Pre- Review Report:

Preparations of codeine listed in Schedule lll

of the 1961 Single Convention on Narcotic
Drugs

Acetyldihydrocodeine
Codeine
Dihydrocodeine
Ethlymorphine
Nicocodine
Nicodicodine
Norcodeine
Pholcodine

Expert Committee on Drug Dependence

Forty-second Meeting
Geneva, 21-25 October 2019

This report contains the views of an international group of experts, and does not necessarily represent the decisions or
the stated policy of the World Health Organization
42nd ECDD (2019): Preparations of codeine

© World Health Organization 2019

All rights reserved.

This is an advance copy distributed to the participants of the 42nd Expert Committee on Drug Dependence,
before it has been formally published by the World Health Organization. The document may not be reviewed,
abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any
form or by any means without the permission of the World Health Organization.

The designations employed and the presentation of the material in this publication do not imply the
expression of any opinion whatsoever on the part of the World Health Organization concerning the legal
status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers
or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may
not yet be full agreement.

The mention of specific companies or of certain manufacturers’ products does not imply that they are
endorsed or recommended by the World Health Organization in preference to others of a similar nature that
are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by
initial capital letters.

The World Health Organization does not warrant that the information contained in this publication is
complete and correct and shall not be liable for any damages incurred as a result of its use.

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Contents
Acknowledgements ............................................................................................................................ 5
Executive Summary ............................................................................................................................ 6
1. Substance identification................................................................................................................... 8

2. Chemistry........................................................................................................................................11
B. Chemical Structure ........................................................................................................................ 12
C. Stereoisomers................................................................................................................................ 15
D. Methods and Ease of Illicit Manufacturing ................................................................................... 16
A. Chemical Properties ...................................................................................................................... 16
B. Identification and Analysis ............................................................................................................ 18
3. Ease of Convertibility Into Controlled Substances ............................................................................19

4. General Pharmacology ...................................................................................................................19

A. Routes of administration and dosage............................................................................................ 19
C. Pharmacokinetics .......................................................................................................................... 20
D. Pharmacodynamics ....................................................................................................................... 23
5. Toxicology.......................................................................................................................................25

6. Adverse Reactions in Humans .........................................................................................................26

7. Dependence Potential .....................................................................................................................27

A. Animal Studies ............................................................................................................................... 27
E. Human Studies .............................................................................................................................. 27
8. Abuse Potential...............................................................................................................................27
A. Animal Studies ............................................................................................................................... 27
F. Human Studies .............................................................................................................................. 28
9. Therapeutic Applications and Extent of Therapeutic Use and Epidemiology of Medical Use ............28

10. Listing on the WHO Model List of Essential Medicines ....................................................................29

11. Marketing Authorizations (as a Medicinal Product) ........................................................................30

12. Industrial Use..................................................................................................................................30

13. Non-Medical Use, Abuse and Dependence ......................................................................................30

14. Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and Dependence .......31

15. Licit Production, Consumption and International Trade ..................................................................31

16. Illicit Manufacture and Traffic and Related Information..................................................................32

17. Current International Controls and Their Impact .............................................................................32

18. Current and Past National Controls.................................................................................................32

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19. Other Medical and Scientific Matters Relevant for a Recommendation on the Scheduling of the
Substance .......................................................................................................................................34

References........................................................................................................................................ 35

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Acknowledgements

This document was produced for the WHO Expert Committee on Drug Dependence (ECDD) under
the overall direction of the WHO Secretariat led by Dr Gilles Forte (Division of Access to Medicines,
Vaccines, and Pharmaceuticals). The document was written by Professor Kim Wolff under the
technical direction of Dr Dilkushi Poovendran (Division of Access to Medicines, Vaccines, and
Pharmaceuticals). The report was edited by Professor Jason White. The member state
questionnaire was produced under the technical direction of Ms Judith Sprunken (Division of
Access to Medicines, Vaccines, and Pharmaceuticals).

The WHO Secretariat would also like to thank the European Monitoring Centre for Drugs and Drug
Addiction (EMCCDA), International Narcotics Control Board (INCB), United Nations Office of Drugs
and Crime (UNODC), and Member States for providing relevant information for the review of
substances.

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Executive Summary
Preparations listed in Schedule lll of the 1961 Single Convention on Narcotic Drugs include a variety
of compounds: acetyldihydrocodeine, codeine, dihydrocodeine, ethlymorphine, nicocodicine
(nicocodeine), nicodicodeine (nicodicodeine), norcodeine and pholcodine. The Schedule also
includes these compounds when formulated with one or more other ingredients containing not
more than 100 milligrams of the drug per dosage and with a concentration of not more than 2.5 per
cent in undivided preparations

The preparations are all opioids (derived from a natural opiate or of a synthetic origin); one
norcodeine is a non-active metabolite. Some such as nicocodine and nicodicodine (nicodicodeine)
were discovered in 1904, and acetyldihydrocodeine in Germany in 1914. Most if not all have been
marketed as antitussive medicines (cough suppressants), and to provide analgesia for mild to
moderate pain (acetyldihydrocodeine, ethylmorphine, nicocodine, nicodicodine). Pholcodine helps
suppress unproductive coughs and acts as a mild sedative effect, but little or no analgesic effects.

Some, notably acetyldihydrocodeine (a very close relative derivative of Thebacon), nicocodine, an

ester of codeine closely related to dihydrocodeine and nicodicodine are not commonly used.
Norcodeine is the N-demethylated a metabolite of codeine and has relatively little opioid activity in
its own right. Whereas codeine and dihydrocodeine either alone or compounded with paracetamol
or a nonsteroidal anti-inflammatory drug such as aspirin or ibuprofen are commonly used
worldwide.

In the main, preparations listed in Schedule lll are administered orally. Both codeine and
dihydrocodeine products can be purchased over the counter in many European and Pacific Rim
countries and generally contain from 2 to 30 mg per dosing unit. As weak opioid drugs the Schedule
lll preparations (except norcodeine) reduce the sensitivity of the respiratory centre to carbon
dioxide, which may result in decreased tidal volume and decreased respiratory rate. The triad of
coma, pinpoint pupils, and respiratory depression apply to these substances as evidence of toxicity.

The preparations are thought to show stereochemistry (certainly codeine and dihydrocodeine) and
are metabolised by the genetically polymorphic enzyme CYP2D6, although the clinical significance
of this activity remains unresolved even for codeine and dihydrocodeine. Pholcodine is an exception
with regards its pharmacokinetics, the others being short acing compounds.
It is difficult to estimate the prevalence of use of the preparations listed in Schedule lll because of
the variation in regulations governing the different formulations of the drugs. However, abuse of
over the counter (OTC) antitussives containing codeine, dihydrocodeine and pholcodine is a
continuing problem in the United States and throughout the world. The continuing problem is
thought to be due to increasing availability, social acceptance and the perception, especially among
the young that pharmaceutical drugs are safe. With legislative activity, educational, and economic
initiatives there may have been a shift to abuse to easily attainable cough and cold preparations.

Codeine and dihydrocodeine misuse and dependence has been described.

