IPCS INCHEM Home
    Summary for UKPID




    OPIOID ANALGESIC




    Kathryn Pughe, BSc (Hons) MRPharmS

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP
    UK


    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information
    Service.


    PRODUCT DETAILS

    Name

         Generic             Alfentanil hydrochloride
         Proprietary         Rapifen,
                             Rapifen Intensive Care

    Chemical Group/Family

         Opioid analgesic
         BNF 4.7.2

    Reference Number

         CAS 71195-58-9 alfentanil
         CAS 69049-06-5 alfentanil HCl, anhydrous
         CAS 70879-28-6 alfentanil HCl, monohydrate

         Product licence
         0242/0091 (Rapifen)
         0242/0137 (Rapifen Intensive Care)

    Manufacturer/Supplier

         Janssen-Cilag Ltd
         PO Box 79
         Saunderton
         High Wycombe
         Bucks
         HP14 4HJ

         Tel  01494 567567
         Fax  01494 567568

    Presentation

         Rapifen
         Clear, colourless injection alfentanil HCl 0.5 mg/ml
         2 ml and 10 ml ampoules, packs of 10

         Rapifen Intensive Care
         Clear, colourless injection alfentanil HCl 5 mg/ml
         1 ml ampoules, packs of 10

    Physico-Chemical Properties

    Chemical structure
         C21H32N6O3HCl.H2O
         N-[1-[2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-
         (methoxymethyl)-4-piperidyl]propionanilide hydrochloride
         monohydrate

    Physical state at room temperature
         White crystalline powder

    Molecular weight (free base)
         471.0 (416.5)

    pKa (>N-)
         6.5

    Solubility
         in alcohol               1 in 5
         in water                 1 in 7

    Name

         Generic        Buprenorphine
         Proprietary    Temgesic

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 52485-79-7 buprenorphine
         CAS 53152-21-9 buprenorphine HCl

         Product licence numbers
         0063/0007 (0.3 mg inj)
         0063/0008 (0.2 mg tabs)
         0063/0009 (0.4 mg tabs)

    Manufacturer/Supplier

         Reckitt & Colman Products Ltd.,
         Dansom Lane,
         Hull
         HU8 7DS

         Tel: 01482 326151
         Fax: 01482 582526

    Presentation

         Temgesic Sublingual
         White 200 mcg tabs marked with a 2 and a sword symbol in blister
         pack of 5x10
         White 400 mcg tabs marked with a 4 and a sword symbol in blister
         pack of 5x10

         Temgesic Injection
         Colourless injection 300 mcg/ml,
         1 ml ampoules, packs of 5

    Physico-Chemical Properties

    Chemical structure
         C29H41NO4.HCl
         N-Cyclopropylmethyl-7-[1-(S)-hydroxy-1,2,2-trimethylpropyl]- 
         endoethano-6,7,8,14-tetrahydro-nororipavine

    Physical state at room temperature
         white odourless powder

    Molecular weight (free base)
         468

    pKa
         8.42, 9.92

    Solubility
         in alcohol     1 in 24

    Name

         Generic             Codeine phosphate
                             Compound prep -
                             Co-codamol, Co-codaprin

         Proprietary         Compound preparations -
                             Aspav, Codafen Continus, Galcodine,
                             Kaodene, Kapake, Migraleve, Panadeine,
                             Paracodol, Parake, Solpadol, Terpoin,
                             Tylex

                             Also in various OTC products

         Synonym / street    Schoolboy

    Chemical Group/Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 52-28-8 (Codeine PO4 - anhydrous)
         CAS 41444-62-6 (Codeine PO4 - hemihydrate)
         CAS 5913-76-8 (Codeine PO4 - sesquihydrate)

    Manufacturer/Supplier

         Generic

    Presentation

         15 mg round white tabs in containers of 100
         30 mg round white tabs in containers of 100 or 500
         60 mg round white tabs in containers of 100
         25 mg/5 ml syrup bottles of 100 ml and 500 ml
         60 mg/ml inj in boxes of 10 amps
         15 mg/5 ml linctus bottles of 100 ml and 1L
         3 mg/5 ml paediatric linctus bottles of 100 ml and 1L

    Physico-Chemical Properties

    Chemical structure
         C18H21NO3.H3PO4.H2O
         7,8-Didehydro-4,5alpha-epoxy-3-methoxy-N-methylmorphinan-
         6alpha-ol phosphate hemihydrate

    Physical state at room temperature
         fine, white, needle-shaped crystals or a white crystalline powder

    Molecular weight (free base)
         299.4

    pKa
         8.2

    Solubility
         in alcohol     1 in 325
         in water       1 in 4

    Name

         Generic             Dextromoramide tartrate
         Proprietary         Palfium
         Synonym / street    Peach palf

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 2922-44-3

         Product licence numbers
         0075/5015R (5 mg tabs)
         0075/0035R (10 mg tabs)
         0075/5014R (10 mg suppositories)

    Manufacturer/Supplier

         Boehringer Mannheim UK
         (Pharmaceuticals) Ltd,
         Simpson Parkway,
         Kirkton Campus,
         Livingston,
         West Lothian
         EH54 7BH

         Tel  01506 412512
         Fax  01506 411395

    Presentation

         Palfium
         White scored 5 mg tabs in blister packs of 60
         Peach scored 10 mg tabs in blister packs of 60
         Light cream 10 mg suppositories in packs of 10

    Physico-Chemical Properties

    Chemical structure
         C25H32N2O2.C4H6O6
         (d)-1-(3-Methyl-4-morpholino-2,2-diphenylbutyryl)- 
         pyrrolidine tartrate

    Physical state at room temperature
         white, amorphous or crystalline powder

    Molecular weight (free base)
         542.6 (392.5)

    pKa
         7.1

    Solubility

         in alcohol          1 in 85
         in water            1 in 25

    Name

         Generic        Dextropropoxyphene hydrochloride
         Proprietary    Doloxene
                        Compound preparations - 
                        Cosalgesic, Distalgesic, Doloxene Compound

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 1639-60-7

         Product licence number
         0006/5068

    Manufacturer/Supplier

         Eli Lilly & Co Ltd
         Dextra Court,
         Chapel Hill,
         Basingstoke,
         Hampshire,
         RG21 5SY

         Tel  01256 315000
         Fax  01256 315569

         Compound preparations available from APS, Berk, Cox, Dista,
         Norton, Sterwin

    Presentation

         Doloxene
         Opaque pink 65 mg caps marked Lilly H64 in blister packs of 10 x
         10

         Doloxene compound
         Light grey opaque cap, red opaque body marked H91 in blister
         packs of 100

    Physico-Chemical Properties

    Chemical structure
         C22H29NO2.HCl
         (d)-(1S,2R)-1-Benzyl-3-dimethylamino-2-methyl-1-phenylpropyl 
         proprionate hydrochloride

    Physical state at room temperature
         white to slightly yellow odourless powder

    Molecular weight (free base)
         375.9 (339.5)

    pKa (amino)
         6.3

    Solubility
         in alcohol     1 in 1.5
         in water       1 in 0.3

    Name

         Generic             Diamorphine hydrochloride
         Proprietary         Diagesil
         Synonym / street    Heroin; Boy; Brown sugar; Black tar; Chinese;
                             Chinese rock; Crap; Dana; Dujie; Elephant;
                             H;Harry; Horse; Joy powder; Junk; Mexican
                             brown;Noise; Persia; Poor man's speedball;
                             Rock; Rock'n roll; Rufus; Smack; Speedball;
                             Stuff; TNT; White elephant; White junk; White
                             stuff.

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 561-27-3 (diamorphine)
         CAS 1502-96-0 (diamorphine HCl)

         Product licence numbers

         5 mg inj       0039/5662
         10 mg inj      0039/5663
         30 mg inj      0039/5665
         100 mg inj     0039/0154
         500 mg inj     0039/0163

    Manufacturer/Supplier

         Generics -     Aurum, Berk, CP, Evans, Hillcross

         Evans Medical Ltd
         Evans House
         Regent Park
         Kingston Rd
         Leatherhead
         Surrey
         KT22 7PQ

         Tel  01372 364000
         Fax  01372 364190

    Presentation

         Round white scored 10 mg tabs in packs of 100 (Aurum)
         White / off-white powder for reconstitution, 5 mg, 10 mg, 30 mg,
         100 mg and 500 mg injections in boxes of 5 ampoules

    Physico-Chemical Properties

    Chemical structure
         C21H23NO5.HCl.H2O
         7,8-Dehydro-4,5-epoxy-N-methyl morphinan-3,6-diol diacetate
         hydrochloride

    Physical state at room temperature
         almost white crystalline powder

    Molecular weight (free base)
         423.9 (369.4)

    pKa
         7.6

    Solubility
         in alcohol          1 in 12
         in water            1 in 1.6

    Name

         Generic             Dihydrocodeine tartrate
         Proprietary         DF 118, DF 118 Forte, DHC Continus
                             Compound preparations -
                             Co-dydramol, Galake, Paramol, Remedeine,
                             Remedeine Forte

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 125-28-0 (dihydrocodeine)
         CAS 5965-13-9 (dihydrocodeine tartrate)

         Product licence numbers
         0337/0230 (DF118 Forte)
         0337/0196 (DF118 Inj)
         0337/0115 (60 mg tabs)
         0337/0140 (90 mg tabs)
         0337/0141 (120 mg tabs)
         0337/0197 (elixir)
         0530/0229 (30 mg tabs by Norton)

    Manufacturer/Supplier

         Napp, Aurum and generics

         Napp Laboratories Ltd
         Cambridge Science Park
         Milton Road
         Cambridge
         CB4 4GW

         Tel  01223 424444
         Fax  01223 424441

    Presentation

         Generics
         30 mg tabs bottles of 20, 100, 500

         Dihydrocodeine Elixir BP
         Brown syrup of 10 mg/5ml in bottles of 150 ml and 1 litre

         DF118 Injection
         Colourless solution of 50 mg/ml in boxes of 5 ampoules

         DF118 Forte Tablets
         Round, white 40 mg tabs marked with DF118 and Forte, in bottles
         of 100

         DHC Continus Tablets
         White capsule-shaped tablets
         60 mg tabs m/r, marked DHC 60 packs of 56
         90 mg tabs m/r, marked DHC 90 packs of 56
         120 mg tab m/r, marked DHC120 pack of 56

    Physico-Chemical Properties

    Chemical structure
         C18H23NO3.C4H6O6
         4,5-Epoxy-3-methoxy-17-methylmorphinan-6-ol tartrate

    Physical state at room temperature
         odourless white crystalline powder

    Molecular weight
         451.5

    pKa
         8.8

    Solubility
         in alcohol          sparingly
         in water            1 in 4.5

    Name

         Generic             Dipipanone hydrochloride
         Proprietary         Diconal (with 30 mg cyclizine)
         Synonym / street    Dike

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 467-83-4 (dipipanone)
         CAS 856-87-1 (dipipanone HCl)

         Product licence number
         0003/5027R

    Manufacturer/Supplier

         Glaxo Wellcome
         Stockley Park West
         Uxbridge
         Middlesex
         UB11 1BT

         Tel  0800 413524
         Fax  0181 990 4372

    Presentation

         Round pink 10 mg tabs, scored and marked WELLCOME F3A, in blister
         packs of 50

