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Dextromethorphan

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS
      1.4.2 Other numbers
   1.5 Brand names/trade names:
   1.6 Manufacturers and importers:
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosages
      4.2.1 Adults
      4.2.1 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parental
   5.6 Others
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 by route of exposure
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
      7.2.3 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/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
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 contact
      9.2.4 Eye contact
      9.2.5 Parental 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 Neurologic
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic
         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 Dermatologic
      9.4.9 Eye, ear, throat: local effects
      9.4.10 Hematological
      9.4.11 Immunologic
      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 Others
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic treatment
   10.3 Decontamination
   10.4 Enhancd elimination
   10.5 Antidote
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case report from the literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S) DATES (INCLUDING EACH UPDATING), COMPLETE ADDRESSES
    DEXTROMETHORPHAN

    International Programme on Chemical Safety
    Poisons Information Monograph 179
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Dextromethorphan

        1.2  Group

             Cough and cold preparations (R05)/
             Antitussives, excl. combinations with expectorants
             (R05D)/ Opium alkaloids and derivatives (R05D A)

        1.3  Synonyms 

             Dextromethorphan hydrobromide monohydrate;
             dextromethorphani hydrobromidum;
             demorphan hydrobromide

        1.4  Identification numbers

             1.4.1  CAS

                    125-69-9 (anhydrous)

             1.4.2  Other numbers

                    CAS: 6700-34-1 (monohydrate)

        1.5  Brand names/trade names:

             Polistirex Extended Release suspension.

        1.6  Manufacturers and importers:

             To be completed by each centre using the mongraph.

    2.  SUMMARY

        2.1  Main risks and target organs

             The main risks associated with dextromethorphan are
             ataxia, central nervous system (CNS) stimulation, dizziness,
             lethargy and psychotic behavior. Less frequently with large
             doses seizures and respiratory depression can occur. Nausea,
             vomiting, constipation and tachycardia may occur. The main
             target organ is the central nervous system (CNS).

        2.2  Summary of clinical effects

             Central nervous system effects include ataxia,
             drowsiness, vertigo and rarely coma. CNS stimulation may be
             observed. Restlessness, increased muscle tone with body    
             rigidity have been reported. With extremely large ingestions
             respiratory depression can occur. Gastrointestinal effects 
             include nausea, vomiting, constipation and dry mouth. Urinary
             retention may be seen. Dextromethorphan abuse has been
             described and produces euphoria, CNS stimulation, visual
             and/or auditory hallucinations. There does not appear to be
             any evidence of dependence of the morphine type.
             The possibility of bromide poisoning should be considered in
             the long term abuser.

        2.3  Diagnosis

             Diagnosis of dextromethorphan toxicity is primarily
             based on the history of an ingestion of dextromethorphan or
             dextromethorphan containing products. The presence of
             dextromethorphan may be confirmed by qualitative
             determination of the drug in urine.

        2.4  First aid measures and management principles

             Assess and support airway, respiration and
             cardiovascular function if needed. Gastric decontamination is
             recommended for recent ingestions of more than 10 mg/kg.
             Seizures and/or CNS depression have occurred within 30
             minutes of ingesting dextromethorphan. 
    
             ACTIVATED CHARCOAL/CATHARTIC.
             Activated charcoal may be given alone or with a cathartic  
             such as sorbitol or magnesium citrate even though at this   
             time there is no data concerning the adsorption or clinical
             efficacy of activated charcoal in the treatment of
             dextromethorphan ingestions.
    
             GASTRIC LAVAGE followed by activated charcoal may be
             indicated for the treatment of recent large ingestions, or in
             patients who are comatose or at risk of convulsing.  NALOXONE
             may be of benefit to reverse the respiratory and CNS effects
             of dextromethorphan although its efficacy is yet to be
             adequately determined.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Dextromethorphan is a synthetic compound.
             Dextromethorphan has been abused and is claimed to be habit
             forming but has not been reported to produce physical
             dependence (Ellenhorn & Barceloux 1988). It is not a
             substitute for opiates in dependent individuals.