Codeine dependence was associated with daily use of codeine, faking or exaggerating symptoms to

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get a prescription for codeine and 'pharmacy shopping', while dependence arose with
dihydrocodeine through treatment of pain and cough.

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1. Substance identification

A. International Non-proprietary Name (INN)

Acetyldihydrocodeine (O-Acetyldihydrocodeine)
Codeine
Dihydrocodeine
Ethlymorphine (chlorhydrate de Codethyline, codethyline)
Nicocodine (nicocodeine)
Nordicodine (nicodicodeine)
Norcodeine
Pholcodine (β-4-morpholinylethylmorphine, homocodeine, pholcodin;
pholcodinum).

B. Chemical Abstract Service (CAS) Registry Number

Acetyldihydrocodeine 0003861-72-1
Codeine1
Codeine base (anhydrous) 76-57-3
Codeine base (monohydrate) 6059-47-8
Codeine hydrochloride 1422-07-7
Codeine phosphate (anhydrous) 52-28-8
Codeine phosphate (hemihydrate) 41444-62-6
Codeine phosphate (sesquihydrate) 5913-76-8
Codeine sulfate (anhydrous) 1420-53-7
Codeine sulfate (trihydrate) 6854-40-6
Dihydrocodeine 125-28-0
Dihydrocodeine bitartrate 5965-13-9
Dihydrocodeine hydrochloride 36418-29-8
Dihydrocodeine hydroiodide 5965-15-1
Dihydrocodeine phosphate 24204-13-5
Ethlymorphine 0000076-58-4
Nicocodine 3688-66-2 or 58263-01-7 (HCl)
Nicodicodine 808-24-2
Norcodeine Not available: metabolite of codeine
Pholcodine 509-67-1

C. Other Chemical Names

Acetyldihydrocodeine
4,5-Epoxy-3-methoxy-9a-methylmorphinan-6-yl acetate
3-0-Methyl-6-0-acetylmorphine

1 http://www.inchem.org/documents/pims/pharm/codeine.htm#SectionTitle:3.2%20Chemical%20structure

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acetylcodone dihydrocodeine 6-acetate, dihydrothebacone,

Codeine
(5α,6α)-7,8-didehydro-4,5-epoxy- 3-methoxy-17-methylmorphinan-6-ol

Dihydrocodeine
4,5α-epoxy-3-methoxy-17-methyl-morphinan-6α-ol.
(5α,6α)-3-Methoxy-17-methyl-4,5-epoxymorphinan-6-ol

Ethlymorphine
3-ethylmorphine
Morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-etoxy-17-metyl-, (5α,6α)-
(5α,6α)-3-Ethoxy-17-methyl-7,8-didehydro-4,5-epoxymorphinan-6-ol

Nicocodine
6-nicotinylcodeine
(5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-yl pyridine-3-
carboxylate hydrochloride

Nicodicodine
6-nicotinyldihydrocodeine
Dihydrocodeine 6-nicotinate;4,5α-Epoxy-3-methoxy-17-methylmorphinan-6α-ol 3-
pyridinecarboxylate
(5α,6α)-3-Methoxy-17-methyl-4,5-epoxymorphinan-6-yl nicotinate

Norcodeine
N-demethylcodeine
(5α,6α)-3-Methoxy-7,8-didehydro-4,5-epoxymorphinan-6-ol

Pholcodine
3-(2-(4-Morpholinyl)ethyl)morphine
β-morfolinoetylmorfin
7,8-didehydro-4,5-alpha-Epoxy-17-methyl-3-(2-morpholinoethoxy) morphinan-6-alpha-ol
(5α,6α)-17-Methyl-3-[2-(4-morpholinyl)ethoxy]-7,8-didehydro-4,5-epoxymorphinan-6-ol
6-hydroxy-N-methyl-3-(2-morpholinoethoxy)-4,5 epoxymorphinen-7
3-(2-morfolinoetossi)-4,5-epossi-6-idrossi-N-metil-7-morfinene

D. Trade Names (including combinational medicinal products)[1]

Acetyldihydrocodeine
Logicin

Codeine
Abitran, Actifed ,Adibeta, Afebralgo, Aferin, Algiespas, Amiorel, Anakod, Antigrippine, APC,
Apex, Asekod, Benamine Expectorans, Benzokodin, Bisolvon Compositum, Bromocod N,
Bromocodeina, Bronchocodine, Bronchofluid, Broncoton, Bronquibasol, Bronchotussine,
Brosol, Buscalginol, Cerebrol, Cimex, Co-Efferalgan, Co Dafalgan, Codasel, Codeidol,
Codeinol, Codelasa, Codephal, Codidoxal, Codipront, Codol, Coedefen, Coldeks, Corex,
Coveral, Dafalgan Codeina, Codeine Linctus, Codis, Codeinum, Codicept, Coducept ,

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Dephedrine, Devasko, Dicton, Dinacode N, Doladamon, Doladoman P, Dolofrix, Dolopyrine,

Dolviran, DP1, Euphon N, Expectosan, Famel, Farmebron Compuesto, Fenergan, Fitotos,
Foral, Fulpen, Gayakodin, Gelonida, Geralgine K, Hederix Plan, Ibukod, Ipeca, Ipecarin,
Koden, Korylan, Küramol, Lactocol, Lonarid, Methylmorphine, Metilmo, Micracalm,
Migraleve, Natuscap Retard, Neo Codion N, Pacofen, Phensedyl, , Pankopan, Percode,
Pertussex Compositum, Phensedyl, Piraud-Pect, Piribenzamina, Pirosal, Pleumolysin,
Pseudocodeine, Radipon, Radyocodine, Resyl Plus, Sano-Tuss, Sedeks B, Sekodin, Senodin-
An, Solucamphre, Spasmo Barbamine Compositum, Spasmo Cibalgine Compositum,
Spasmopan, Spasmoplus, Spedro, Supotos, Syrocol, Talvosilen, Tarminent, Temsaljin,
Theraflu C&C, Tossamine, Toxambay, Treuphadol Plus, Tricodeine, Tussifed, Tusso, Volpan,
Winadeine, Zeller.
With paracetamol (co-codamol): e.g., brands Paracod, Panadeine
Tylenol-with-codeine series, including Tylenol 3 and 1,2, and 4)
With aspirin (co-codaprin);
With ethylmorphine, Codenur, Fenekodin, Jucodine, Kodineks, Kodipen, Kodis, Kodulumine,
Koludine, Ludicodine, Neocodin/e
With ibuprofen (Nurofen Plus).
With phenacetin (Emprazil with codeine No. 1, 2, 3, 4, 5)
With naproxen, indomethacin, diclofenac
More complex mixtures:
Aspirin + paracetamol + codeine ± caffeine ± antihistamines (e.g., Synalgos-DC)

Dihydrocodeine
Brontuss, Cardiasol Paracodina, Codicontine Retard, Contugesic, Drocode, Dico and DF-118,
Drocode, Codidol, Dehace, DHC , DHC Continus, Didor Continus, Dicogesic, Codhydrine,
Dekacodin, DH-Codeine, Didrate, Dihydrin, Hydrocodin, Hydrocodin, Huscode, Neo
Makatussine N, Paracodin N, Paracodin/a, Paracodine, Paracodine Retard, Paramorfan,
Remedacen, Tiamon Mono Paracodeine and Parzone, Rikodeine, Trezix, Synalgos DC, Panlor
DC, Panlor SS, Contugesic, New Bron Solution-ACE, Paracodin, Makatussin, Makatussin Forte
Nadeine, Novicodin, Rapacodin, Fortuss, Paramol, Remedeine, , Tuscodin