    Physico-Chemical Properties

    Chemical structure
         C24H31NO.HCl.H20
         4,4-Diphenyl-6-piperidino-3-hepanone hydrochloride

    Physical state at room temperature
         white crystalline powder

    Molecular weight (free base)
         404.0 (349.5)

    pKa (amine)
         8.5

    Solubility
         in alcohol          1 in 1.5
         in water            1 in 40

    Name

         Generic             Fentanyl citrate
         Proprietary         Durogesic, Sublimaze
         Synonym / street    China white

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS

         Product licence numbers
         0242/0192 (Durogesic 25)
         0242/0193 (Durogesic 50)
         0242/0194 (Durogesic 75)
         0242/0195 (Durogesic 100)
         0242/5001R (Sublimaze)

    Manufacturer/Supplier

         Janssen-Cilag Ltd
         Saunderton
         High Wycombe
         Buckinghamshire
         HP14 4HJ

         Tel  01494 567444
         Fax  01494 567445

    Presentation

         Durogesic patches
         Transparent self-adhesive patches containing a reservoir of
         fentanyl.
         '25' patch, marked Durogesic 25 g fentanyl/h in pink, in boxes
         of 5
         '50' patch, marked Durogesic 50 g fentanyl/h in green, in boxes
         of 5
         '75' patch, marked Durogesic 75 g fentanyl/h in blue, in boxes
         of 5
         '100' patch, marked Durogesic 100 g fentanyl/h in grey, in boxes
         of 5

         Sublimaze injection
         Clear, colourless, aqueous injection
         0.05 mg/ml 2 ml ampoules in packs of 10
         0.05 mg/ml 10 ml ampoules in packs of 10

    Physico-Chemical Properties

    Chemical structure
         C22H28N2O.C6H8O7
         N-(1-Phenethyl-4-piperidyl)propionanilide dihydrogen citrate

    Physical state at room temperature
         white crystalline powder

    Molecular weight (free base)
         528.6 (336.5)

    pKa (amino)
         8.43

    Solubility
         in alcohol          1 in 140
         in water            1 in 40

    Name

         Generic             Meptazinol hydrochloride
         Proprietary         Meptid

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 54340-58-8 (meptazinol)
         CAS 59263-76-2 (meptazinol HCl)
         CAS 34154-59-1 (+/_ - meptazinol HCl)

         Product licence number
         10536/0007 (tablets)
         10536/0008 (injection)

    Manufacturer/Supplier

         Monmouth Pharmaceuticals Ltd
         3 & 4 Huxley Road
         Surrey Research Park
         Guildford
         Surrey
         GU2 5RE

         Tel  01483 565299
         Fax  01483 563658

    Presentation

         Oval, orange film-coated 200 mg tabs, marked MPL 023, in 5
         blister packs of 20
         Clear solution of 100 mg/ml for injection in 1 ml clear glass
         ampoules in packs of 10

    Physico-Chemical Properties

    Chemical structure
         C15H23NO.HCl
         3-(3-Ethyl-1-methyl-hexahydro-1H-azepin-3-yl)-phenol
         hydrochloride

    Physical state at room temperature
         white or creamy powder

    Molecular weight (free base)
         269.8 (233.3)

    pKa  (phenol)            8.7
         (amino)             11.9

    Solubility
         in alcohol          -
         in water            -

    Name

         Generic             Methadone hydrochloride
         Proprietary         Physeptone
         Synonym / street    Doll, dollies, dolophine

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 76-99-3 (methadone)
         CAS 297-88-1 (methadone, +/_)
         CAS 1095-90-5 (methadone HCl)
         CAS 125-56-4 (methadone HCl, +/_)

    Manufacturer/Supplier

         Generics- CP, Martindale

         Glaxo Wellcome
         Stockley Park West
         Uxbridge
         Middlesex
         UB11 1 BT

         Tel  0800 413524
         Fax  0181 990 4372

    Presentation

         Physeptone
         Round, white 5 mg tabs, scored and marked                        
         WELLCOME L4A in 5 blister strips of 10
         10 mg/ml inj in 1 ml ampoules in boxes of 5 and 100

         Generics
         Injections - 10 mg/ml in 1ml, 2 ml, 3.5 ml and 5 ml amps in boxes
         of 10
         Linctus BP in bottles of 500 ml
         Mixture 1 mg/ml in bottles of 30 ml, 50 ml, 100 ml and 500 ml
         (also sugar free versions)

    Physico-Chemical Properties

    Chemical structure
         C21H27NO.HCl
         6-Dimethylamino-4,4-diphenyl-3-heptanone hydrochloride

    Physical state at room temperature
         white or colourless crystalline powder

    Molecular weight (free base)
         345.9 (309.5)

    pKa (amino)
         8.3

    Solubility
         in alcohol          1 in 7
         in water            1 in 12

    Name

         Generic             Morphine
                             Combination products:
                             Kaolin & Morphine mixture,
                             Morphine & Atropine injection
         Proprietary         Cyclimorph, Morcap SR, MST,
                             MXL, Oramorph, Oramorph
                             SR , Sevredol

         Synonym / street    Cube juice, dreamer, hard stuff, hocus, M,
                             monkey, Miss Emma, morf, morpho

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 57-27-2 (anhydrous morphine)
         CAS 6009-81-0 (morphine monohydrate)
         CAS 52-26-6 (anhydrous morphine HCl)
         CAS 6055-06-7 (morphine HCl trihydrate)
         CAS 64-31-3 (anhydrous morphine SO4)
         CAS 6211-15-0 (morphine SO4 hydrate)
         CAS 302--31-8 (anhydrous morphine tartrate)
         CAS 6032-59-3 (morphine tartrate trihydrate)

         Product licence numbers
         0003/5022R (Cyclimorph 10)
         0003/5023R (Cyclimorph 15)

         Morcap SR
         20 mg 4515/0080
         50 mg 4515/0081
         100 mg 4515/0082

         MST Continus tablets
         10 mg 0337/0055; 15 mg 0337/0180;
         30 mg 0337/0059; 60 mg 0337/0087;
         100 mg 0337/0088; 2000 mg 0337/0149.

         MST Continus suspensions
         20 mg 0337/0165; 30 mg 0337/0166;
         60 mg 0337/0225; 100 mg 0337/0226;
         200 mg 0337/0227.

         MXL capsules
         0337/0259-0264 (marketing authorisation)

         Oramorph SR tablets
         10 mg 0015/0208; 30 mg 0015/0209;
         60 mg 0015/0210; 100 mg 0015/0211

         Oramorph solutions
         10 mg/5 ml 0015/0122; 20 mg/ml 0015/0125;
         10 mg/5 ml UDV 0015/0157;
         30 mg/5 ml UDV 0015/0158;
         100 mg/5 ml UDV 0015/0159

         Sevredol tablets
         10 mg 0337/0142; 20 mg 0337/0143;
         50 mg 0337/0265 (marketing authorisation)

    Manufacturer/Supplier

         Boehringer Ingelheim, Napp, IMS, Sanofi
         Winthrop, Wellcome.
         Generics - Evans, Martindale

         Napp Laboratories Ltd
         Cambridge Science Park
         Milton Road
         Cambridge
         CB4 4GW

         Tel: 01223 424444
         Fax: 01223 424441

    Presentation

         Cyclimorph inj - 1 ml amps in boxes of 5
         Morcap SR - transparent caps containing creamy-white / tan
         pellets in blister strips of 30 or 60.
         MST Continus tablets - blister packs of 60
         10 mg tabs golden brown; 15 mg tabs green;
         30 mg tabs dark purple; 60 mg tabs orange;
         100 mg tabs grey; 200 mg tabs teal green.
         MST Continus susp - cartons of 30 foil sachets containing pink
         granules.
         MXL caps - containers of 28 or 30 caps or blister strips of 28 or
         30.
         30 mg light blue marked MS OD30; 60 mg brown marked MS OD60; 90
         mg pink marked MS OD90;
         120 mg olive marked MS OD120;
         150 mg blue MS OD150; 200 mg  rust MS OD200.
         Oramorph SR tabs - blister pack of 10 or 60.
         10 mg greyish orange; 30 mg purple;
         60 mg orange; 100 mg grey.
         Oramorph oral solution - clear, colourless solution 10 mg/5 ml in
         bottles of 100 ml, 300 ml and 500 ml.
         Oramorph concentrate - clear, red solution in bottles of 30 ml
         and 120 ml with calibrated dropper.
         Oramorph unit dose vials - clear, colourless solution in 5 ml
         polyethylene vials, packs of 25 vials. Available as 10 mg/5 ml,
         30 mg/5 ml and 100 mg/5 ml.
         Sevredol - film coated, capsule shaped tablets in blister packs
         and containers of 56 and 112.
         10 mg blue marked IR 10; 20 mg pink marked IR 20;
         50 mg pale green marked IR 50.

    Physico-Chemical Properties

    Chemical structure
         C17H17NO3.H2O
         7,8-Didehydro-4,5-epoxy-3,6-dihydroxy-n-methylmorphinan

    Physical state at room temperature
         colourless white crystalline powder

    Molecular weight (anhydrous)
         303.4 (285.3)

    pKa
         tertiary amine      7.93
         phenolic hydrogen   9.63

    Solubility
         in alcohol          1 in 250
         in water            1 in 5000

    Name

         Generic             Nalbuphine hydrochloride
         Proprietary         Nubain

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 20594-83-6 (nalbuphine)
         CAS 23277-43-2 (nalbuphine HCl)

         Product licence number
         11173/0013

    Manufacturer/Supplier

         Du Pont Pharmaceuticals Ltd
         Avenue One
         Letchworth Garden City
         Herts
         SG6 2HU

         Tel  01462 488200
         Fax  01462 488319

    Presentation

         Clear, colourless solution of 10 mg/ml in 1 ml and 2 ml ampoules
         in boxes of 10

    Physico-Chemical Properties

    Chemical structure
         C21H27NO4.HCl
         (I)-(-)-(5R,6S,14S)-9a-(Cyclobutylmethyl)-4,5-epoxymorphinan-
         3,6alpha,14-triol hydrochloride

    Physical state at room temperature
         white to off-white powder

    Molecular weight (free base)
         393.9 (357.4)

    pKa
         8.71, 9.96

    Solubility

         in alcohol          soluble
         in water            soluble

    Name

         Generic             Oxycodone
         Proprietary         -

    Chemical Group/Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 76-42-6 (oxycodone)
         CAS 124-90-3 (oxycodone HCl)

    Manufacturer/Supplier

         BCM Specials

    Presentation

         Only available in UK through above supplier as suppositories for
         use in palliative care

    Physico-Chemical Properties

    Chemical structure
         C18H21NO4,HCl

    Physical state at room temperature
         NIF

    Molecular weight (free base)
         351.8

    pKa
         NIF

    Solubility

         in alcohol          NIF
         in water            NIF

    Name

         Generic             Papaveretum
         Proprietary         Aspav (with aspirin)

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS -NA

         Product licence
         0142/5597 (Aspav)

    Manufacturer/Supplier

         Martindale Pharmaceuticals
         Bampton road
         Harold Hill
         Romford
         Essex
         RM3 8UG

