds. (1993) 
        Naloxone, flumazenil and dantrolene as antidotes. Cambridge, 
        Cambridge University Press, p 20. 

        Moffat AC, ed. (1986) Clarke's isolation and identification of 
        drugs in pharmaceuticals, body fluids, and post-mortem material. 
        2nd ed. London, The Pharmaceutical Press, pp 490-491. 

        Nomoff N, Elliott HW, & Parker KD (1977) Actions and metabolism 
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        Reynolds JEF, ed. (1982) Martindale, the extra pharmacopoeia, 
        28th ed. London, The Pharmaceutical Press, pp  1004, 1006-1031, 
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        Reynolds JEF, ed. (1989) Martindale, the extra pharmacopoeia, 
        29th ed. London, The Pharmaceutical Press. pp 1297-1299 

        Reynolds JEF, ed. (1993) Martindale, the extra pharmacopoeia, 
        30th ed. London, The Pharmaceutical Press. pp 1069-1071. 

        Sax NI & Lewis RJ sr (1989) Dangerous properties of industrial 
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        Shee E  & Pounder RE (1980) Loperamide, diphenoxylate and 
        codeine phosphate in chronic diarrhoea. Br Med J, 280: 524. 

        Sklar J & Timms RM (1977) Codeine-induced pulmonary edema. 
        Chest, 72(2): 230-231. 

        United States Pharmacopeia, 21st rev. The National formulary 
        16th ed. (1985) Rockville MD, United States Pharmacopeial 
        Convention,  pp 571-578. 

        Von Muhlendahl KE, Krienke EG, Scherf-Rahne B, & Baukloh G  
        (1976) Codeine intoxication in childhood. Lancet, 2:303-305. 

        Vivian D (1979) Three deaths due to hydrocodone in a resin 
        complex cough medicine. Drug Intell Clin Pharmacol, 13:445-446. 

        Wilkes TCR, Davies DP, & Dar MR (1981) Apnoea in a 3-month old 
        baby prescribed compound linctus containing codeine, letter. 
        Lancet 1: 1166-1167. 

    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