Ethlymorphine
Codetilina Eucaliptolo Hè , Clarix 0,1%, Codethylin, Coselan, codethyline, dionine)Dinacode
N, Dionina, Gripkill, Mindol Merck, Saintbois, Codethyline (Erfa) / Dionina
(Merck) / Lepheton (Meda)

Nicodicone
Lyopect, Nicotinoylcodeine, Tusscodin, Tusscodin retard

Nicodicodine
Not known to be available as a medicine

Norcodeine
Metabolite of codeine: not available as a medicine

Pholcodine
Benylin, Galenphol, Covonia, Children’s dry coughs, Evaphol, Famel linctus, Pholcomed,
Pervioral, Phol Tussil, Phol Tux Expectorans, Rectoceptal, Tixilix daytime, Pavacol-D

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E. Street Names

The street cocktail “purple drank” may take several forms but seems to involve some type of cough
syrup containing codeine and promethazine hydrochloride, an antihistamine with sedative
properties. The cough syrup typically mixed with a soft drink and candy, with some variants including
alcohol is popular with professional American athletes and southern rap music. Other names include
“lean”, “drank”, “barre”, “purple stuff”, “syrup”, and “sizzurp” [2].

Street names for codeine alone include captain cody, cody, little c, and school boy. For Tylenol
with codeine, street names include T1, T2, T3, T4, and dors and fours. Dihydrocodeine is sold as DFs
or Diffs on the street. Triple C, Robitussin or CCC are also names for cough syrups containing codeine
or pholcodine.

Street names for acetyldihydrocodeine, ethlymorphine, pholcodine, nicocodine and nicodicodine

were not found.

F. Physical Appearance

Codeine, pholcodine and ethylmorphine appear as colourless crystals or white crystalline powders:
light affects codeine, which effervesces in dry air, and has a bitter taste. Dihydrocodeine is a white
to yellowish crystalline powder. The physical appearance of acetyldihydrocodeine, nicocodine,
nicodicodine and norcodeine were not ascertained.

G. WHO Review History

A review of the analgesic and antitussive effects of codeine, dihydrocodeine, ethylmorphine,

pholcodine, nicocodeine, and nicodicodine was published in the Bulletin of the World Health
Organization in five instalments between 1968 and 1969 in 5 instalments. The first, second, and
third instalments dealt, with the analgesic action of codeine; its alternates for pain relief; and the
antitussive action of codeine. The fourth instalment and fifth an assessment of potential alternates
with antitussive action [3-7].

Preparations of codeine have not previously been reviewed by the WHO ECDD.

2. Chemistry
A. Chemical Name (IUPAC Name: CA Index Name)

Acetyldihydrocodeine
[(4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1H- 4,12-
methanobenzofuro[3,2-e]isoquinolin-7-yl] acetate

Codeine
(4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-
methanobenzofuro[3,2-e]isoquinolin-7-ol

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Dihydrocodeine
(4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1H-4,12-
methanobenzofuro[3,2-e]isoquinolin-7-ol

Ethlymorphine
(4R,4aR,7S,7aR,12bS)-9-ethoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-
methanobenzofuro[3,2-e]isoquinolin-7-ol

Nicodicodine
[(4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1H-4,12-
methanobenzofuro[3,2-e]isoquinolin-7-yl] pyridine-3-carboxylate

Nicocodine
[(4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-
methanobenzofuro[3,2-e]isoquinolin-7-yl] pyridine-3-carboxylate

Norcodeine
(4R,4aR,7S,7aR,12bS)-9-methoxy-1,2,3,4,4a,7,7a,13-octahydro-4,12-methano
benzofuro[3,2-e]isoquinolin-7-ol

Pholcodine
(4R,4aR,7S,7aR,12bS)-3-methyl-9-(2-morpholin-4-ylethoxy)-2,4,4a, 7,7a,13-hexahydro-1H-
4,12-methanobenzofuro[3,2-e]isoquinolin-7-ol

B. Chemical Structure
The molecular formula and weight of the preparations listed in Schedule lll of the 1961 Single
Convention on Narcotic Drugs can be found in Table 1. Chemical structures are detailed below:

Chemical structure acetyldihydrocodeine

(http://www.chemspider.com/Chemical-Structure.4576412.html?rid= af91bd92- 9376-47aa-8b96-
46749eabe094)

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Chemical structure codeine

(https://pubchem.ncbi.nlm.nih.gov/#query=codeine)

Chemical structure dihydrocodeine

(http://www.chemspider.com/Chemical-Structure. 4447600.html)

Chemical structure ethlymorphine

(https://pubchem.ncbi.nlm.nih.gov/#query=ethylmorphine)

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Chemical structure nicodicodine

(https://pubchem.ncbi.nlm.nih.gov/#query=Nicodicodine)

Chemical Structure nicocodine

(https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=5463872&t=l)

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Chemical structure norcodeine

(http://www.chemspider.com/Chemical-Structure.8101508.html? Rid =74ad9a70-48a5-
4fee-9e5c-123fcbbdd8ef)

Chemical structure pholcodine

(http://www.chemspider.com/Chemical-Structure.4470854.html? rid= de0a8e6f -0d7f-
48a4-ac23-b252fe4beb44)

C. Stereoisomers
Details about the stereoisomerism of acetyldihydrocodeine was not established. The Drugbank
(https://www.drugbank.ca/drugs/DB01538) describes the compound as
polycyclic with a four-ring skeleton with three condensed six-member rings forming a partially
hydrogenated phenanthrene moiety, one of which is aromatic while the two others are alicyclic.

Opiates however, are known for their stereospecificity and codeine is no exception. In early pre-
clinical work, l-codeine was active in the mouse tail-flick test as well as in the hot plate test whether
given orally or subcutaneously. The d-isomer of codeine was inactive in both tests up to 100 mg/kg
but caused hyperexcitability, convulsions and ultimately death. Although l-codeine was more potent

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than d-codeine inhibiting the cough reflex in the anesthetized cat, the d-compound did have good
activity. In these animals, l-codeine did not significantly affect the cardiovascular parameters at the
doses tested, whereas d-codeine caused a significant but transient decrease in the blood pressure
and heart rate [8].

The production of (–)-dihydrocodeine has been described [9], whereas, details of any
stereoisomeric form for ethlymorphine, nicocodine, nicodicodine, norcodeine and pholcodine were
not found.

D. Methods and Ease of Illicit Manufacturing

Many of the opioid preparations listed in Schedule lll of the 1961 Single Convention on Narcotic
Drugs are older drugs developed in the early 1900s such as nicocodine and nicodicodine
(nicodicodeine) in 1904. Nicocodine production involves treating anhydrous codeine base with
nicotinic anhydride at 130 °C (Pongratz and Zirm in Monatshefte für Chemie in 1957).
Acetyldihydrocodeine was discovered in Germany in 1914.