         Tel: 01708 386660
         Fax: 01708 384032

    Presentation

         Papaveretum inj
         7.7 mg/ml - 1 ml amps in boxes of 10
         15.4 mg/ml - 1 ml amps in boxes of 10

         Papaveretum with hyoscine inj
         15.4 mg/ml + hyoscine 400 mcg/ml - 1 ml amp in boxes of 10

         Aspav
         Round, white tablets containing 7.71 mg papaveretum + 500 mg
         aspirin, marked AP, in containers of 100

    Physico-Chemical Properties

    Chemical structure
         mixture of opium alkaloid hydrochlorides
         253 parts of morphine HCl
         23 parts of papaverine HCl
         20 parts of codeine HCl

    Physical state at room temperature
         yellowish-brown powder

    Molecular weight (free base)
         NA

    pKa
         NA

    Solubility

         in alcohol          NA
         in water            NA

    Name

         Generic             Pentazocine hydrochloride
         Proprietary         Fortral
                             Fortagesic ( with paracetamol)

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 359-83-1 (pentazocine)
         CAS 2276-52-0 (pentazocine HCl)
         CAS 64024-15-3 (pentazocine HCl)

         Product licence numbers
         11723/0028 (Fortagesic)
         11723/0033 (Fortral 25 mg tabs)
         11723/0090 (Pentazocine 25 mg tabs)
         11723/0088 (Pentazocine 50 mg caps)
         11723/0031 (Fortral injection)
         11723/0032 (Fortral suppositories)

    Manufacturer/Supplier

         Sanofi Winthrop Ltd (& Sterwin)
         One Onslow Street
         Guildford
         Surrey
         GU1 4YS

         Tel  01483 505515
         Fax  01483 35432

    Presentation

         Pentazocine
         Orange / grey 50 mg caps, marked PZN 50; Cox NP; PT50 G; yellow /
         grey ftl 50 in bottles of 100
         Round, white 25 mg tabs, marked PZN 25; Cox PZ; S 24; G PT 25 in
         bottles of 100

         Fortral
         Round, white 25 mg tabs, marked STERWIN / Fortral in bottles of
         100

         30 mg/ml inj 1 ml and 2 ml amps in boxes of 10
         50 mg supp in boxes of 20

         Fortagesic
         Round, white 15 mg tabs, marked FORTAGESIC in bottles of 100

    Physico-Chemical Properties

    Chemical structure
         C19H27NO.HCl
         1,2,3,4,5,6-Hexahydro-6,11-dimethyl-3-(3-methylbut-2-enyl)-2,6-
         methano-3-benzazocin-gamma-ol hydrochloride

    Physical state at room temperature
         white or cream crystalline powder

    Molecular weight (free base)
         321.9 (285.4)

    pKa
         8.7, 10.0

    Solubility
         in alcohol          1 in 16
         in water            1 in 30

    Name

         Generic             Pethidine hydrochloride
         Proprietary         Pamergan P100 (with promethazine)
         Synonym / street    Meperidine

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 57-42-1 (pethidine)
         CAS 50-13-5 (pethidine HCl)

         Product licence numbers

         Marketing authorisation number
         0156/0020R (Pamergan P100)

    Manufacturer/Supplier

         Generics - Martindale, Roche

         Martindale Pharmaceuticals
         Brampton Road
         Harold Hill
         Romford
         Essex
         RM3 8UG

         Tel  01708 386660
         Fax  01708 384032

    Presentation

         50 mg tabs in containers of 50
         50 mg/ml inj in boxes of 10
         100 mg/ml inj in boxes of 10

         Pamergan P100
         50 mg inj with promethazine 25 mg/ml - 2 ml ampoules in packs of
         10

    Physico-Chemical Properties

    Chemical structure
         C15H21NO2.HCl
         Ethyl 1-methyl-4-phenylpiperine-4-carboxylate hydrochloride

    Physical state at room temperature
         white colourless crystalline powder

    Molecular weight (free base)
         283.8 (247.3)

    pKa
         8.6

    Solubility

         in alcohol          1 in 20
         in water            >1 in 2

    Name

         Generic             Phenazocine hydrobromide
         Proprietary         Narphen

    Chemical Group / Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 127-35-5 (phenazocine)
         CAS 1239-04-9 (phenazocine HBr)

         Product licence number
         0337/0198

    Manufacturer/Supplier

         Napp Laboratories Ltd
         Cambridge Science Park
         Milton Road
         Cambridge
         CB4 4GW

         Tel  01223 424444
         Fax  01223 424441

    Presentation

         Round white 5 mg tabs, marked N / 5 in containers of 100

    Physico-Chemical Properties

    Chemical structure
         C22H27NOHBr.H2O
         1,2,3,4,5,6-Hexahydro-6,11-dimethyl-3-phenethyl-2,6-methaon-3-
         benzazocin-8-ol hydrobromide hemihydrate

    Physical state at room temperature
         white microcystalline powder

    Molecular weight (free base)
         411.4 (321.4)

    pKa (amino)
         8.5

    Solubility
         in alcohol          1 in 45
         in water            1 in 350

    Name

         Generic             Phenoperidine
         Proprietary         Operidine

    Chemical Group/Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 562-26-5 (phenoperidine)
         CAS 3627-49-4 (phenoperidine HCl)

         Product licence number
         0242/5000R

    Manufacturer/Supplier

         Janssen-Cilag Ltd
         Saunderton
         High Wycombe
         Buckinghamshire
         HP14 4HJ

         Tel: 01494 567444
         Fax: 01494 567445

    Presentation

         Clear, colourless solution containing 1 mg/ml for inj in 2 ml
         amps in packs of 10 and 10 ml amps in packs of 5

    Physico-Chemical Properties

    Chemical structure
         C23H29NO3.HCl
         Ethyl 1-(3-hydroxy-3-phenylpropyl)-4-phenylpiperidine-4-
         carboxylate hydrochloride

    Physical state at room temperature
         white, crystalline powder

    Molecular weight (free base)
         403.9 (367.5)

    pKa
         8.01

    Solubility

         in alcohol          1 in 10
         in water            -

    Name

         Generic             Pholcodine
         Proprietary         Galenphol, Pavacol-D
                             Also in various OTC preps

    Chemical Group/Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 509-67-1 (anhydrous pholcodine)

    Manufacturer/Supplier

         Generics - APS, Norton

         Galen Ltd
         Seagoe Industrial Estate
         Craigavon
         Northern Ireland
         BT63 5UA

         Tel 01762 334974

    Presentation

         Pholcodine linctus 5 mg/5 ml in bottles of 100 ml, 140 ml, 200
         ml, 300 ml, 2 L
         Pholcodine linctus strong 10 mg/5 ml in bottles of 100 ml, 2 L
         Pholcodine paediatric linctus 2 mg/5 ml in bottles of 90 ml, 2 L

    Physico-Chemical Properties

    Chemical structure

         C23H30N2O4.H2O
         3-O-(2-Morphinoethyl)morphine monohydrate

    Physical state at room temperature
         colourless crystalline powder

    Molecular weight (anhydrous)
         416.5 (398.5)

    pKa
         8.0, 9.3

    Solubility
         in alcohol          1 in 3
         in water            1 in 50

    Name

         Generic             Tramadol hydrochloride
         Proprietary         Tramake, Zydol, Zydol SR

    Chemical Group/Family

         Opioid analgesics
         BNF 4.7.2

    Reference Number

         CAS 27203-92-5 (tramadol)
         CAS 22204-88-2 (tramadol HCl)
         CAS 36282-47-0 (tramadol HCl)

         Product licence numbers
         08821/0005 (Zydol caps)
         08821/0004 (Zydol amps)

    Manufacturer/Supplier

         Searle
         PO Box 53
         Lane End Road
         High Wycombe
         Buckinghamshire
         HP12 4HL

         Tel: 01494 521124
         Fax: 01494 447872

    Presentation

         Zydol
         Green / yellow 50 mg caps - blister packs of 10, 100 and 140
         50 mg soluble tabs in packs of 20 and 100
         Colourless aqueous solution containing 100 mg in 2 ml amps in
         boxes of 5

         Zydol SR
         Round white 100 mg tabs, marked T1 in blister packs of 60 and 100
         Round orange 150 mg tabs, marked T2 in blister packs of 60
         Round orange 200 mg tabs, marked T3 in blister packs of 60

         Tramake
         Yellow / green 50 mg caps, marked TRAMAKE, in blister packs of
         100

    Physico-Chemical Properties

    Chemical structure
         C16H25NO2,HCl
         (+/-) - trans-2- Dimethyl-nomethyl-methoxyphenyl)cyclohexanol
         hydrochloride

    Physical state at room temperature
         NIF

    Molecular weight (free base)
         299.8

    pKa
         NIF

    Solubility
         in alcohol          NIF
         in water            NIF

    SUMMARY

    The effects in overdosage will be potentiated by simultaneous
    ingestion of alcohol and other psychotropic drugs.

    Progressive depression of the central nervous system leading to deep
    coma, cyanosis and marked reduction of the respiratory rate before
    respiratory arrest occurs.

    The pupils are usually pin-point in size and nausea and vomiting are
    common in less severe cases.

    Hypotension, tachycardia, hallucinations and rhabdomyolysis have been
    reported.

    Additional features in addicts:
    Overdosage in these cases may be due to ingestion, smoking (e.g.
    heroin) or intravenous or subcutaneous injection. Injection sites may
    therefore be present in some cases, particularly over the antecubital
    fossae, feet and groins.

    Beware of the risks of hepatitis B and HIV infection.

    Non-cardiogenic pulmonary oedema and rhabdomyolisis are particularly
    common after intravenous injection of opioid analgesics.

    Management

    1. Give naloxone (NARCAN) preferably intravenously if coma or
    respiratory depression are present. Adults: naloxone 800 mcg IV to
    start, then 400 mcg every 2 minutes until the patient improves
    (respiratory rate, consciousness, pupil size) or until 3.2 mg have
    been given. Children: 0.01 mg/kg body weight, increase up to 0.1 mg/kg
    if no response or sub-optimal response; Neonates: Initial doses of 10
    to 30 mcg/kg IV.

    Failure of a definite opioid overdose to respond to naloxone suggests
    that another CNS depressant drug or brain damage is present.

    2. Observe the patient carefully for recurrence of CNS and respiratory
    depression. The plasma half-life of naloxone is shorter than that of
    most opioid analgesics. Repeated doses of naloxone may be required.
    Intravenous infusions of naloxone have been recommended in situations

    where repeated doses have been necessary. Set up an infusion (5 x 400
    mcg ampoules naloxone = 2 mg in 500 ml 5% dextrose) at a rate equal to
    2/3 of the dose required to wake the patient per hour. Infusions are
    not substitutes for frequent review of the patients clinical state and
    administration of bolus doses of naloxone as required.

    3. Do not delay in establishing a clear airway, adequate ventilation
    and oxygenation if there is no response to naloxone.

    4. Assisted ventilation with positive end-expiratory pressure may be
    necessary if pulmonary oedema is a complication.