        3.2  Chemical structure

             Chemical name:
             Dextromethorphan is 3 Methoxy-17-methylmorphinan monohydrate,
             which is the d isomer of levophenol, a codeine analogue and
             opioid analgesic.
    
             Molecular formula: (Dextromethorphan Hydrobromide):
             C18H25NO.HBr.H2O
    
             Molecular weight 370.3

        3.3  Physical properties

             3.3.1  Colour

                    White

             3.3.2  State/form

                    Solid-crystals
                    Solid-powder

             3.3.3  Description

                    Odourless verging on a faint odour. Solubility
                    in water 1.5 g/100 mL at 25 C.
                    Soluble 1 in 10 of ethanol.
                    Practically insoluble in ether.
                    Freely soluble in chloroform.
                    pH of a 1% aqueous solution 5.2 to 6.5 (Budavari,
                    1996).

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    No information available.

             3.4.2  Storage conditions

                    Powder should be preserved in air-tight
                    containers and solutions stored in light-resistant
                    containers (USP National Formulary).
    

                    Lozenges: store between 15 and 30 degrees C in well
                    closed containers.
                    Syrup USP: Store between 15 and 30 degrees C in light,
                    resistant container, protected from freezing.

    4.  USES

        4.1  Indications

             4.1.1  Indications

                    Cough/cold preparation
                    Antitussive (not with expectorant); 
                    cough/cold
                    Opioid; 
                    antitussive

             4.1.2  Description

                    Antitussive.

        4.2  Therapeutic dosages

             4.2.1  Adults

                    Oral doses of 10 to 20 mg every four hours or
                    30 mg every 6 to 8 hours not to exceed 120 mg
                    daily.
    
                    Long-acting preparations: 60 mg twice a day.

             4.2.1  Children

                    Children aged 6 to 12 years may be given 5 to
                    10 mg every 4 hours or 15 mg every six to eight hours,
                    not to exceed 60 mg daily.

                    Children aged 2 to 6 years 2.5 to 5.0 mg every 4 hours
                    or 7.5 mg every 6 to 8 hours not to exceed 30 mg
                    daily.
                    The recommended dose in a child is 1 mg/kg/day to 2
                    mg/kg/day given in three to four divided doses (Benitz
                    & Tatro, 1988). 
                    Dextromethorphan is not generally recommended in
                    children less than two years of age unless under
                    medical supervision (USPC, 1991).
    
                    Long-acting preparations: children aged 6 to 12 years
                    30 mg twice a day and children aged 2 to 6 years 15 mg
                    twice a day (AHFS, 1992).

        4.3  Contraindications

             Dextromethorphan should not be administered in patients
             taking selective serotonin reuptake inhibitors (eg
             fluoxetine, paroxetine) (Skop et al., 1994) and monoamine

             oxidase inhibitors (Rivers & Horner, 1970). This may produce
             a life threatening serotonergic syndrome which consists of:
             restlessness, sweating, hypertension, hyperthermia, tremor,
             myoclonus and seizures.
    
             Dextromethorphan may be associated with histamine release and
             should not be used in atopic children. Dextromethorphan
             should not be taken for persistent or chronic cough (e.g.
             with smoking, emphysema, asthma) or when coughing is
             accompanied by excessive secretions, unless directed by a
             physician (AHFS, 1992).
             Alcohol and CNS depressants should be avoided with    
             dextromethorphan.

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Dextromethorphan is usually taken orally.
             It has been abused orally.

        5.2  Inhalation

             Dextromethorphan has been sniffed in the abuse setting.

        5.3  Dermal

             No data available

        5.4  Eye

             No data available

        5.5  Parental

             No data available

        5.6  Others

             No data available

    6.  KINETICS

        6.1  Absorption by route of exposure

             Dextromethorphan is well absorbed from the
             gastrointestinal tract with maximum serum level occurring at
             2.5 hours (Barnhart et al., 1979).  Peak concentration of the
             major metabolite dextrorphan) was 1.6  to 1.7 hours (Silvasti
             et al., 1987).  Onset of effect is rapid, often beginning 15
             to 30 minutes after oral ingestion (Pender & Parks, 1991).
    