Codeine, a natural product of the poppy plant paver somniferum var. album can be extracted from
opium. The synthetic production of codeine is possible by the methylation of morphine. ‘Krokodil’
(also known as crocodile, croc, krok, and poor man's heroin), a homemade injectable drug that has
been used as a cheap heroin substitute in Russia, Europe, the UK and North America has codeine as
its starting point [10, 11].

A. Chemical Properties
Chemical Properties of preparations listed in Schedule lll of the 1961 Single Convention on Narcotic
Drugs include a variety of compounds: acetyldihydrocodeine, codeine, dihydrocodeine,
ethlymorphine, nicocodicine (nicocodeine), nicodicodeine (nicodicodeine), norcodeine and
pholcodine (www.ChemSpider.com/; https://www.chemicalbook.com/; US Environmental
Protection Agency’s EPISuite™ (Table 1)

Home manufacture using over-the-counter codeine or illicitly sourced pharmaceuticals has also
been reported among injecting and recreational drug users [12]. The illicit manufacture of
acetyldihydrocodeine, ethlymorphine, nicocodine, nicodicodine, norcodeine and pholcodine has
not been described in the peer-reviewed literature.

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 Table 1: Chemical properties of preparations listed in Schedule III

Parameter Acetyl Codeine Dihydrocodeine Ethlymorphine Nicocodeine Nicodicodine Norcodeine Pholcodine

Dihydrocodeine

Molecular Formula C20H23NO4 C18H21NO3 C18H23NO3 C19H23NO3 C24H24N2O4 C24H26N2O4 C17H19NO3 C23H30N2O4

Molecular Weight 341.4 299.36 301.38 313.39 404.5 406.47 285.34 398.55
(g/moL)
Melting point (°C) 172.37 154 192-193 123 209.51 208.80 309 91

Boiling Point (°C) 465.4 ± 45.0 440.69°C 462.0 ± 45.0 472.2 ± 45.0 549.7 ± 50.0 553.3 ± 50.0 467.7 ± 45 521.67°C
at 760 mmHg
Density ( g/cm3) 1.300 1.3200 1.3 ± 0.1 1.30 1.40 1.300 1.4±0.1 1.1772

Index of Refraction: 1.609 1.550 1.643 1.654 1.668 1.650 1.675 1.659

Solubility (in water) 1 in 120 1 in 4.5 1 in 10 In ethanol 1 in 50

Dissociation Constant: 9.02 8.2 (20°) 8.8 (25°) 8.2 (20°) 9.23 (25°) 9.2 (25°) 8.0, 9.3 (37°)
pKa
Log partition coefficient:
Log P (octanol-water) 2.26 0.6 1.5 1.8 2.80 2.96 0.69 0.6

Ultraviolet Spectrum 285 283 284 284 283

(nm)
 B. Identification and Analysis
Chemical spot tests[13]

Acetyldihydrocodeine Not reported

Codeine Liebermann’s Test Black
Mandelin’s Test Green
Marquis Test Violet
Dihydrocodeine Mandelin’s Test Grey, Green
Marquis Test Violet
Ethlymorphine Marquis Test Yellow, Violet, Black

Nicocodine Not reported

Norcodeine Marquis Test Blue, Yellow, Violet
Nicodicodine Not reported
Norcodeine Not reported
Pholcodine Liebermann’s Test Black
Marquis Test Violet

To analyse the preparations listed in Schedule lll of the 1961 Single Convention on Narcotic Drugs a variety
of different chromatographic tests are available.

For instance:

• an ultra-performance liquid chromatographic-tandem mass spectrometric method was

developed and fully validated for the simultaneous determination of pholcodine, morphine,
hydromorphone, oxymorphone, norcodeine, codeine, dihydrocodeine, oxycodone, 6-
Monoacetylmorphine (6-MAM), hydrocodone, ethylmorphine, tramadol, 2-ethylidine-1 ,5-
dimethyl-3,3-diphenyl pyrrolidine (EDDP), buprenorphine, propoxyphene, and methadone
in blood. The limit of quantification ranged from 0.5 to 2.5 ng/mL depending on the
compound and the therapeutic concentration [14].
• Sixteen different opioids including codeine, dihydrocodeine, ethylmorphine, fentanyl,
hydrocodone, hydromorphone, morphine, norbuprenorphine, norcodeine, norfentanyl,
oxycodone, oxymorphone, pholcodine have been detected using a triple-quadrupole and a
quadrupole time-of-flight mass analyzer to quantify 16 opioids in human plasma [15]
• The quantitative detection of ethylmorphine has been determined in human hair using
UHPLC high-resolution mass spectrometry [16].
• A chemiluminescence (CL) method has been described for pholcodine in human plasma and
syrup samples based on the fact that pholcodine can greatly enhance the weak CL emission
of reaction between tris(1,10 phenanthroline)ruthenium(II), Ru(phen)32+ , and acidic Ce(IV).
The limit of detection (LOD) (S/N = 3) was 2.5 ng/mL [17].
42nd ECDD (2019): Preparations of codeine

3. Ease of Convertibility Into Controlled Substances

Some preparations listed in Schedule lll of the 1961 Single Convention on Narcotic Drugs can be
converted into a controlled substance. For instance, the treatment of codeine in chloroform with
boron tribromide has consistently given morphine in 90-91% yield after a simple isolation procedure
[18].

In the early 1980s a large number of small-scale illicit laboratories were reported to be
producing morphine and heroin from commercially available, codeine-based pharmaceutical
products in New Zealand. The codeine demethylation procedure was based on the use of pyridine
hydrochloride. Only very simple laboratory equipment and reagents were required and production
was achieved easily with little or no chemical background, by following a recipe. The process yielded
a product known as 'homebake' [19]. See also section D above.

Codeine is also used to manufacture dihydrocodeine and acetyldihydrocodeine, and may also be
used to manufacture the drugs usually manufactured by conversion of thebaine (UNODC, 2019).
(https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1953-01-01_3_page005.html/).

Information about the ease of convertibility of acetyldihydrocodeine, ethlymorphine, nicocodine,

nicodicodine, norcodeine and pholcodine into controlled substances has not been reported in the
scientific literature

4. General Pharmacology
A. Routes of administration and dosage
In the main, preparations listed in Schedule lll of the 1961 Single Convention on Narcotic Drugs
where they are clinically available as medicines as shown in section D above (acetyldihydrocodeine,
codeine, dihydrocodeine, ethlymorphine, nicocodicine (nicocodeine), and pholcodine are
administered orally.

The drug bank (https://www.drugbank.ca/drugs/DB01538) suggests that details of the

pharmacology of acetyldihydrocodeine and nicodicodeine (nicodicodeine), are currently
unavailable.

Nicocodeine cough medicines are available as syrups, extended-release syrups, and sublingual
drops. Analgesic preparations are also available in the form of sublingual drops and tablets for oral
administration (https://www.revolvy.com/page/Nicocodeine).