    5. Other supportive measures as indicated by the patient's progress.

    SUBSTANCE

    SUBSTANCE /PRODUCT NAME

    Alfentanil
    Buprenorphine
    Codeine
    Dextromoramide
    Dextropopoxyphene
    Diamorphine
    Dihydrocodeine
    Dipipanone
    Fentanyl
    Meptazinol
    Methadone
    Nalbuphine
     Opium
    Oxycodone
    Pentazocine
    Pethidine
    Phenazocine
    Phenoperidine
    Pholcodine
    Tramadol

    PROPERTIES

    USES

    Indications

    Opioid analgesics are mainly used for the relief of moderate to severe
    pain. They are also used in anaesthesia for premedication induction or
    maintenance. Morphine is generally the standard against which other
    opioids are compared and is considered by many to be the analgesic of
    choice for severe pain associated with terminal illness. Opioids with
    a quicker onset and shorter duration of action such as fentanyl are
    preferred for use in anaesthesia.

    Codeine and pholcodine are used for the suppression of cough; for
    intractable cough in terminal illness morphine or diamorphine may be
    used.

    Methadone is used in the treatment of opioid dependence.

    Therapeutic doses

    SUMMARY

    Opioids are subject to dosage variability based on the intended
    indication and the patient's ability to handle the drug. The goal of
    therapy for analgesia is to use the smallest effective dose. The
    following summarizes usual dosages.

    ALFENTANIL

    By iv infusion with  assisted ventilation adult and child initially
    50 to 100 micrograms per kg over 10 mins or as a bolus followed by
    maintenance of 0.5 - 1 microgram/kg/min.

     Analgesia and suppression of respiratory activity during intensive 
     care, with assisted ventilation, initially 2 mg/hour (approx. 30
    microgram/kg/hour), adjusted according to response (usual range 0.5-10
    mg/hour); more rapid initial control may be obtained with an iv dose
    of 5 mg in divided portions over 10 minutes (slowing if hypotension or
    bradycardia occur); additional doses of 0.5-1 mg may be given by iv
    injection during short painful procedures.

    By iv injection,  spontaneous respiration, adult, initially up to 500
    micrograms over 30 seconds; supplemental 250 micrograms. With assisted
    ventilation adult and child initially 30-50 micrograms/kg;
    supplemental 15 micrograms/kg

    BUPRENORPHINE

     Pain - by im or slow iv injection 300-600 micrograms every 6-8
    hours; child over 6 months 3-6 microgram/kg every 6-8 hours (max 9
    microgram/kg).

    By sublingual administration, initially 200-400 microgram every 8
    hours, increasing if necessary to 200-400 micrograms every 6-8 hours;
    child over 6 months, 16-25 kg, 100 micrograms; 25-37.5 kg, 100-200
    micrograms; 37.5-50 kg, 200-300 micrograms.

     Premedication - by sublingual administration 400 micrograms, by im
    injection 300 micrograms

     Peri-operative analgesia - by slow iv injection, 300-450 micrograms

    CODEINE

     Mild to moderate pain - 30 to 60 mg orally, every 4 hours when
    necessary, to a maximum of 240 mg daily. Child, 1-12 years, 3 mg/kg
    daily in divided doses

    By intramuscular injection 30-60 mg every 4 hours when necessary

     Diarrhoea - 30 mg 3-4 times daily (range 15-60 mg). Child not
    recommended.

     Cough - 5-10 ml 3-4 times daily; child 5-12 years, 2.5-5 ml 3-4
    times daily. Paediatric linctus, child 1-5 years 5 ml 3-4 times daily.

    DEXTROMORAMIDE

    Oral 5 mg increasing to 20 mg when required.
    Rectal 10 mg when required.
    Child not recommended.

    DEXTROPOPOXYPHENE

    65 mg every 6-8 hours when necessary
    65 mg dextropopoxyphene hydrochloride = 100 mg dextropopoxyphene
    napsylate
    Child not recommended

    DIAMORPHINE

     Acute pain by sc or im injection 5 mg repeated every 4 hrs if
    necessary (up to 10 mg for heavier well-muscled patients).
    By slow iv injection quarter to half corresponding im dose.
     Myocardial infarction, by slow iv injection (1 mg/minute), 5 mg
    followed by a further 2.5-5 mg if necessary; elderly or frail
    patients, reduce dose by half.
     Acute pulmonary oedema, by slow iv injection (1 mg/minute), 2.5-5
    mg.
     Chronic pain, oral, sc or im injection 5-10 mg regularly every 4
    hrs; increased according to needs.
    Child not recommended.

    DIHYDROCODEINE

    Oral 30 mg every 4-6 hrs when necessary.
    Child over 4 yrs 0.5-1 mg/kg every 4-6 hrs
    Deep sc or im injection up to 50 mg every 4-6 hrs if necessary.
    Child over 4 yrs 0.5-1 mg/kg every 4-6 hrs

    DIPIPANONE

    Diconal (dipipanone 10mg, cyclizine 30 mg) 1 tablet gradually
    increased to 3 tablets every 6 hours. Child not recommended.

    FENTANYL

    By iv injection,  spontaneous respiration 50-200 micrograms, then 50
    micrograms as required; Child, 3-5 micrograms/kg then 1 microgram/kg
    as required.
    With  assisted ventilation 0.3-3.5 mg, then 100-200 micrograms as
    required; Child, 15 micrograms/kg then 1-3 micrograms/kg as required.
    Patches - apply to skin on torso or upper arm and replace after 72
    hours. Child not recommended.

    MEPTAZINOL

    Oral 200 mg every 3-6 hrs as required. Child not recommended.
    By im injection 75-100 mg every 2-4 hrs if necessary, obstetric
    analgesia 100-150 mg according to patient's weight (2 mg/kg). Child
    not recommended.
    By slow iv injection 50-100mg every 2-4 hrs if necessary. Child not
    recommended.

    METHADONE

     Pain - oral, sc or im injection 5-10 mg every 6-8 hrs, adjusted
    according to response. Child not recommended.
     Opioid dependence - initially 10-20 mg daily, increased by 10-20 mg
    daily until no signs of withdrawal or intoxication; usual dose 40-60
    mg daily. Child not recommended.
     Cough in terminal disease - linctus, 2.5-5 ml every 4-6 hours,
    reduced to twice daily on prolonged use.

    MORPHINE

     Acute pain - by sc or im injection 10 mg every 4 hrs if necessary
    (15 mg for heavier well-muscled patients); Child, up to 1 month 150
    micrograms/kg, 1-12 months
    200 micrograms/kg, 1-5 years 2.5-5 mg/kg, 6-12 years 5-10 mg.
    By slow iv injection quarter to half corresponding im dose.
     Chronic pain - oral, sc or im injection 5-20 mg regularly every 4
    hrs; increased according to needs. Rectal, 15-30 mg regularly every 4
    hours. (NB. modified release preparations have different dosage
    schedules).
     Myocardial infarction, by slow iv injection (2 mg/minute), 10 mg
    followed by a further 5-10 mg if necessary. Elderly or frail patients
    reduce dose by half.
     Acute pulmonary oedema, by slow iv injection (2 mg/minute) 5-10 mg.
     Analgesia - by sc or im injection, up to 10 mg 1-1 hours before
    operation; child, by im injection, 150 microgram/kg.

    NALBUPHINE

     Pain - by sc, im, or iv injection, 10-20 mg for 70 kg patient every
    3-6 hrs, adjusted according to response; Child up to 300 micrograms/kg
    repeated once or twice as necessary.

     Myocardial infarction - by slow iv injection, 10-20 mg repeated
    after 30 minutes if necessary.

     Premedication - by sc, im or iv injection, 100-200 micrograms/kg.

     Induction - by iv injection, 0.3-1 mg/kg over 10-15 minutes.

     Intra-operative analgesia, by iv injection, 250-500 micrograms/kg at
    30 minute intervals.

    OPIUM

    Parenteral: 5-20 mg by im or sc injection every 4-5 hours as needed
    Rectal: 1 suppository once or twice a day

    OXYCODONE

     Analgesia: 5 mg every 6 hours as needed, or 4.88 mg of the combined
    salt every 6 hours as needed. Children 6-12 years 0.61 mg of the
    combined salt every 6 hours as needed. Children 12 years or older 1.22
    mg of the combined salt every 6 hours as needed.

    OXYMORPHONE

    Parenteral

     Analgesia - initially 1-1.5 mg by sc or im injection every 4-6 hours
    as needed.
    Initial iv dose 0.5 mg, increased cautiously until satisfactory
    analgesia obtained.
     Labour - 0.5-1 mg by im injection
    Rectal: One 5 mg suppository every 4-6 hours as needed.
    Not for use in children under 12 years.

    PAPAVERETUM

    By sc, im or iv injection, 7.7-15.4 mg repeated every 4 hours if
    necessary; Elderly initially 7.7 mg; Child up to 1 month 115.5
    micrograms/kg, 1-12 months 115.5-154 micrograms/kg. 1-12 years 154-231
    micrograms/kg.
    In general the iv dose should be quarter to half the corresponding sc
    or im dose.
    Papaveretum and hyoscine injection -  premedication, by sc or im
    injection, 0.5-1 ml.

    PENTAZOCINE

     Pain - oral 50mg every 3-4 hours (range 25-100 mg); Child 6-12 years
    25 mg.
    By sc, im or iv injection moderate pain 30mg, severe pain 45-60 mg
    every 3-4 hours when necessary; Child over 1 year, by sc or im
    injection, up to 1 mg/kg, by iv injection up to 500 microgram/kg.
    Suppositories 50 mg up to 4 times daily. Child not recommended.

    PETHIDINE

     Pain - oral 50-150 mg every 4 hours; Child 0.5-2 mg/kg.
    Sc or im injection, 25-100 mg repeated after 4 hours; Child im
    injection 0.5-2 mg/kg.
    Slow iv injection, 25-50 mg, repeated after 4 hours
     Obstetric analgesia - sc or im injection 50-100 mg, repeated 1-3
    hours later if necessary; max 400 mg in 24 hours.
     Premedication - by im injection, 25-100 mg 1 hour before operation;
    Child 0.5-2 mg/kg.  Adjunct to nitrous oxide-oxygen, by slow iv
    injection, 10-25 mg repeated as required.
    Pamergan P100 - by im injection, for obstetric analgesia, 1-2 ml every
    4 hours if necessary; severe pain, 1-2 ml every 4-6 hours if
    necessary.
     Premedication - 2 ml by im injection 1-1 hours before operation;
    Child, by im injection, 8-12 years 0.75 ml, 13-16 years 1 ml.

    PHENAZOCINE

     Severe pain - oral or sublingual, 5 mg every 4-6 hrs when necessary;
    single doses may be increased to 20 mg; Child not recommended.

    PHENOPERIDINE

     Analgesia during operation, enhancement of anaesthetics, by iv
    injection, with spontaneous respiration, up to 1 mg, then 500
    micrograms every 40-60 minutes as required; child 30-50 micrograms/kg.
    With  assisted ventilation, 2-5 mg, then 1 mg as required; child 100-
    150 micrograms/kg.

    PHOLCODINE

     Dry or painful cough

    Pholcodine linctus - 5-10 ml 3-4 times daily; child 5-12 years 2.5-5
    ml.
    Pholcodine linctus, strong - 4 ml 3-4 times daily.
    Paediatric linctus - child 1-5 years 5 ml 3 times daily; 6-12 years
    5-10 ml.