             Peak levels for sustained release products generally occur
             about 6 hours after ingestion (Amsel, 1981) although
             absorption may be erratic.

        6.2  Distribution by route of exposure

             There is no information about the volume of distribution
             in humans. In dogs, the volume of distribution is reported to
             range from 5.0 to 6.4 L/Kg (Baselt & Cravey, 1989).

        6.3  Biological half-life by route of exposure

             The half life of the parent compound is approximately 2
             to 4 hours in people with normal metabolism.

        6.4  Metabolism

             There is a clear first pass metabolism and it is
             generally assumed that the therapeutic activity is primarily
             due to its active metabolite, dextrophan (Silvasti et al.,
             1987; Baselt & Cravey, 1982).
             Genetic polymorphism has profound effects on its metabolism
             (Hildebrand et al 1989).  Dextromethorphan undergoes
             polymorphic metabolism depending on variation in cytochrome
             P-450 enzyme phenotype. The specific cytochrome P-450 enzyme
             is P450 2D6(CYP2D6) (Schadel et al., 1995).
             Fast metabolizers constitute about 84% of the population.
             After a 30 mg dose plasma levels are less than 5 ng/mL four
             hours postingestion (Woodworth et al., 1987). Intermediate
             metabolizers constitute about 6.8% of the population. After
             an oral dose of 30 mg plasma levels are 10 to 20 ng/mL at 4
             hours and less than 5 ng/mL at 24 hours postingestion
             (Woodworth et al., 1987).  Poor metabolizers constitute 5% to
             10% of the Caucasian population. The ratio of metabolite to
             parent drug in 8 hour urine sample is less than 10 to 1 after
             a 15 mg dose (Hildebrand et al., 1989).  After an oral dose
             of 30 mg plasma levels are greater than 10 ng/mL at 4 hours
             and greater than 5 ng/mL at 24 hours (Woodworth et al.,
             1987).
             It is metabolized in the liver by extensive metabolizers to
             dextrorphan. Dextrorphan is itself an active antitussive
             compound (Baselt & Cravey, 1982). Only small amounts are
             formed in poor metabolizers (Kupfer, 1986).  Less than 15% of
             the dose form minor metabolites including D-methoxymorphinane
             and D-hydroxmorphinane (Kupfer, 1986).

        6.5  Elimination by route of exposure

             Dextromethorphan and its metabolites are excreted via
             the   kidney. Depending on the metabolism phenotype up to 11%
             may be excreted unchanged or up to 100% as demethylated

             conjugated morphinan compounds (Hildebrand, 1989).  In the
             first 24 hours after dosing, less than 0.1% is eliminated in
             the faeces (Baselt & Cravey, 1989).

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    The toxicodynamic actions of dextromethorphan
                    are not completely defined. Dextromethorphan enhances
                    serotonin activity by inhibiting the reuptake of
                    serotonin (Kramei et al., 1992; Bem & Peck, 1992)
                    Specific non-opioid dextromethorphan binding sites are
                    present in the central nervous system (CNS) which
                    mediate the antitussive effects, separate from codeine
                    and other opioids (Hardman et al., 1996).
                    Dextromethorphan and dextrorphan both affect the NMDA 
                    receptor (Carpenter et al., 1988; Reynolds, 1993).

             7.1.2  Pharmacodynamics

                    The antitussive effects of dextromethorphan and
                    the metabolite dextrorphan are secondary to binding in
                    the CNS at non-opioid receptors. Dextromethorphan does
                    not have analgesic or addictive properties, although
                    abuse and dependence have been described(Hardman et
                    al, 1996). One of the major metabolites, dextrorphan
                    has cough suppressant activity.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Coma was reported in an adult who
                             ingested 720 mg over 36 hours (Schneider,
                             1991).  Rated as lethal at oral doses of 50
                             to 500 mg/kg (Gosselin, 1981).
                             Death has been reported after overdose in two
                             cases but quantity was uncertain (Rammer et
                             al., 1988).
                             Long-acting products: adults have tolerated
                             up to 960 mg/day with minor adverse effects
                             (Walker and Hunt, 1989).
                             Abuse: Has been used for abuse. Orally in
                             doses of 300 mg to 1800 mg in adults it can
                             cause intoxication with hyperexcitability,
                             visual and/or auditory hallucinations (Dodds
                             & Revai, 1967; Orrell & Campbell, 1986). It