Dihydrocodeine products can be purchased over the counter in many European and Pacific Rim
countries and generally contain from 2 to 20 mg of dihydrocodeine per dosing unit combined with
one or more other active ingredients such as paracetamol (acetaminophen), aspirin, ibuprofen,
antihistamines, decongestants, vitamins, medicinal herb preparations, and other such ingredients.
In some countries 30 mg tablets and 60 mg controlled-release tablets are available over the counter
and 90 and 120 mg strengths may be dispensed for specific indications
(https://www.dralways.com/product/416).

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In the United States, dihydrocodeine is dispensed in 16 and 32 mg formulations and many include
acetaminophen and caffeine. In the UK and other countries, 30 mg tablets containing only
dihydrocodeine as the active ingredient are available. In the UK, a 40 mg Dihydrocodeine tablet is
available as DF-118 Forte and can be prescribed for palliative care.
(https://bnf.nice.org.uk=dihydrocodeine).

Ethylmorphine considered to be less potent than morphine but more potent than codeine [20], is
available in oral dosages ranging from 5 to 30 or 50 mg. Like codeine and close chemical relatives,
ethylmorphine is not advocated for intravenous administration as the sudden histamine release can
have dangerous impacts (https://infogalactic.com/info/Ethylmorphine).
Psychonaut reports Tussipax tablets available as over-the-counter medication in France contain 10
mg of ethylmorphine and 10 mg of codeines; in Norway Cosylan and Solvipect comp. cough syrups
contain 1.7 mg/mL and 2.5 mg/mL ethylmorphine hydrochloride respectively; in Sweden the
prescription medication Cocillana-Etyfin cough syrup contains 2.5mg/mL ethylmorphine. Lepheton,
a combination containing 0.82 mg/mL ethylmorphine hydrochloride and 2.05 mg/mL ephedrine is
also available. In the UK and USA there are no legal preparations of ethylmorphine and it is not
available for medical purposes (https://psychonautwiki.org/wiki/Ethylmorphine). Ethylmorphine
was used in ophthalmic preparations as Dionine to treat inflammations of the eye in 1904, but this
preparation does not seem to have survived today [21].

Pholcodine classified as an antitussive (opioid cough suppressant) has a mild sedative effect with
little or no analgesic effects. According to the electronic medicines compendium
(https://www.medicines.org.uk/emc/product/4598/smpc), Pholcodine syrup is a clear orange viscous
syrup containing 5mg/5 mL pholcodine and may be taken (up to 10 mL), 6 times a day. Pholcodine
is not prescribed in the United States or Canada where it is classified as a Schedule I drug. The British
National Formulary (bnf.nice.org.uk/drug/pholcodine.html) states when prepared
extemporaneously, Pholcodine Linctus, BP should consist of pholcodine 5 mg/5 mL in a flavoured
vehicle, containing citric acid monohydrate 1% and Pholcodine Linctus, Strong, BP consists of
pholcodine 10 mg/5 mL in a suitable flavoured vehicle, containing citric acid monohydrate 2%

C. Pharmacokinetics
Acetyldihydrocodeine
For some of the preparations listed in Schedule lll of the 1961 Single Convention on Narcotic Drugs
the pharmacokinetics are poorly described, such as acetyldihydrocodeine, which is a 6-acetyl
derivative of dihydrocodeine and is metabolised in the liver by demethylation and deacetylation to
produce dihydromorphine. However, it has been shown that phenanthrenic opioids, including
codeine, can modulate morphine glucuronidation in preclinical studies. Dihydrocodeine and
acetyldihydrocodeine were ineffective in primary cultures of rat hepatocytes previously incubated for
72 h with either codeine or its derivatives [22]. Little else has been reported about the
pharmacokinetics of acetyldihydrocodeine in man or animals.

Nicodicodine

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Pharmacokinetic data has not been reported in the scientific literature as far as it has been possible
to ascertain for nicodicodine.

Nicocodine
The US National Formulary of Medicine, National Centre for Biotechnology Information (NCBI) describes
nicocodine is an ester of codeine closely related to dihydrocodeine and the codeine analogue of
nicomorphine and is metabolised in the liver by demethylation to produce nicomorphine (6-
nicotinoylmorphine). Nicodicodine is metabolised in the liver by demethylation to produce 6-
nicotinoyldihydromorphine, and also subsequently further metabolised to dihydromorphine
(https://pubchem.ncbi.nlm.nih.gov/compound/ Nicocodeine).

Codeine and Norcodeine

Much more is known about codeine than the other preparations. Oral absorption of codeine from
the gastrointestinal tract is almost complete (94% ± 4%) and the onset of action occurs 30–45
minutes after administration, when given orally. Volume of distribution was reported to be 3.6 L/kg,
indicating extensive distribution of the drug into tissues and plasma protein binding was low at 7%–
25%. Renal excretion has been reported to account for the major elimination pathway: major
metabolites appear in the urine within 6 hours, and 40%–60% of the codeine is excreted free or
conjugated, approximately 5%–15% as free and conjugated morphine and 10%–20% as free and
conjugated norcodeine. Codeine has a plasma half-life that ranges from 2.2 h [23] to 3.2 h [24-26].

Figure 1: Metabolism of codeine showing three major pathways [27]

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Metabolism of codeine follows three major pathways: conjugation to codeine-6-glucuronide, N-

demethylation to norcodeine, and O-demethylation to morphine (Figure 1). The conjugation
pathway is quantitatively the most important, with codeine-6-glucuronide recovered in urine
accounting for 70% of an oral dose of codeine. The corresponding values for N-demethylation and
O-demethylation are probably 7% and 5%, respectively; approximately 4% is excreted unchanged
[27, 28].
In a study to compare codeine and pholcodine codeine was absorbed and eliminated relatively
rapidly (half-life 2.3 ± 0.4 h) and kinetics were adequately described by a one-compartment open
model with first-order absorption. A two-compartment model was required to describe pholcodine
elimination from plasma (half-life, 37.0 ± 4.2 h). Plasma concentrations of conjugated codeine were
much greater than the unconjugated alkaloid. By contrast, pholcodine appeared to undergo little
conjugation. Biotransformation of codeine to morphine was evident in all subjects, although the
extent of this metabolic conversion varied considerably between subjects. Morphine was not
detectable in the plasma of any subject after pholcodine administration [29].

Dihydrocodeine
The pharmacokinetics of dihydrocodeine have been determined in seven human volunteers who
received the drug orally (30 mg and 60 mg) and intravenously (30 mg) on separate occasions, and
in twenty-four patients receiving 25 mg or 50 mg of the drug intravenously. Dihydrocodeine follows
a two-compartment distribution model. After oral administration, absorption was relatively quick
with mean peak concentrations at 1.6 h-1.8 h. The mean bioavailability was 21% (range 12-34%).
The mean half-lives varied between 3.3 h-4.5 h depending upon dose. Peak concentrations of
metabolites occurred between 1.8 h-2.0 h after oral administration and 2.2 h-2.5 h after intravenous
administration suggesting substantial first-pass metabolism [30].