    TRAMADOL

     Moderate to severe pain - oral 50-100 mg not more often than every 4
    hours; total of more than 400 mg daily not usually required; Child not
    recommended.
    By im or iv injection (over 2-3 minutes), or iv infusion, 50-100 mg
    every 4-6 hrs.
     Postoperative pain, 100 mg initially then 50 mg every 10-20 minutes
    if necessary during first hour to total max 250 mg (including initial
    dose) in first hour, then 50-100 mg every 4-6 hours; max 600 mg daily.
    Child not recommended.

    Modified release - 100 mg twice daily increased if necessary to
    150-200 mg twice daily; total of more than 400 mg daily not usually
    required; child not recommended.

    NALOXONE

    2 mg (adult) or 0.01 mg/kg body weight for children if coma or
    respiratory depression are present. Repeat the dose if there is no
    response within two minutes. Child, 0.01 mg/kg body weight for
    children if coma or respiratory depression are present. Repeat the
    dose if there is no response within two minutes.

    NALTREXONE

    To prevent relapse in detoxified formerly opioid dependent patients:
    25 mg initially then 50 mg daily; the total weekly dose may be divided
    and given on 3 days of the week for improved compliance. Child not
    recommended.

    Contraindications

    Known opiate sensitivity. Avoid in acute respiratory depression, acute
    alcoholism and where risk of paralytic ileus. Not indicated for acute
    abdomen. Avoid in raised intracranial pressure or head injury (in
    addition to interfering with respiration, affect pupillary responses
    vital for neurological assessment). Avoid injection in
    phaeochromocytoma (risk of pressor response to histamine release).

    Abuses

    Dependence can occur with most of the opioid analgesics; it is not
    generally a problem when they are used legitimately.
    All opiates, in particular diamorphine (heroin), have potential for
    abuse because of their euphoriant effect. Dependence can develop
    rapidly with repeated administration.

    EPIDEMIOLOGY

    EPIDEMIOLOGY OF POISONING

    In 1991 226 deaths (190 male, 36 female) were attributed to opiates
    and related narcotics. This represents 11.4% of deaths from poisoning
    by drugs, medicaments and biological substances. 144 deaths (130 male,
    14 female) were due to accidental poisoning, 32 (20 male, 12 female)
    to suicide and self-inflicted injury, 1 (female) to homicide and
    injury purposely inflicted by other persons, and 49 to injury
    undetermined whether accidentally or purposely inflicted (HMSO
    Mortality Statistics).

    Codeine is a constituent of many over-the-counter analgesics commonly
    taken in overdosage, but its effects are usually (but not always)
    overshadowed by those of salicylate or paracetamol. Self-poisonings
    with combined preparations of dextropopoxyphene and paracetamol are

    now much less common than previously, although still pose potentially
    serious problems.

    Poisoning with morphine, heroin and methadone is usually the result of
    accidental iv overdosage by drug addicts due to the unpredictable
    potency of 'street' drugs. There are therefore likely to be marked
    differences in the incidence of this type of opioid poisoning, with a
    much larger problem expected in selected quarters of large cities than
    in rural areas. Dextromoramide and dipipanone are now rarely
    encountered (Proudfoot 1993).

    ADVERSE EFFECTS AND INTERACTIONS

    ADVERSE EFFECTS

    Opioid analgesics share many side-effects, although qualitative and
    quantitative differences exist. The most common effects include nausea
    and vomiting (particularly in the initial stages), constipation,
    drowsiness and confusion. Larger doses produce respiratory depression
    and hypotension, with circulatory failure and deepening coma.

    Other adverse effects include difficulty with micturition, ureteric or
    biliary spasm, dry mouth, sweating, headache, facial flushing,
    vertigo, bradycardia, tachycardia, palpitations, postural hypotension,
    hypothermia, hallucinations, dysphoria, mood changes, dependence,
    miosis, decreased libido or potency, rashes, urticaria, and pruritis.

    Nystagmus was reported in a woman who received tetracaine and
    preservative-free morphine intrathecally. Naloxone reversal was
    successful (Ueyama et al, 1992).

    Paradoxical pain responses have been reported with high-dose
    therapeutic use of nalbuphine and buprenorphine with naloxone.

    A case of seizures following pethidine administration has been
    reported in a child (Kyff & Rice, 1990).

    A case of jerking movements progressing to seizures and
    unconsciousness was reported in a 60-year-old man given 25 mcg/kg
    alfentanil over 30 seconds (Strong & Matson, 1989).

    Myoclonic activity has been reported in two patients on high-dose
    spinal opioid therapy for pain (Parkinson et al, 1990).

    High-dose pethidine has been reported to cause muscle twitching
    (Morisy & Platt, 1986).

    A trauma victim given high doses of nalbuphine (up to 300 mg/day)
    experienced nightmares and extreme pain.

    INTERACTIONS

    Alcohol - enhanced sedative and hypotensive effect

    Anti-Arrhythmics - delayed absorption of mexiletine

    Antibacterials
    rifampicin accelerates metabolism of methadone (reduced effect);
    erythromycin increases plasma concentration of alfentanil
    ciprofloxacin - manufacturer advises avoid premedication with opioid
    analgesics (reduced plasma ciprofloxacin concentration)

    Anticoagulants - dextropopoxyphene enhances effects of warfarin and
    nicoumalone

    Antidepressants - CNS excitation or depression (hypertension or
    hypotension) with MAOIs (including moclobemide) and pethidine, and
    possibly other opioids

    Antiepileptics -    carbamazepine - effect enhanced by
                        dextropopoxyphene
                        carbamazepine - decreases effect of tramadol

    Antipsychotics - enhanced sedative and hypotensive effect

    Antivirals - plasma concentration of zidovudine possibly increased by
    methadone

    Anxiolytics & Hypnotics - enhanced sedative effect

    Cisapride - possible antagonism of gastro-intestinal effect

    Dopaminergics - hyperpyrexia and CNS toxicity with selegilene

    Metoclopramide & Domperidone - antagonism of gastro-intestinal effects

    Ulcer-Healing Drugs - cimetidine inhibits metabolism of opioid
    analgesics notably pethidine (increased plasma concentration)

    MECHANISM OF ACTION / TOXICITY

    Opioid analgesics possess some of the properties of naturally
    occurring opioid peptides, including encephalins, endorphins and
    dynorphins.
    Pharmacologically the opioid analgesics are broadly similar,
    qualitative and quantitative differences may be dependent on their
    interaction with opioid receptors.
    There are several types of opioid receptor, distributed in distinct
    patterns through the central and peripheral nervous systems. The three
    main types in the CNS have been designated  (mu), (kappa) and
    (delta).

     - analgesia (mainly supraspinal sites), respiratory depression,
    miosis, reduced gastro-intestinal motility and euphoria; 1
    (supraspinal analgesia) and 2 (respiratory depression and
    gastro-intestinal activity) subtypes have been postulated.
    kappa - analgesia (mainly in the spinal cord), less intense miosis and
    respiratory depression, dysphoria and psychomimetic effects
    delta - probably analgesia, selective for encephalins
    Other receptors include (sigma) and (epsilon). The psychomimetic
    effects of agonist-antagonists such as pentazocine that are poorly
    antagonised by naloxone have been thought to be mediated by sigma
    receptors.

    Opioid analgesics act at one or more of these receptors as full
    agonists, partial agonists, or antagonists. Opioid analgesics have
    differing affinities for particular receptors and different degrees of
    activation once bound.

    A weak or partial agonist, is a partial agonist at one receptor site
    and has some antagonist activity at other receptors.

    Opioid antagonists are those drugs that bind but do not activate
    opioid receptor sites. Naloxone, an opioid receptor antagonist, acts
    at , kappa and delta receptor sites.

    FEATURES OF POISONING

    Acute Effects

    Ingestion

    Summary

    Opioid overdosage may result in central nervous system and respiratory
    depression with hypoxia, hypotension, shock, gastric hypomotility with
    ileus, and noncardiogenic pulmonary oedema.

    Opioid overdose may result in central nervous system depression.
    Decreased mental status is one of the most prominent symptoms in a
    narcotic overdose, which may progress to coma. Lethargy and coma
    associated with pinpoint pupils occur frequently. Pupils may be
    dilated in the presence of severe acidosis, hypoxia, or respiratory
    depression. Prolonged coma may result due to delayed gastric emptying.
    Seizures, myoclonic reactions, and spongiform encephalopathy have been
    reported in abusers of opioids.

    Respiratory depression and apnea are characteristic effects of opioid
    overdose and when severe may result in severe hypoxia, leading to
    hypotension and shock, pulmonary edema, and respiratory arrest (Wilkes
    et al, 1981; Jaffe & Martin, 1990).

    Delayed onset respiratory depression has been described 3, 6, 9, 14
    and 24 hours following oral methadone ingestions (Wilen et al, 1975;
    Sey et al, 1971; Geller et al, 1994). Prolonged toxicity of 24 to 48

    hours duration including respiratory depression may occur in
    individuals overdosing with methadone (Sey et al, 1971; Romac et al,
    1986; Gayle et al, 1991). Respiratory depression that was NOT
    reversible by naloxone 10 mg was reported in a 61-year-old woman who
    ingested 50 meptazinol 200 mg tablets (Davison et al 1987).

    Hypotension, cardiac arrhythmias, pulmonary hypertension and cyanosis
    have been reported following overdose. Hypotension and shock may
    occur, especially in the presence of prolonged and severe hypoxia
    (Miller et al, 1980; Whipple et al, 1994; Lawrenson et al, 1993).

    Atrial fibrillation has been reported following abuse of crude heroin
    in an adult male patient (Lawrenson et al, 1993). Pentazocine overdose
    has been associated with ventricular dysrhythmias (Stahl & Kasser,
    1983). Bradycardia may develop in patients with severe respiratory
    depression (Sey et al, 1971).

    Increased pulmonary artery pressure, pulmonary wedge pressure, LVEDP,
    arterial pressure, and pulmonary vascular resistance may be noted
    following overdosage of butorphanol.

    Hypothermia has been reported following overdoses of opiates.
    Hypomotility with ileus may occur following overdose.

    Acute tubular necrosis secondary to rhabdomyolysis and myoglobinuria,
    glomerulonephritis, glomerulosclerosis, renal amyloidosis and renal
    failure have been reported in heroin abusers. Rhabdomyolysis has been
    reported following heroin abuse or seizures associated with opioid
    overdose (Blain et al 1985).

    Hypoglycaemia has been reported following a heroin overdose. ACTH
    inhibition may occur with therapeutic and toxic opioid doses.
    Haemolysis has occurred in some patients following administration of
    high doses of fentanyl. Seborrhoea may be seen following MPTP (a
    derivative of pethidine) overdose.

    Inhalation

    Inhalation of opioids may result from drug abuse by persons crushing
    and 'snorting' tablets. Clinical effects and treatment are based on
    the oral route of exposure.
    Airway obstruction and bronchospasm have been associated casually with
    inhalation of heroin heated over metal foil. Eosinophils have been
    detected in the peripheral blood and/or respiratory secretions in
    these patients. More investigation is needed to determine the factors
    and the mechanisms involved.

    Hughes & Calverley (1988) report three cases of severe acute asthma
    following inhalation of heroin vapor. Fatal respiratory arrest
    occurred in two of these patients.