                             has been reported that sniffing 0.25 g two to
                             three times a day over 2 to 3 months produced
                             euphoria and restlessness for up to 2 hours
                             followed by dizziness, nausea, depression and
                             fatigue (Fleming, 1986).
                             Chronic effects: It should be noted that
                             dextromethorphan is marketed as the
                             hydrobromide and can produce bromide toxicity
                             with chronic use.
                             Dextromethorphan has been abused at doses of
                             2160 to 2880 mg daily for up to five years
                             producing hallucinations, euphoria,
                             disorientation, insomnia and nausea.
                             Withdrawal produced dysphoria and craving for
                             the drug (Wolf and Caravati 1995).

                    7.2.1.2  Children

                             Toxicity may be variable in
                             children. Ingestion of as little as 17 mg/Kg
                             has resulted in signs and symptoms of
                             toxicity.  At this dosage range some children
                             have shown no symptoms whilst others have
                             shown ataxia, stupor, transient fever,
                             lethargy or nystagmus (Versie et al., 1962;
                             Katona & Wason, 1986). Seizures have been
                             reported.
                             Long-acting products may be more toxic in
                             children, producing prolonged CNS depression
                             at 10 mg/kg (Devlin, 1985).

             7.2.3  Animal data

                    LD 50 in mice 165 mg/kg
                    LD 50 in rats 350 mg/kg (Gosselin, 1981)
                    LD 50 in mice 39 mg/Kg (Benson, 1953)

             7.2.3  Relevant in-vitro data

                    No data available

        7.3  Carcinogenicity:

             No data available

        7.4  Teratogenicity

             There was no association between dextromethorphan and
             malformations (Heinonen et al., 1977). Dextromethorphan is
             generally considered safe to use during pregnancy (Berkowitz
             et al., 1981).

        7.5  Mutagenicity

             No data available

        7.6  Interactions

             Concomitant use of monoamine oxidase inhibitors has
             caused toxicity leading to death (Rivers & Horner, 1970;
             Hansten, 1989).
             Not to be taken with serotonin re-uptake inhibitors
             (Skop et al., 1994)
             Alcohol and drugs causing CNS depression should be avoided
             when taking dextromethorphan.

        7.7  Main adverse effects

             Adverse effects are very uncommon with therapeutic doses.
             Infrequent adverse effects include dizziness, drowsiness,
             nausea, vomiting and stomach ache (USPC, 1989).

    8.  TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.2  Urine

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Monitoring dextromethorphan serum levels is not useful
             clinically in the overdose situation because a correlation 
             between levels and clinical effects has yet to be determined
             (Walker & Hunt, 1989). However plasma levels may be measured
             to determine metabolizer phenotype.  The presence of
             dextromethorphan may be confirmed by qualitative
             determination of the drug in urine or serum.
    
             Plasma dextromethorphan concentrations have not been
             correlated with clinical toxicity. Monitoring concentrations
             of dextromethorphan, therefore, would not be useful
             (Ellenhorn & Barceloux, 1983; Walker & Hunt, 1989) Plasma
             dextromethorphan concentrations are used to determine hepatic
             metabolism phenotype.
    
             Sample collection
             If required arterial blood for blood gasses.
    
             Biomedical analysis
             Arterial blood gasses to determine the degree of ventilatory
             depression.
    
             Toxicological analysis
             The presence of dextromethorphan may be confirmed by
             qualitative determination of the drug in urine or blood, see
             Section 8. Plasma levels may be used to determine metabolizer
             phenotype.