Ethylmorphine
The pharmacokinetics of ethylmorphine after administration of a single dose of the cough mixture
Cosylan were investigated in 10 healthy subjects and the half-life of the drug was reported to be 2
h. Ethylmorphine-6-glucuronide was found to be the major metabolite. Serum and urine samples
taken more than 8 and 24 h after administration of ethyl-morphine respectively, contained
morphine and morphine-glucuronides, but no ethylmorphine, ethylmorphine-6-glucuronide or
(serum only) norethylmorphine. Norethylmorphine was detected after hydrolysis of urine samples
in all subjects [31]. Intra- and interindividual differences in morphine formation after single-dose
intake of ethylmorphine at 25 and 50 mg has been explored in in 10 healthy volunteers. The decline
in urinary ethylmorphine was more rapid than for morphine, which leads to an increasing
morphine/Ethylmorphine ratio in urine over time. Morphine was formed from ethylmorphine at a
high and variable rate and may be present in urine in concentrations greater than those of
ethylmorphine even shortly after drug intake [32]

Pholcodine
In early work on the pharmacokinetics of pholcodine following two single doses (20 and 60 mg) with
an interval of 3 weeks between the two treatments. Subsequently, the same subjects received 20
mg pholcodine 8 hourly orally for 10 days. After the single doses, pholcodine was absorbed rapidly
and slowly eliminated with a mean half-life of 50.1 ± 4.1 h. The renal clearance of pholcodine was
137 +/- 34 ml min-1 and was inversely correlated with urine pH (r = 0.60). The protein binding of
pholcodine is of approximately of 21-23% and it tends to have a slight variation depending if the

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administration is chronic. The concentration of pholcodine in oral fluid was 3.6 times higher than in
plasma. After chronic administration, the pharmacokinetics of pholcodine were not statistically
different from the single dose parameters. The plasma protein binding was 23.5%. Morphine, in
unconjugated or conjugated form, was not detected in the urine of any subject after pholcodine
administration [25]. After oral administration of 60 mg of pholcodine, the Tmax and Cmax were
reported to be 1.3 hours and 26.3 ng/ml. The absorption of pholcodine was reported to represent
approximately 88% of the administered dose [25]. The volume of distribution differs according to
the pharmacokinetic model applied: being 265L based on a one-compartment model to 3207L in a
two-compartment model [29].

D. Pharmacodynamics
Acetyldihydrocodeine
Acetyldihydrocodeine has reportedly higher lipophilicity than codeine and is converted into
dihydromorphine rather than morphine, and has been postulated to be more potent and longer-
lasting. It also has a higher bioavailability than codeine.

Codeine
Codeine is a pro-drug with a weaker affinity for μ-opioid receptors than morphine (200-fold less).
Glucuronidation inactivates up to 80% of the administered drug to codeine-6-glucuronide by uridine
5′-diphosphate glucuronosyltransferase-2B7 (UGT2B7) and N-demethylation to norcodeine
by CYP3A4, 5-10% of codeine undergoes O-demethylation to morphine, its active form via CYP2D6
[33]. Without O-demethylation, codeine may confer only a small fraction of the analgesic potency
of morphine: much of its analgesic effect coming from codeine 6-glucuronide [34]. Earlier work has
shown analgesic and antitussive properties in experimental animal species [35]. An effective review
of the receptor pharmacology of codeine as well as its binding affinity to mu- and delta-opioid
receptors has been carried out by Trescot et al, (2008) [36].

Nevertheless the conversion of codeine to morphine have been investigated because this metabolic
route is via CYP2D6, and patients with genetic variations in this enzyme may find codeine to be less
effective as an analgesic. It has been widely reported that the genetic polymorphism of CYP2D6 is
at least partly responsible for the variable response to medication. Individuals with the poor
metaboliser CYP2D6 phenotype may not achieve adequate analgesia with codeine. There are inter-
ethnic differences in frequency of these phenotypes; while 10% of Caucasians and 30% of Hong
Kong Chinese are PM [37], 1% in Denmark and Finland, 10% in Greece and Portugal and 29% in
Ethiopia [38] are UM. Hence, while codeine (single oral dose of codeine, 75 or 100 mg against
morphine, 20 or 30 mg) may be less effective as an analgesic in about 2-10% of ethnic groups [39],
it could be a dangerous analgesic in the latter populations, as excessive doses of morphine may be
rapidly produced [37].

The INGENIOUS clinical trial in Indiana, USA, examined implementing pharmacogenomics into
clinical practice (INdiana GENomics Implementation: an Opportunity for the Under Served
INGENIOUS trial, NCT02297126). It was found that within 60 days of receiving codeine, clinicians
more frequently prescribed an alternative opioid in ultra-rapid and poor metabolizers (odds ratio:
19.0; 95% CI: 2.8-160.4) as compared with normal or indeterminate metabolizers (p = 0.01). After

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adjusting the CYP2D6 activity score for drug-drug interactions, uncontrolled pain was reported
more frequently in individuals with reduced CYP2D6 activity (odds ratio: 0.50; 95% CI: 0.25-0.94)
[40].

Ethylmorphine
Ethylmorphine is metabolised by N-demethylation to norethylmorphine and by O-deethylation to
morphine, the latter step being due to CYP2D6. This was initially shown in human liver microsomes
and is consistent with previous findings in healthy volunteers [41]. Studies also have found wide
variation in the recovery of morphine and morphine-glucuronides after oral administration of
ethylmorphine that could not be explained simply by a difference in CYP2D6 genotype. It was felt
that constitutional variation in other enzymatic pathways involved in ethylmorphine metabolism
was also likely and concluded that ratios of morphine to parent drug cannot be used to distinguish
the source of morphine after administration of ethylmorphine. [31].

Dihydrocodeine
In early work, Kirkwood et al (1997) showed in human liver microsomes that CYP2D6 was the major
O-demethylating enzyme involved in the biotransformation of dihydrocodeine to dihydromorphine,
whereas CYP3A was the enzyme involved in the production of nordihydrocodeine [42]. The
analgesic activity of dihydrocodeine has often been attributed to the dihydromorphine metabolite
based on dihydromorphine having a binding affinity to µ receptors similar to that of morphine and
possessing approximately 100 times the activity of the parent drug. However, CYP2D6 enzyme,
mediates the conversion of dihydrocodeine to dihydromorphine. Inter-ethnic differences (greater
than 10% of Asians lack the functional activity of CYP2D6) suggest that the analgesic effects of
dihydrocodeine might be diminished in those races with high prevalence of the poor metaboliser
phenotype of CYP2D6 [43].

However, more recently, Webb et al (2001) observed the analgesic effect following dihydrocodeine
ingestion was mainly attributed to the parent drug rather than its dihydromorphine metabolite. This
contradicts the view that polymorphic differences in dihydrocodeine metabolism to
dihydromorphine have little or no effect on the analgesic affect [44]. Others have confirmed the
work of Webb: Schmidt et al (2003) found that CYP2D6 phenotype has no major impact on opioid
receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of
CYP2D6 in the formation of highly active metabolites [45]. Further work is needed in this area.