    Delayed onset respiratory depression has been described 4 hours
    following intranasal heroin use (Steinberg & Karlinger, 1968).

    Dermal

         - NIF

    Ocular

         - NIF

    Other Routes

    Bronchospasm and wheezing have been reported in both intravenous and
    inhalational abusers of heroin. Respiratory arrest occurred in 3
    patients after epidural infusion of fentanyl and bupivicaine. Each
    patient responded dramatically to naloxone (Weightman, 1991).

    If pulmonary oedema occurs it is generally abrupt in onset (immediate-
    2 hours) following intravenous heroin overdose (Duberstein & Kaufman,
    1971). An adult male who injected heroin once into his right brachial
    plexus area presented in a coma with acute pulmonary edema, flaccid
    paralysis of the ipsilateral arm and leg, and severe edema of the arm.
    Severe brachial plexitis was present, which the authors speculated was
    a hypersensitivity response (Stamboulis et al, 1988).

    Fever may occur several hours after injection of aqueous mixtures of
    pentazocine and tripelennamine tablets.

    Chronic Effects

    Ingestion

    Respiratory depression leading to respiratory arrest, pulmonary
    oedema, hypoxia, bronchospasm, acute asthma, bullous pulmonary damage
    and pneumonitis have occurred with therapeutic use and abuse of
    opioids.

    Coma, seizures, myoclonic reactions and spongiform encephalopathy have
    been reported in abusers of opioids. Grand mal seizures have been
    reported with doses of fentanyl.
    Seizures may occur with chronic use or abuse of pethidine and are
    often proceeded by myoclonus, are of limited duration, respond to
    conventional treatment, and resolve following a discontinuation of
    pethidine. Other signs of nervous system stimulation may continue for
    7 days. 48 of 67 patients demonstrated agitation, tremors, myoclonus,
    or seizures following chronic pain therapy with pethidine. A
    Parkinson-like syndrome has been seen in abusers of pethidine
    analogues.

    PAIN

    High doses of opioids or combination opioid agonists/antagonists have
    been reported to cause a paradoxical pain reaction which resolves upon
    cessation of the drug.

    Severe respiratory depression and pain were reported after
    administration of a high dose of buprenorphine. These signs were
    alleviated after naloxone administration.

    PERIPHERAL NEUROPATHY

    HEROIN: De Gans et al (1985) report 7 patients who developed
    rhabdomyolysis and neuropathy of a peripheral nerve or nerve plexus
    after heroin abuse without evidence of muscle or nerve compression.

    Hypomotility with ileus may occur with chronic abuse, or in patients
    on methadone maintenance. Constipation is common. Tolerance does not
    develop.

    Naltrexone may cause dose-related increases in liver enzymes when used
    chronically.

    Morphine has been found to stimulate prolactin release. Opioids such
    as morphine are implicated in causing hypoglycaemia.

    Morphine and some other opioids have a histamine releasing effect
    which may be responsible for urticaria and pruritis. Urticarial rash
    has been reported during therapeutic use of codeine.

    Inhalation

    SPONGIFORM LEUCOENCEPHALOPATHY

    Spongiform leucoencephalopathy was reported in two patients who were
    regular heroin smokers. Both had neurological signs (cerebellar
    ataxia, bilateral pyramidal signs, dysarthria); CT scan and autopsy
    showed extensive white-matter spongiosis and vacuolization.
    "Chinesing," or inhaling preheated heroin, has been associated with
    severe neurological illness and postmortem findings of spongiform
    encephalopathy.

    Dermal

         - NIF

    Ocular

         - NIF

    Other routes

    iv injection

    Pain and irritation may occur on injection as morphine and some other
    opioids have a histamine releasing effect

    iv and intranasal

    PARKINSON'S SYNDROME

    A syndrome closely resembling moderate to severe idiopathic
    Parkinson's Disease has been described in intravenous and intranasal
    drug users following use of a derivative of pethidine, 1-methyl-4-
    phenyl-1,2,3,6-tetrahydropyridine (MPTP). Symptoms may partially
    respond to levodopa and/or bromocriptine and usually slowly resolve
    over 18 months or longer. If recovery does not occur following an
    acute phase, a chronic and permanent parkinsonian syndrome is
    observed. Prolonged industrial exposure to MPTP has also resulted in
    Parkinsonism.

    AT RISK GROUPS

    Elderly

    Plasma half -lives of opiates are usually longer in older age groups
    due to reduced clearance. Adverse effects are likely to occur at lower
    doses than in younger adults

    Pregnancy

     Buprenorphine

    There are no studies on the use of buprenorphine in human pregnancy.
    Animal studies indicate that buprenorphine is not teratogenic in rats
    or rabbits (Heel et al 1979), but caused delayed parturition in the
    rat (Evans et al 1989).

     Codeine

    Despite the fact that codeine has been extensively used, there are
    very few data available on the effects of codeine in either animal or
    human pregnancy.

    Retrospective studies involving first trimester use of codeine have
    shown conflicting evidence of possible teratogenic effects. A wide
    range of anomalies have been associated with its use, including CVS
    defects, cleft lip and palate, musculoskeletal defects, dislocated hip
    and inguinal hernia (Saxen 1975a; Bracken & Holford 1981; Rothman et
    al 1979; Zeitler & Rothman 1985; Bracken 1986). Other studies
    involving over 1200 pregnancies found no significant increase in
    either major or minor malformations, or any pattern of defects (Saxen
    1975b; Heinonen et al 1977; Jick et al 1981; Aselton et al 1985).

    Although the retrospective studies imply an association of codeine use
    with fetal malformations, the inherent bias and methods of data
    collection do not permit a causal relationship to be established. It
    would seem that occasional therapeutic use of codeine in pregnancy is
    not likely to cause fetal damage.

    Like other narcotic analgesics, codeine use near term or during
    delivery can produce respiratory depression in the neonate which can
    be alleviated by naloxone (Bonica 1967).

    Neonatal withdrawal symptoms eg. tremor, jitteriness, diarrhoea and
    poor feeding may be seen following either short term (prior to or
    during delivery) or long term use of codeine by the mother (van
    Leeuwen et al 1965; Mangurten & Benawra 1980).

    Codeine overdose in pregnancy

    Data from the UK TIS on a small number of pregnancies (16) in which
    the mother overdosed with codeine phosphate either alone or as a
    combined analgesic preparation does not suggest an increased fetal
    risk above the background rate in the absence of severe maternal
    toxicity.

     Dextropropoxyphene

    There are very few published data on the effects of dextropropoxyphene
    in human pregnancy. There are a small number of anecdotal case reports
    of malformations allegedly associated with its use, but with no
    recurrent pattern of malformations or syndrome of defects. From the
    data presented a causal relationship seems unlikely (Boelter, 1980;
    Golden et al 1982).

    The Boston Collaborative Perinatal Project identified 2914 women who
    had taken propoxyphene at sometime during their pregnancy, 686 were
    first trimester exposures. There was no increase in either major or
    minor malformations and no syndrome of defects was detected (Heinonen
    et al 1977). Similarly, in another cohort of over 100 pregnancies, all
    first trimester exposures, no increase in fetal toxicity was reported
    (Jick et al 1981).

    Transient neonatal toxicity i.e. withdrawal symptoms have been
    reported in the infants of mothers who were on long term therapy with
    dextropropoxyphene (Tyson, 1974; Klein et al 1975; Quillian & Dunn,
    1976 and Ente & Mehra 1978). Irritability, hyperactivity, tremors and
    high-pitched cries are the most common features observed.

    Overdoses

    Follow-up data from the NTIS on over 400 cases of paracetamol overdose
    (including 40 taking coproxamol) during pregnancy shows no increase in
    the incidence of either spontaneous abortions or malformations in the
    absence of severe maternal toxicity.
    There were over 130 first trimester exposures.

     Diamorphine (heroin)

    No convincing evidence for an increase in abnormalities has been
    presented in humans but the numbers of mother/child pairs are too
    small to exclude an increase in abnormalities. All investigations are
    hampered by numerous confounding factors.

    There is conformity in numerous reports of an increased frequency of
    growth retardation including reduced head circumference, and in
    perinatal mortality. Retardations in development of the babies is
    reported and in some studies may predominantly be due to inadequacies
    in postnatal care.

    In a high proportion of newborns from heroin using mothers, withdrawal
    symptoms are seen lasting a few days or weeks but may persist for
    several months, though only a low percentage of the infants require
    therapy.

     Methadone

    The data available relate to use of heroin and methadone in pregnancy,
    and provide no convincing evidence for an increased risk of
    malformations. However, the number of mother-child pairs is small.

    The most consistent findings are; IUGR, decreased head circumference,
    and increased perinatal mortality. It is not clear whether the
    retardation in postnatal development are directly related to drug
    exposure in utero or to deficiencies in postnatal care. A high
    proportion of the babies have neonatal withdrawal symptoms which may
    last from several days -months.

    In some pregnancies substitution of methadone for heroin seems to
    reduce pregnancy risks . However the withdrawal symptoms in the
    neonate are often more severe and persistent. Higher risk of SIDS
    (Sudden Infant Death Syndrome).

    If exposure is to continue throughout pregnancy, it would be important
    to ensure adequate maternal nutrition and monitor fetal growth. Access
    to good paediatric care would be essential.

     Morphine

    No evidence linking the therapeutic use of morphine with abnormalities
    (Heinonen et al 1977). Case reports have associated use of morphine in
    the first trimester with malformations, but other drugs were also
    taken so it is difficult to establish a causal relationship.

    Neonatal respiratory depression may occur at birth if morphine is used
    during labour. Neonatal withdrawal effects may be seen in the infants
    of addicted mothers 12 to 72 hours after birth. Infants may be
    dehydrated, irritable, and experience tremors and cry continually.

     Naloxone

    There is little data available on the use of naloxone during human
    pregnancy. Animal studies do not indicate any teratogenic effects.

    Few adverse neonatal effects have been seen when naloxone has been
    used to antagonise respiratory depression following maternal analgesic
    use. There have been case reports of naloxone induced fetal asphyxia
    (Goodlin 1981) and fits in the neonate of an opiate addict (Gibbs et
    al 1989).

     Pentazocine

    There are few data available on the effects of pentazocine in human
    pregnancy. Animal studies in rats and rabbits showed no evidence of
    adverse effects on fertility, length of gestation, litter size or
    fetal development.

    Pentazocine crosses the human placenta, and has been associated with
    enhanced uterine activity but no adverse fetal effects (Filler &
    Filler 1966). Neonatal withdrawal effects may occur if pentazocine is
    used near term.

     Tramadol

    There are no published data on the outcome of human pregnancy after
    tramadol exposure in the first trimester. Tramadol has been used
    during labour with no significant adverse effects on the
    fetus/neonate.
    Animal studies have not demonstrated any increase in fetal
    malformation.
    Searle have outcome data from 9 pregnancies:

    3 premature deliveries - no malformations
         (2x 1st trimester and 1x1-3 trimester exposures)
    1 neonatal opiate withdrawal - no malformations (1-3 trimester
    exposure)
    1 neonatal convulsions - no malformations (exposed at 38/40)
    2 Caesarean deliveries - no malformations
    (1 for fetal distress - exposed just prior to delivery, 1 for uterine
    rupture - exposed at 5/40)
    1 maternal and fetal death (malaria infection) - 3rd trimester
    exposure
    1 spontaneous abortion at 7/40, exposed at 4-5/40
    1 ETOP (spina bifida) - exposed at 15/40 - therefore not causally
    related to tramadol

    Children

    Plasma half-lives of opiates are usually longer in children due to
    reduced clearance.