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Oral ingestion is the most common route of
                    acute poisoning. The most common clinical effects
                    involve the central nervous system (CNS).
                    Neurologic: drowsiness, lethargy, ataxia, nystagmus,
                    CNS stimulation, vertigo, coma, psychosis and
                    hyperreflexia (Cetaruk & Aaron, 1995; Wolfe &

                    Caravati, 1995; Devlin et al., 1985; Shaul et al.,
                    1977; Schneider et al., 1991).
                    Seizures have been reported within 30 minutes of
                    ingestion.
                    Respiration: Respiratory depression has been noted
                    (Katona and Wason, 1986; Shaul et al., 1977).
                    Cardiovascular: Long-acting preparations may cause
                    tachycardia (Devlin et al.,  1985).
                    Gastrointestinal: Nausea, vomiting (Versie at al.,
                    1962) constipation and dry mouth may occur.
                    Eye: Mydriasis, miosis and nystagmus may be seen.
                    Genitourinary: Retention of urine may be seen.
                    Skin: Urticaria was noted after ingestion of a long-
                    acting preparation in a child (Devlin et al.,
                    1985).
                    Long-acting preparations: With 10 mg/Kg or more taken
                    orally ataxia, lethargy, nystagmus and tachycardia
                    have been reported.

             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.

                    No data available

             9.1.6  Other

                    No data available.

        9.2  Chronic Poisoning

             9.2.1  Ingestion

                    The daily abuse of oral dextromethorphan has
                    been described as causing hallucinations (visual and
                    auditory), dyspnea, floating and flying sensations,
                    and increased perception (Wolfe & Caravati, 1995). 
                    Central nervous system (CNS) stimulation has also been
                    reported (Dodds & Revai, 1967; Orrell & Campbell,
                    1986). When the drug was stopped no withdrawal
                    symptoms were noted, however, craving for
                    dextromethorphan continued.
    

                    It should be noted that dextromethorphan may be
                    marketed as the hydrobromide salt and can produce
                    bromide toxicity with chronic use.

             9.2.2  Inhalation

                    No data available.

             9.2.3  Skin contact

                    No data available

             9.2.4  Eye contact

                    No data available

             9.2.5  Parental exposure

                    No data available

             9.2.6  Other

                    It has been reported that sniffing 0.25 g two
                    to three times a day over 2 to 3 months produced
                    euphoria and restlessness for up to 2 hours followed
                    by dizziness, nausea, depression and fatigue (Fleming,
                    1986).  This patient did not demonstrate withdrawal
                    symptoms on cessation but did complain of continuing
                    craving for dextromethorphan.

        9.3  Course, prognosis, cause of death:

             Following overdose of short acting dextromethorphan
             patients may become clumsy, hyperkinetic and ataxic a few
             hours after the ingestion. There may be vomiting, drowsiness,
             dizziness, blurred vision, nystagmus, and visual and auditory
             hallucinations. Later unsteadiness and unstable gait are
             observed with truncal ataxia. In severe cases, shallow
             respirations, urinary retention, stupor, or coma may
             supervene, especially if high doses of alcohol have been
             ingested. The prognosis for recovery is good (Ellenhorn &
             Barceloux, 1988).
             Following ingestion of long acting dextromethorphan symptoms
             of over use in children include urticaria, restlessness,
             lethargy, nystagmus, ataxia, tachycardia and blood pressure
             elevation. This may require admission to an intensive care
             unit. Long acting preparations may produce a higher rate of
             toxic symptoms in children than short-acting
             dextromethorphan. There does not appear to be a correlation
             between the amount of long-acting dextromethorphan ingested
             and the severity of symptoms (Ellenhorn & Barceloux,
             1988).

        9.4  Systematic description of clinical effects:

             9.4.1  Cardiovascular

                    Long-acting preparations may cause tachycardia
                    (Devlin et al., 1985).  No reports of chronic effects
                    were found in the literature.

             9.4.2  Respiratory

                    Respiratory depression has been noted following
                    large doses (Katona and Wason, 1986; Shaul et al.,
                    1977). No reports of chronic effects were found in the
                    literature.