Pholcodine
In very early work cough of any origin (upper respiratory tract, larynx, pleuro-pulmonary diseases
etc) was always soothed by a single dose of pholcodine between 10 mg and 80 mg. The average
daily doses were of the order of 40-120 mg orally or by subcutaneous injection [46]. The antitussive
action of pholcodine was assessed to be similar to codeine but as a centrally sedative product it was
seen as superior to codeine. Pholcodine depresses the respiration less than morphine and a little
more than codeine and has low addiction liability [46]. Pholcodine is an anti-convulsant, unlike
morphine, codeine and morphine derivatives, which are all convulsants
(https://www.unodc.org/unodc/en/data-and-analysis/bulletin/ bulletin_1961-01-
01_2_page004.html).

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5. Toxicology
Little recent data is available for the preparations listed in Schedule lll of the 1961 Single Convention
on Narcotic Drugs (acetyldihydrocodeine, dihydrocodeine, ethlymorphine, nicocodicine
(nicocodeine), nicodicodeine (nicodicodeine), norcodeine and pholcodine). The material available
stems form the 1950s and 1960s [3-7, 46].

Calen (1961) concluded that the toxicity of pholcodine was low in animals (mice, rabbits and dogs),
(https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1961-01-01_2
page004.html). Others at the time concurred with these findings. The general sedative action of
pholcodine was superior to that of codeine. In rabbits pholcodine depressed the respiratory rate
and volume less than morphine and somewhat more than codeine [46]. Animal studies do not
reveal a carcinogenic effect of codeine [47] . Mutagenicity studies do not show evidence of a
genotoxic risk to man [48].

A. Clinical
One of the main Antitussives such as the preparations listed in Schedule lll of the 1961 Single
Convention on Narcotic Drugs include a variety of compounds though elicit their clinical affect by
directly inhibiting the medullary cough centre of the brain [49]. Various models suggest that cough
suppression occurs via agonism of the μ2 or κ opioid receptors, or antagonism of the δ opioid
receptor and the σ or N-methyl-d-aspartate (NMDA) receptors are likely also involved [27].

B. Respiratory depression
Opioid drugs reduce the sensitivity of the respiratory centre to carbon dioxide, which may result in
decreased tidal volume and decreased respiratory rate. The triad of coma, pinpoint pupils, and
respiratory depression is strongly suggestive of opioid poisoning. In severe overdose, particularly by
the intravenous route, apnoea, circulatory collapse, cardiac arrest, and death may occur.
Promethazine may add to the depressant effects of codeine. Children can be particularly
susceptible to the toxicological effects of some of the preparations listed in Schedule lll of the 1961
Single Convention on Narcotic Drugs. A 10 month of child was given ethylmorphine in the evening
(five milliliters of Cosylan® or Solvipect®, the two available antitussive preparations containing
ethylmorphine, would amount to 8.5 or 12.5 mg of ethylmorphine, respectively. and was found
dead the next morning. The autopsy report concluded a combination of opiate-induced sedation
and weakening of respiratory drive, a respiratory infection, and a sleeping position that could have
impeded breathing caused death [50].

The therapeutic doses of pholcodine do not cause depression of respiration, CNS excitation or other
side effects associated with narcotics: the impact of pholcodine is selective on the cough centre
without affecting the respiratory centre [46].

C. Seizures
Seizures are not common in opioid preparations listed in Schedule lll of the 1961 Single Convention
on Narcotic Drugs such as codeine, dihydrocodeine, ethlymorphine, nicocodicine and pholcodine.
However, codeine phosphate-induced seizures following intravenous administration when patients
are in need of acute pain control requiring intravenous narcotics [51].

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D. Fatalities
In a study in Sweden twenty years ago, 14 fatal poisonings attributed to drug abuse were studies.
The cause of death was specified as fatal ethylmorphine poisoning in two cases. Among the
unspecified medicinal drug poisonings there were five cases with very high blood levels
of ethylmorphine, indicating that this drug played an important contribution to the cause of death.
The results indicate that deaths due to ethylmorphine in antitussive medicines may occur among
drug addicts and alcoholics taking it in overdose [52].

E. Cardiovascular
Cardiac arrest leading to death was reported in a 52-year-old man, who ingested 750 mg of
pholcodine syrup. This was determined to be the result of hypoxia due to respiratory arrest
connected to the opioid nature of pholcodine Toxicological analysis showed a pholcodine blood
level of 2500 ng mL (a lethal dose is >1000 ng mL, extrapolated from animal studies) [53].

Dihydrocodeine in overdose significantly reduces peripheral and aortic systolic, mean, end systolic
pressures, and decreased peripheral pulse pressure. In a prospective study of patients who
overdosed on dihydrocodeine reduced systemic and aortic diastolic blood pressure were observed.
Augmentation index and heart rate, however, did not change but decreased arterial oxygen
saturation occurred Dihydrocodeine therefore has a notable effect on central and peripheral
hemodynamics, which could reduce cardiac afterload, providing a pharmacological explanation for
the apparent benefit of opioids in cardiovascular diseases [54].

6. Adverse Reactions in Humans

A. Acute
Acute side effects have been widely reported for opioids including codeine, dihydrocodeine and
pholcodine and itching, nausea and respiratory depression. During higher doses especially during
higher steady state doses headache, nausea, vomiting, dizziness, constipation, and a dry mouth [55].

Nausea, vomiting, headache, dizziness, drowsiness and confusion were the most commonly
reported adverse effects with a single dose of oral dihydrocodeine 30 mg compared with placebo.
These problems tend to occur in more than one patient out of 100 treated with DHC [56].

B. Chronic
There is a dearth of evidence on the chronic use of weak opioids. In practice, with opioid therapy,
there is no evidence that codeine and dihydrocodeine are less risky than morphine at its lowest
effective dose. Compared to morphine, the efficacy of these drugs varies more from one patient to
another, and their multiple pharmacokinetic interactions can be difficult to manage. There is also a
sometimes unpredictable risk of serious over-dose [57].

Natural alkaloids extracted from Papaver somniferum have long been known to cause allergic
contact dermatitis, but the number of reported cases remains small. Affected workers have included
nurses or other health personnel who handle the drugs, or factory employees engaged in their
preparation. Most of these workers have been exposed to the drugs in powder form, and have

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developed an airborne pattern of contact dermatitis particularly codeine (3‐methylmorphine) [58-

60] but there are also case reports for dihydrocodeine [61] but not ethylmorphine [62].

7. Dependence Potential
A. Animal Studies
Previous studies have demonstrated that codeine produces anti-nociceptive effects in mice, rats,
and guinea pigs using a variety of tests [63] and antitussive effects in cats, guinea pigs and mice
using variety of approaches to stimulate cough reflex (for example [64]). The peak effect of codeine,
as a short acting drug, occurs within 1–2 hours, and the duration of antitussive action is 4–6 hours.

B. Human Studies
Codeine misuse and dependence has been described in in the UK and Ireland with both prescribed
and OTC codeine. Codeine dependence was associated with daily use of codeine, faking or
exaggerating symptoms to get a prescription for codeine and 'pharmacy shopping'. A higher number
of respondents had sought advice on the Internet (12%) rather than from their general medical
practitioner (GP) (5.4%) to control their codeine use [65]. In 1978, Marks et al, reported that
dependence following prescription of dihydrocodeine occurs, with severe physical and
psychological traits and abrupt withdrawal upon cessation. Five cases were used to illustrate the
risk of physical dependence of this drug [66].