    Others

    Addicts

    Addicts develop tolerance to high doses which would be fatal to a new
    user.
    Addicts experience withdrawal symptoms on discontinuation of drug.

    Renal impairment

    Patients with renal impairment have increased systemic effects.

    Hepatic dysfunction

    Some patients with hepatic dysfunction are especially sensitive to
    opioids and experience prolonged sedation and respiratory depression,
    whereas many patients with liver impairment are able to tolerate
    opioids normally.

    MANAGEMENT

    Decontamination

    If patient is unconscious or has respiratory depression, attend to
    this first - see supportive care (airway and naloxone).

    Opiates delay gastric emptying and may be slow release (MST). Slow
    release preparations have a slower onset of action and increased
    duration of action than immediate release preparations. In overdose,
    onset of symptoms may be delayed, but last longer, thus continued
    observation and supportive care will be indicated.

    Gastric lavage carries the risk of gut perforation and aspiration.
    Endotracheal intubation is mandatory in unconscious patients or those
    with poor gag reflexes.

    Activated charcoal may be a safer option, however, lavage may be
    justified if performed soon after ingestion for very large overdoses,
    especially in the presence of alcohol as activated charcoal is less
    effective in these circumstances.

    Induction of emesis is not recommended because of the potential for
    CNS depression and seizures.

    For the asymptomatic body packer whole bowel irrigation may be a
    relatively safe and effective means of rapid decontamination (see case
    data).

    Prevention Of Absorption

    Activated charcoal is effective for reducing the absorption of opiates
    for up to 4 hours post ingestion (Proudfoot suggests up to 6 hours) as
    opiates delay gastric emptying. The dose should be at least 10 times 

    the quantity of drug taken. Doses of 50-100 g (adults) or
    25-50 g (children) should be aimed for. Lactulose (20 ml) should be
    given to prevent constipation.
    Patients who vomit, or who have reduced levels of consciousness can be
    treated via a nasogastric tube protecting the airway if necessary.

    Supportive care

    Support respiratory and cardiovascular function.

    If the patient is unconscious or has respiratory depression:
    Ensure clear airway

    ADULTS: give naloxone 800 mcg IV to start, then 400 mcg every 2
    minutes until the patient improves (respiratory rate, consciousness,
    pupil size) or until 3.2 mg have been given.

    CHILDREN: 0.01 mg/kg body weight if coma or respiratory depression are
    present. Repeat the dose if there is no response within two minutes. A
    larger dose of 0.1 mg/kg may be used if no improvement is seen, or
    response is sub-optimal.

    NEONATES: Initial doses of 10 to 30 mcg/kg IV are recommended.

    Failure of a definite opioid overdose to respond to naloxone suggests
    that another CNS depressant drug or brain damage is present.
    Observe the patient carefully for recurrence of CNS and respiratory
    depression. The plasma half-life of naloxone is shorter than that of
    most opioid analgesics. Relapse may occur after 20 minutes. Repeated
    doses of naloxone may be required.

    Intravenous infusions of naloxone have been recommended in situations
    where repeated doses have been necessary. Set up an infusion (5 x 400
    mcg ampoules naloxone = 2 mg in 500 ml 5% dextrose) at a rate equal to
    2/3 of the dose required to wake the patient per hour.
    Infusions are not substitutes for frequent review of the patients
    clinical state and administration of bolus doses of naloxone as
    required.

    Do not delay in establishing a clear airway, adequate ventilation and
    oxygenation if there is no response to naloxone.
    If pulmonary oedema is a complication maintain ventilation and
    oxygenation with close arterial blood gas monitoring. Assisted
    ventilation with positive expiratory pressure may be necessary.

    SEIZURES

    Administer diazepam IV bolus (DOSE: ADULT: 5 to 10 mg initially which
    may be repeated every 15 minutes PRN up to 30 mg. CHILD: 0.25 to 0.4
    mg/kg/dose up to 10 mg/dose). If seizures cannot be controlled or
    recur, administer phenytoin or phenobarbitone.

    HYPOTENSION: Administer IV fluids and place in Trendelenburg position.
    If unresponsive to these measures, administer dopamine (2 to 5
    mcg/kg/min) (first choice) or norepinephrine (0.1 to 0.2 mcg/kg/min)
    and titrate according to response.

    PARKINSON'S SYNDROME

    A syndrome closely resembling moderate to severe idiopathic
    Parkinson's Disease has been described in intravenous and intranasal
    drug users following use of a derivative of pethidine,
    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Symptoms may
    partially respond to levodopa and/or bromocriptine and usually slowly
    resolve over 18 months or longer.

    Other supportive measures as indicated by the patient's progress.

    Monitoring

    Plasma opioid levels are not clinically useful.
    Treatment is based more on clinical presentation than on specific
    laboratory data.
    Monitor arterial blood gases, pulmonary function, and chest x-ray for
    patients with significant exposure.

    Patients with intravenous overdose requiring naloxone reversal should
    be monitored for 4 hours after the last dose of naloxone to observe
    for evidence of pulmonary edema.
    Patients with oral opioid overdose should be monitored for 6 hours and
    admitted if signs or symptoms develop. Patients with overdose of
    methadone or other long acting opioids require admission as clinical
    effects may be delayed.

    Antidotes

    NALOXONE

    A pure opioid antagonist, may be used for the complete or partial
    reversal of opioid depression, including mild to severe respiratory
    depression induced by natural and synthetic opioids, the
    agonist/antagonists nalbuphine and pentazocine, or dextropropoxyphene.
    It may also be used for the diagnosis of suspected acute opioid
    overdose.

    Adverse effects

    Abrupt reversal of narcotic depression may result in nausea, vomiting,
    sweating, tachycardia, increased blood pressure, tremulousness,
    seizures and cardiac arrest.
    Acute withdrawal effects may be precipitated in large opioid
    overdoses, or in patients physically opioid dependent.
    In postoperative patients, larger than necessary dosage of naloxone
    may result in significant reversal of analgesia and excitement. 

    Hypotension, hypertension, ventricular tachycardia and fibrillation,
    and pulmonary oedema have been associated with postoperative use of
    naloxone.

    Hoffman et al (1991) recommend administering naloxone only to altered
    mental status patients with bradypnoea (respirations of 12 or less) in
    questionable opiate overdoses.

    DOSE

    Adults

     Opioid overdose: 0.8-2 mg by iv injection repeated at intervals of
    2-3 minutes up to a maximum of 10 mg if respiratory function does not
    improve (question diagnosis).
    Can also be given by sc or im injection if no iv access.
     Post-operative use: 100-200 mcg iv is usually sufficient, a full 2
    minutes should be allowed to elapse between each 100 mcg increment.
    The dose should be titrated for each patient to obtain optimum
    respiratory response while maintaining adequate analgesia.

    Children: Initial iv dose 10mcg/kg, a subsequent dose of 100 mcg/kg
    may be given according to response.

    Neonates: Infants born to mothers given analgesics in labour, initial
    iv, im or sc dose of 10 mcg/kg, repeated after 2-3 minutes according
    to response. Alternatively, a single dose of 200 mcg (approx. 60
    mcg/kg) may be given im at birth.

    Observe the patient carefully for recurrence of CNS and respiratory
    depression. The plasma half-life of naloxone is shorter than that of
    most opioid analgesics, particularly dextropropoxyphene,
    dihydrocodeine and methadone. Relapse may occur after 20 minutes.
    Repeated doses of naloxone may be required.

    Intravenous infusions of naloxone have been recommended in situations
    where repeated doses have been necessary. Set up an infusion (5 x 400
    mcg ampoules naloxone = 2 mg in 500 ml 5% dextrose) at a rate of 2/3
    of the dose required to wake the patient per hour.
    Infusions are not substitutes for frequent review of the patients
    clinical state and administration of bolus doses of naloxone as
    required.

    Alternative routes

    Subcutaneous or intramuscular routes may be effective if iv route is
    not feasible (onset of action slower). Naloxone can also be given
    intralingually or intrathecally in the absence of intravenous access.

    CASE DATA

    CODEINE

    A 3-month-old preterm infant received codeine 6.6 mg/kg within 24
    hours, well above the recommended dose of 1 to 2 mg/kg. The infant
    developed apnea and presented at the hospital with pinpoint pupils and
    was semi-comatose. Effects were reversed with IV naloxone (Wilkes et
    al, 1981).

    A 30 year old woman was admitted after having ingested 100 compound
    aspirin / codeine tablets (30 g aspirin and 800 mg codeine) and an
    unknown amount of diazepam. She was drowsy but responded to verbal
    commands, had pinpoint pupils, and was sweating and hyperventilating
    with a pulse rate of 115/min and blood pressure of 120/80 mm Hg.
    Arterial blood gas analysis showed a mixed respiratory alkalosis and
    metabolic acidosis pH 7.4, carbon dioxide tension 3.1 kPa, oxygen
    tension 13.6 kPa and bicarbonate 15 mmol/l. Immediately after
    administration of naloxone (0.8 mg iv) the pupils dilated and she
    became fully conscious. Plasma salicylate and codeine concentrations
    were 1006 mg/l and 650 mcg/l respectively. Plasma urea, sodium and
    potassium concentrations were normal. Diazepam and nordiazepam
    concentrations were 0.38 mg/l and 0.84 mg/l respectively. Forced
    alkaline diuresis was performed; 21 hours post admission the plasma
    salicylate concentration measured 462 mg/l. On 3 occasions during
    forced alkaline diuresis her conscious level deteriorated such that
    she responded only to painful stimuli and pinpoint pupils. These
    effects were reversed by naloxone, with a further 4 mg being
    administered in total. The authors also report a second case (Leslie
    et al 1986).

    DEXTROPROPOXYPHENE

    Young & Lawson (1980) reviewed 82 patients admitted with acute
    Distalgesic(R) poisoning. On admission 20 patients had grade 4 and 2
    had grade 3 coma; 12 had respiratory arrest, 4 severe convulsions, 3
    aspiration pneumonia, 1 cardiac arrest and 3 patients died. All of the
    complication were considered directly attributable to
    dextropropoxyphene and were treated with naloxone and assisted
    ventilation where appropriate. 23 patients had one or more of these
    complications.

    A 14 day old infant weighing 4.43 kg was admitted to hospital after
    his 2 yr old brother was discovered feeding him Distalgesic(R) 2 hours
    previously. One hour after ingestion the infant became pale, drowsy
    and unresponsive with shallow respirations. On arrival at hospital he
    was pale, mottled and limp. The pupils were markedly constricted and
    he was practically apnoeic with only occasional shallow gasps.
    Naloxone 0.1 mg im resulted in complete recovery after only 20-30s.
    Four further episodes of apnoea occurred, responding to naloxone each
    time. The infant was discharged home after 4 days.