             9.4.3  Neurologic

                    9.4.3.1  Central nervous system (CNS)

                             In acute overdose ataxia, drowsiness
                             (Devlin et al., 1985; Shaul et al., 1977)
                             vertigo and coma (Schneider et al.,
                             1991).
                             CNS stimulation may be noted.  Restlessness,
                             increased muscle tone with body rigidity have
                             been reported (Benson et al., 1953). 
                             Seizures have been reported within 30 minutes
                             of ingestion.
                             In the abuse situation it can cause CNS
                             stimulation and visual and/or auditory
                             hallucinations (Dodds & Revai, 1967; Orrell &
                             Campbell, 1986). It has been reported that
                             sniffing 0.25 g two to three times a day over
                             2 to 3 months produced euphoria and
                             restlessness for up to 2 hours followed by
                             dizziness, nausea, depression and fatigue
                             (Fleming, 1986).
                             Cognitive deterioration resulting from
                             prolonged abuse has been reported (Hinsberger
                             et al., 1994).

                    9.4.3.2  Peripheral nervous system

                             No data available

                    9.4.3.3  Autonomic

                             No data available

                    9.4.3.4  Skeletal and smooth muscle

                             No data available

             9.4.4  Gastrointestinal

                    After acute overdose nausea, vomiting (Versie
                    et al., 1962), constipation and dry mouth may occur. 
                    No chronic effects were found.

             9.4.5  Hepatic

                    No data available.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             No data available.

                    9.4.6.2  Others

                             Urinary retention has been seen.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatologic

                    Urticaria was reported in a child after acute
                    overdose of a long-acting preparation (Devlin et
                    al.,1985).

             9.4.9  Eye, ear, throat: local effects

                    After acute overdose mydriasis or miosis
                    (Schneider et al.,  1991) and nystagmus (Katona &
                    Wason, 1986; Devlin et al., 1985) may be noted.
                    Nystagmus may persist from 7 to 8 hours with long-
                    acting preparations (Devlin et al., 1985). No chronic
                    effects were found.

             9.4.10 Hematological

                    No data available.

             9.4.11 Immunologic

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No data available.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No data available.

                    9.4.12.3 Others

                             No data available.

             9.4.13 Allergic reactions

                    A cutaneous lesion consistent with a fixed-
                    drug reaction was reported after ingestion over 2 to 3
                    weeks in therapeutic doses (Stubb & Reitamo,
                    1990).

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Pregnancy:
                    Ingesting dextromethorphan during the first trimester 
                    demonstrated no association between the drug and
                    malformations (Heinonen, 1989).  Dextromethorphan is
                    generally considered safe during pregnancy (Berkowitz,
                    1981).
    
                    Breast feeding:
                    No data available.
    
                    Enzyme deficiencies:
                    No data available.

                    Serotonergic Syndrome (see 4.3)

        9.5  Others

             Dextromethorphan has been used for abuse however there
             were no withdrawal symptoms on cessation but there was a
             continued craving for the drug.

    10. MANAGEMENT

        10.1 General principles

             Assess and support airway, ventilation, and
             circulation. Naloxone may antagonize respiratory depression. 
             Gastric decontamination is recommended for recent ingestions
             of more than 10 mg/kg of dextromethorphan.  Patients with
             respiratory depression may require admission to an intensive
             care unit. Others can be observed in the emergency facility
             for 4 to 6 hours and then discharged. A small number of
             patients with minor symptoms (such as ataxia or restlessness)

             may be sent home under careful supervision. (Ellenhorn &
             Barceloux, 1988) Children who have ingested a long-acting
             preparation should be hospitalized.

        10.2 Life supportive procedures and symptomatic treatment

             Assess and support airway, ventilation, and
             circulation. Naloxone may antagonize respiratory depression. 
             Patients with respiratory depression may require admission to
             an intensive care unit. Other patients can be observed in the
             emergency facility for 4 to 6 hours and then discharged.
             Patients with minor symptoms (such as ataxia or restlessness)
             may be sent home under supervision. (Ellenhorn & Barceloux,
             1988) Children who have ingested a long-acting preparation
             should be hospitalized for 24 observation.

        10.3 Decontamination

             Gastric decontamination is recommended for a recent
             ingestion of more than 10 mg/kg. Seizures and/or central
             nervous system (CNS) depression have occurred within 30
             minutes of ingesting dextromethorphan.
    
             GASTRIC LAVAGE followed by activated charcoal may be used
             within 1 to 2 hours of ingestion and may be indicated in
             recent large ingestions or in patients who are comatose or at
             risk of convulsing. Gastric lavage in a comatose patient
             should be preceded by intubation.
    
             ACTIVATED CHARCOAL/CATHARTIC. Activated charcoal may be given
             alone or with a cathartic such as sorbitol or magnesium
             citrate, even though at this time there is no data concerning
             the adsorption of dextromethorphan by charcoal.
             Because there is no data concerning the adsorption of
             dextromethorphan by charcoal if routine gastric emptying is
             omitted the patient may receive inadequate treatment if
             charcoal alone is used. A reasonable approach might be to
             consider gastric lavage in patients ingesting more than 10
             mg/Kg of dextromethorphan, those with clinical features of
             overdose, or those where the time and quantity of ingestion
             is unknown.
             The optimum dose of activated charcoal has not been
             established, but as a guide 1 g to 2 g/kg of activated
             charcoal is recommended, particularly in infants. The adult
             dose may therefore be 30 g to 100 g and the dose in children
             15 g to 30 g.  If a patient vomits the dose it may be
             repeated.  Do not use charcoal tablets or universal antidote
             as a substitute for activated charcoal.
    
             WHOLE BOWEL LAVAGE. If a long-acting dextromethorphan
             preparation has been ingested whole bowel lavage may be
             considered.
    

             CATHARTIC. A saline cathartic or sorbitol may be administered
             with the first dose of activated charcoal or it may be given
             separately.  Although there is little evidence to support the
             use of cathartics (McNamara, 1988; Stewart, 1983) their use
             would seem logical to shorten transit time and avoid the
             constipation caused by charcoal. Repeated doses of cathartics
             is not recommended especially in children. If the dose is
             repeated this should be done with extreme caution.

        10.4 Enhancd elimination

             There is no information currently available on the
             effectiveness of forced diuresis, alkalinization,
             acidification, haemoperfusion, or dialysis for the treatment
             of dextromethorphan overdose.  The use of these methods of
             potentially increasing drug elimination are not recommended
             for the treatment of dextromethorphan poisonings.

        10.5 Antidote

             10.5.1 Adults

                    NALOXONE may be of benefit to reverse the
                    respiratory and CNS effects of dextromethorphan. 
                    Although there have been reports concerning the
                    response to naloxone (Katona & Wason, 1986; Shaul et
                    al, 1977), in most cases improvement in, and
                    resolution of, neurologic symptoms occurred over three
                    to eight hours after naloxone administration, and this
                    may represent the natural course of dextromethorphan
                    toxicity rather than a response to naloxone
                    (Pender,1991).  There is currently no evidence which
                    suggests significant efficacy associated with naloxone
                    administration (Wolfe & Caravati, 1995).

             10.5.2 Children

                    No data available.

        10.6 Management discussion

             Many references still recommend the use of Ipecac to
             induce emesis in dextromethorphan overdose.  However there
             have been reports of seizures following overdose and thus
             this monograph does not advocate the induction of emesis.
             Also, most dextromethorphan ingestions are the liquid
             formulation which are most likely absorbed quickly. Emesis
             may thus be ineffective and contraindicated due to rapid CNS
             depression, and may delay the administration of activated
             charcoal. Charcoal has been recommended without reports
             proving or disproving its efficacy. However it is commonly

             used for dextromethorphan overdose and is likely to be
             effective and safe. Research on this matter would determine
             if this is so.
             Further information is required before naloxone can be
             accepted as an antidote for dextromethorphan toxicity.  The
             cases presented to date do not support reversal of
             dextromethorphan toxicity by naloxone. This is supported by
             the pharmacology of dextromethorphan (Wolfe & Caravati, 1995;
             Hardman et al., 1996).