    FENTANYL

    A 36 year old male became intoxicated from fentanyl by heating and
    inhaling the contents from a fentanyl patch. He collapsed after 1
    inhalation with a respiratory rate of 6/min, heart rate of 120 bpm and
    an unobtainable blood pressure. He responded to naloxone injection 2
    mg iv and was discharged a few hours later with stable vital signs and
    mental status (Marquardt and Tharratt, 1994). The patient died
    following a subsequent inhalation session.

    HEROIN

    A 31-year-old male ingested 28 heroin-containing packets in an attempt
    to clear US Customs. The patient received a total of 31 litres of
    whole bowel irrigation, with polyethylene glycol electrolyte lavage
    solution, over the course of 52 hours, which resulted in the
    successful recovery of all packets. The procedure was well tolerated
    except for one episode of hypoglycemia. Lab data remained within
    normal limits and the patient denied abdominal cramping throughout the
    procedure (Betzelos & Mueller, 1991). A review article of the
    literature on opioid body-packers is available (Stewart et al, 1990).

    Utecht et al (1992) present a series of 14 patients, nine of whom
    swallowed heroin-containing packets and five of whom inserted them
    rectally. Thirteen had evidence of packets on KUB. Bisacodyl
    suppositories were used to evacuate packets from the rectum. No
    patient received ipecac or gastric lavage.

    MEPTAZINOL

    Respiratory depression that was NOT reversible by naloxone 10 mg was
    reported in a 61-year-old woman who ingested 50 meptazinol 200 mg
    tablets (Davison et al, 1987).

    RHABDOMYOLYSIS

    Blain et al (1985) report 3 cases of opiate overdose were the patients
    developed acute muscle damage with elevated serum aspartate
    aminotransferase and creatine kinase activities, increased serum
    myoglobin concentrations, raised plasma creatinine concentrations,
    hypocalcaemia and hyperphosphataemia. The abnormalities gradually
    resolved over 7-10 days, but recovery was complicated due to the
    development of acute renal failure (requiring haemodialysis) in one
    patient. Plasma drug concentrations, shortly after admission, in the
    patients taking dihydrocodeine and morphine were grossly elevated (184
    and 60 mcg/l respectively). Clinical evidence of myopathy was minimal
    in all three patients and muscle biopsy of one patient was normal at 7
    days.

    Author

    Kathryn Pughe, BSc (Hons) MRPharmS

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP
    UK

    This monograph was produced by the staff of the Newcastle Centre of
    the National Poisons Information Service in the United Kingdom. The
    work was commissioned and funded by the UK Departments of Health, and
    was designed as a source of detailed information for use by poisons
    information centres.

    Peer review was undertaken by the Directors of the UK National Poisons
    Information Service.

    Last updated June 1997

    REFERENCES

    JOURNALS

    1.   Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First
         trimester drug use and congenital disorders. Obstet Gynecol 1985;
         65: 451-455.

    2.   Beattie JO, Chen CP, MacDonald TH. Neonatal Distalgesic
         poisoning. Lancet 1981; : 49.

    3.   BetzelosS, Mueller P. Whole bowel irrigation in a heroin body-
         packer (Abstract). Vet Hum Toxicol 1991; 33: 353.

    4.   Blain PG, Lane RJM, Bateman DN, Rawlins MD. Opiate-induced
         rhabdomyolysis. Human Toxicol 1985; 4: 71-74.

    5.   Boelter W. Proposed fetal propoxyphene Darvon syndrome. Clin Res
         1980; 28: 115a.

    6.   Bracken MB. Drug use in pregnancy and congenital heart disease in
         offspring. N Engl J Med 1986; 314: 1120.

    7.   Bracken MB, Holford TR. Exposure to prescribed drugs in pregnancy
         and association with congenital malformations. Obstet Gynaecol
         1981; 58: 336-344.

    8.   Davison AG et al. Meptazinol overdose producing near fatal
         respiratory depression. Human Toxicol 1987; 6:(4) 331.

    9.   De Gans J, Stam J, Van Wijngaarden GK. Rhabdomyolysis and
         concomitant neurological lesions after intravenous heroin abuse.
         J Neurol Neurosurg Psychiatry 1985; 48: 1057-1059.

    10.  Ente G, Mehra MC. Neonatal drug withdrawal from propoxyphene
         hydrochloride. N Y State J Med 1978; 78: 2084-2085.

    11.  Evans RG, Olley JE, Rice GE, Abrahams JM. Effects of subacute
         opioid administration during late pregnancy in the rat on the
         initiation, duration and outcome of parturition and maternal
         levels of oxytocin and arginine vasopressin. Clin Exp Pharmacol
         Physiol 1989; 16: 169-178.

    12.  Filler WW, Filler NW. Effect of a potent non-narcotic analgesic
         agent (pentazocine) on uterine contractility and fetal heart
         rate. Obstet Gynaecol 1966; 28: 224-232.

    13.  Gibbs J, Newson T, Williams J et al. Naloxone hazard in infant of
         opioid abuser (letter). Lancet 1989; 2: 159-160.

    14.  Golden NL, King KC, Sokol RJ. Propoxyphene and acetaminophen.
         Clin Pediatr 1982; 21: 752-754.

    15.  Goodlin RC. Naloxone and its possible relationship to fetal
         endorphin levels and fetal distress. Am J Obstet Gynaecol 1981;
         139: 16-19.

    16.  Heel RC, Brogden RN, Speight TM et al. Buprenorphine: a review of
         its pharmacological properties and therapeutic efficacy. Drugs
         1979; 17: 81-110.

    17.  Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in
         patients with altered mental status: A reappraisal. Ann Emerg Med
         1991; 20: 246-252.

    18.  Hughes S, Calverley PMA. Heroin inhalation and asthma. Br Med J
         1988; 297: 1511-1512.

    19.  Jick H, Holmes LB, Hunter JR, Madsen S, Stergachis A. First
         trimester drug use and congenital disorders. JAMA 1981; 246: 343-
         346.

    20.  Klein RB, Blatman S, Little GA. Probable neonatal propoxyphene
         withdrawal: A case report. Pediatrics 1975; 55: 882-884.

    21.  Kyff JV, Rice TL. Meperidine-associated seizures in a child
         (letter). Clin Pharm 1990; 9: 337-338.

    22.  Leslie PJ, Dyson EH, Proudfoot AT. Opiate toxicity after
         self-poisoning with aspirin and codeine. Br Med J 1986; 292: 96.

    23.  Mangurten HH, Benawra R. Neonatal codeine withdrawal in infants
         of non-addicted mothers. Pediatrics 1980; 65: 159-160.

    24.  Marquardt KA, Tharratt RS. Inhalation abuse of fentanyl patch.
         Clin Toxicol 1994; 32(1): 75-78.

    25.  Morisy L, Platt D. Hazards of high-dose-meperidine (letter). JAMA
         1986; 255: 467-468.

    26.  Parkinson SK, Bailey SL, Little WL et al. Myoclonic seizure
         activity with chronic high-dose spinal opioid administration.
         Anesthesiology 1990; 72: 743-745.

    27.  Quillian WW, Dunn CA. Neonatal drug withdrawal from propoxyphene.
         JAMA 1976; 235: 2128.

    28.  Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MR. Exogenous
         hormones and other drug exposures of children with congenital
         heart disease. Am J Epidemiol 1979; 109: 433-439.

    29.  Saxn I. Associations between oral clefts and drugs taken during
         pregnancy. Int J Epidemiol 1975a; 4: 37-44.

    30.  Saxn I. Epidemiology of cleft lip and palate. Br J Prevent Soc
         Med 1975b; 29: 103-110.

    31.  Stamboulis E, Psimaras A, Malliara-Loulakaki S. Brachial and
         lumbar plexitis as a reaction to heroin. Drug Alcohol Depend
         1988; 22: 205-207.

    32.  Stewart A, Heaton ND, Hogbin B. Body packing - a case report and
         review of the literature. Postgrad Med J 1990; 66: 659-661.

    33.  Strong WE, Matson M. Probable seizure after alfentanil. Anesth
         Analg 1989; 68: 692-693.

    34.  Tyson HK. Neonatal withdrawal symptoms associated with maternal
         use of propoxyphene hydrochloride (DAVON). J Pediatr 1974; 85:
         684-685.

    35.  Ueyama H, Nishimura M, Tashiro C. Naloxone reversal of nystagmus
         associated with intrathecal morphin administration (letter).
         Anesthesiology 1992; 76: 153.

    36.  Utecht MJ, Stone AF, McCarron MM. Heroin body packers. J Emerg
         Med 1993; 11: 33-40.

    37.  Van Leeuwen G, Guthrie R, Strange F. Narcotic withdrawal reaction
         in a newborn infant due to codeine. Pediatrics 1965; 36: 635-636.

    38.  Wilkes TCR, Davies DP, Dar MF. Apnea in a 3 month old baby
         prescribed compound linctus containing codeine. Lancet 1981; 1:
         1166-1167.

    39.  Young RJ, Lawson AAH. Distalgesic poisoning - cause for concern.
         Br Med J 1980; 1: 1045-1047.

    40.  Zeitler S, Rothman KJ. Congenital heart disease in relation to
         maternal use of benedictin and other drugs in early pregnancy. N
         Engl J Med 1985; 313: 347-352.

    BOOKS

    1.   ABPI Compendium of Data Sheets and Summaries of Product
         Characteristics. Datapharm Publications Ltd. 1996-97.

    2.   AHFS Drug Information. McEvoy GK (Ed.) 1996.

    3.   Bonica JJ. Principles and practice of obstetric analgesia and
         anaesthesia. Philadelphia: F A Davis and Co. 1967: 245

    4.   Briggs GG, Freeman RK and Yaffe SJ. Drugs in Pregnancy and
         Lactation, 4th Edition. Williams & Wilkins, 1994.

    5.   British National Formulary, Number 33 (March 1997). British
         Medical Association and The Royal Pharmaceutical Society Of Great
         Britain, 1997.

    6.   Dollery C (Ed). Therapeutic Drugs. Churchill Livingstone, 1991.

    7.   Ellenhorn MJ. Ellenhorn's Medical Toxicology: Diagnosis and
         Treatment of Human Poisoning. 2nd Edition. Williams & Wilkins,
         1997.

    8.   Heinonen OP, Slone D and Shapiro S. Birth Defects and Drugs in
         Pregnancy. Littleton: Publishing Sciences Group, 1977: 322-34.

    9.   Martindale The Extra Pharmacopeia 31st Edition, Reynolds JEF
         (Ed.). The Royal Pharmaceutical Society Of Great Britain, 1996.

    10.  Mortality Statistics. Series DH2 No.18. Office of Population
         Censuses & Surveys. London: HMSO, 1993.

    11.  Proudfoot AT. Acute Poisoning, Diagnosis & Management. 2nd
         Edition. Butterworth-Heinemann Ltd, 1993.

    CD-ROMs / Databases

    1.   Poisindex System(R) Micromedex Inc, Denver Colorado, Edition
         expires 31/3/97.

    2.   Reprotox System(R), Micromedex inc., Denver Colorado, Edition
         Expires 31/3/97.

    3.   TOXBASE, National Poisons Information Service, 1997.

    Unpublished reports etc.

    1.   Data collated by the National Teratology Information Service
         (NTIS).

    2.   Data collated by the European Network of Teratology Information
         Services (ENTIS).