    11. ILLUSTRATIVE CASES

        11.1 Case report from the literature

             Case 1
             A 41 year old female ingested 720 mg of dextromethorphan over
             a 36 hour period. She presented lethargic and responding only
             to painful stimuli. Respirations were shallow and sporadic,
             pupils pinpoint and minimally reactive to light. Because of
             her decreased level of consciousness and miosis, 1 mg of
             naloxone intravenous (IV) was administered with some
             improvement of consciousness. An additional 2 mg naloxone was
             administered with further improvement and ultimate return to
             normal mental status. Serum samples showed dextromethorphan
             level of 100 ng/mL (Schneider et al., 1991).
    
             Case 2
             A report is given of two young adults who died after overdose
             of dextromethorphan. How much was taken is uncertain (Rammer
             at al 1988).
    
             Case 3
             A 23 year old male presented with psychosis after an acute
             overdose of dextromethorphan. He demonstrated
             hyperexcitability and hallucinations which he compared to his
             experience with LSD.(Dodds & Revai, 1967).
    
             Case 4
             A 26 year old female took approximately 60ml of a cough
             medicine containing dextromethorphan about six hours after
             ingesting 30 mg of phenelzine (Nardil). Thirty minutes later
             she felt nauseated, dizzy and collapsed. Within one hour she
             was brought to the hospital unconscious with rigid
             extremities and fixed, dilated pupils.  She was severely
             hypotensive with a systolic blood pressure that did not rise
             above 70 mm of mercury and a temperature that ranged from
             42C to 42.2C. Despite vasopressors, anti-arrhythmics and
             adrenaline, approximately four hours after arriving at the 
             hospital she had a cardiac arrest and died (Rivers & Horner,
             1970).
    

             Case 5
             An 11 week old infant was given inappropriate doses of a
             dextromethorphan/guaifenesin mixture over a period of 24
             hours. Doses were more frequent and larger than those
             recommended, but the exact amount was unable to be
             determined.  The infant was alert and noted to be
             hyperexcitable with intermittent periods of extremity
             stiffening and cutaneous mottling.  He was given naloxone 0.1
             mg/Kg intravenously.  Within 30 minutes of the naloxone he
             was noted to be calmer and within two hours all signs had
             resolved (Pender & Parks, 1991).
    
             Case 6
             A 3 year old boy ingested an unknown amount of
             dextromethorphan and presented with lethargy, somnolence,
             ataxia and nystagmus. Vital signs were normal, and
             respirations adequate. He awoke after he was given
             intravenous naloxone (0.4 mg).  Twenty five grams of charcoal
             was given and during the next three hours his condition
             steadily improved and he was discharged (Katona & Wason,
             1986).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Dextromethorphan must not be used with monoamine
             oxidase inhibitors (MAOIs) since death has occurred.
             Dextromethorphan should not be used with other CNS
             depressants.
             Dextromethorphan should not be used with serotonin re-uptake
             inhibitors.
             Care should be taken that dextromethorphan is not given in
             overdose, especially to children.
             Medicines containing dextromethorphan are best store in child
             resistant containers.
             Dextromethorphan has been abused and care should be taken not
             to supply it to susceptible individuals.

        12.2 Other

             No data available.

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    14. AUTHOR(S), REVIEWER(S) DATES (INCLUDING EACH UPDATING), COMPLETE
        ADDRESSES

        Author: Jim Magarey
        Poisons Information Centre
        Royal Childrens Hospital
        Flemington Rd, Parkville
        Melbourne, Victoria
        AUSTRALIA   3052
    
        Telephone 03 93455680  Fax 03 93491261

        Date of writing: 1992
    

        Updated by same author August 1996
    
        Peer review: Dr. A.N.P. van Heijst, August 1996
        Dr. W. Watson August, 1996
    
        PIM review group: Intox 9, September, 1996, Cardif, Wales
    
        Editor: Dr M. Ruse (August, 1997)
    


    See Also:
       Toxicological Abbreviations