8. Abuse Potential
A. Animal Studies
The administration of codeine to 60 male Long-Evans rats (Charles River Laboratories Japan, Inc.,
Kanagawa, Japan) by the intraperitoneal route (codeine at 20 mg/kg generalized to the morphine-
training dose) found 14 of the 15 animals displaying 80% or more morphine-lever responses within
the range of 3 to 20 mg/kg. In the administration of codeine by the oral route (codeine at 60 mg/kg
generalized to the morphine-training dose), 14 of the 15 animals showed 80% or more morphine-
lever responses within the range of 10 to 60 mg/kg. Thus, the discriminative stimulus properties of
morphine and codeine were comparable when using different administration routes to those at
discrimination training [67].

When nicocodine was self-administered to the rhesus monkey in cross self-administration

experiments the minimum reinforcing dose was found to be 10 times higher than that of codeine
and 100 times higher than that of heroin. At reinforcing doses the rate of self-administered infusions
of nicocodine were comparable with those of codeine. It was concluded that nicocodine was an
opium-like reinforcing compound [68].

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B. Human Studies
The opioid preparations listed in Schedule lll of the 1961 Single Convention on Narcotic Drugs
(acetyldihydrocodeine, codeine, dihydrocodeine, ethlymorphine, nicocodicine (nicocodeine),
nicodicodeine (nicodicodeine), norcodeine and pholcodine) have not received much attention,
often based on the belief that they are weaker opioids and less likely to cause dependence and fatal
overdose than morphine.

Ethylmorphine is the 3-ethoxy congener of morphine, used mainly as an antitussive and has some
potential for abuse. It is thought likely that the abuse liability of ethylmorphine might be linked to
its metabolism to morphine. In turn, morphine may also mediate its effects through formation of
active metabolites including the 6-glucuronide [5-7]. https://www.drugbank.ca/drugs/DB01466

The abuse potential of pholcodine is reported to be low whereas early work has suggested
acetyldihydrocodeine, nicocodine and nicodicodine may have some abuse liability [3-7].

9. Therapeutic Applications and Extent of Therapeutic Use and Epidemiology of

Medical Use
Most codeine preparations classified under Schedule III are pharmacy controlled with a medical
prescription required however, there is no requirement to keep controlled registers so that the
extent of use is difficult to gauge.
Codeine is marketed as both a single-ingredient drug and in combination preparations with
paracetamol (as co-codamol), and the Tylenol-with-codeine series, with aspirin (co-codaprin) or
with ibuprofen (Nurofen Plus). These combinations are reported to provide greater analgesia than
either compound alone [69]. Codeine in the form of cough syrups, alone or with other active
ingredients, and as a linctus (e.g., Paveral) for all the indications of codeine are available. In some
countries codeine-only products with a prescription as a time-release tablet or as suppositories are
produced. Injectable codeine is also available for subcutaneous or intramuscular injection only;
intravenous injection is contra-indicated, as this can result in nonimmune mast-cell degranulation
and an anaphylactic reaction. Codeine is commonly used in the management of mild to moderate
pain in adults (often dental or post-partum) and under strict monitoring in children [70].
Globally, the demand for codeine remains high and has risen by approximately 27% over the last
decade with figures estimating that global purchasing reached an all-time high at 269 tonnes in 2011
compared to 164 tonnes in 1992 (INCB 2012). In some countries, codeine preparations are available
without prescription in combination preparations (paracetamol, ibuprofen or aspirin) from licensed
pharmacies and in retail outlets. Since the regulation and control of codeine dispensing varies
between countries with some restricting the visual display and advertisement of over the counter
codeine preparations to the consumer. The amount of over the counter sales of codeine containing
medications is not easy to determine due to trade exemptions and because disclosure of
information might prejudice the commercial interests of any person or public authority, but there
is little doubt that it forms a substantial proportion of pharmacy sales [71]. In 2013, the global legal
production of the three most common opiates in descending order were morphine 523 tonnes,
codeine 361 tonnes and oxycodone 261 tonnes [72].

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More codeine was consumed in the United Kingdom, Canada and Australia than any other opioid in
2012 [73]. Codeine is also one of the most accessible opioids, available without prescription (over-
the-counter) in the UK, Canada, France, New Zealand and Australia [74]. In Australia, the overall rate
of codeine–related deaths increased from3.5/million in 2000 to 8.7/million in 2009. Deaths
attributed to accidental overdoses were more common (48.8%) than intentional deaths (34.7%).
Recorded deaths had high rates of prior comorbid mental health (53.6%), substance use (36.1%)
and chronic pain (35.8%) problems [75].

In children aged 0-17 years codeine use has remained largely unchanged from 1996 to 2013 (1.08
vs. 1.03 million children, respectively) in the United States. Odds of codeine use was higher in ages
12–17 (OR, 1.40; [1.21–1.61]), outside of the Northeast US, and among those with poor physical
health status (OR, 3.29 [1.79–6.03]). Codeine use was lower in children whose ethnicity was not
white and those uninsured (OR, 0.47 [0.34–0.63]). Emergency doctors (18%) and dentists (14%)
prescribed codeine to children the most for trauma-related pain [76].

Meta-analysis that investigated low dose codeine 15 to 30 mg and found ten randomised controlled
trials were eligible. They found low-quality evidence (n=211 participants) that a single dose of a
combination analgesic product (with an nonsteroidal anti-inflammatory) containing low-
dose codeine (15 to 30 mg) provides small pain relief for acute dental pain. In addition, moderate-
quality evidence (n=93) was determined for pain relief for post-episiotomy pain and orthopedic
surgery pain. There was also low-quality evidence (n=80) that a multiple-dose regimen provides
small pain relief for acute pain following photorefractive keratectomy and moderate-quality
evidence of moderate pain relief for certain chronic pain conditions such as hip osteoarthritis and
temporomandibular joint pain. Thus combination analgesic products containing low-
dose codeine provide small to moderate pain relief for acute and chronic pain conditions in the
immediate short term with limited trial data on use beyond 24 hours [77].

Dihydrocodeine is available in Japan as tablets which contain 2.5 mg of dihydrocodeine phosphate

and caffeine, the decongestant d,l-methylephedrine HCl, and the antihistamine chlorpheniramine,
and packets of granules which effervesce like Alka-Seltzer with 10 mg of dihydrocodeine
with lysozyme and chlorpheniramine, marketed for OTC sale as New Bron Solution-ACE.

For a single dose of oral dihydrocodeine tartrate 30 mg compared with placebo the Number Needed
to Treat (NNT) was 8.1 (4.1 to 540) for at least 50% pain relief over four to six hours in postoperative
pain of moderate to severe intensity. Thus one in every eight participants with moderate to severe
postoperative pain experienced at least 50% pain relief with dihydrocodeine 30 mg who would not
have done with placebo. However, Ibuprofen 400 mg was significantly more effective than
dihydrocodeine 30 mg or dihydrocodeine 60 mg for at least 50% pain relief over a period of four to
six hours in postoperative pain of moderate to severe intensity [78].

10. Listing on the WHO Model List of Essential Medicines

The World Health Organization’s (WHO) model list of essential medicines
(http://www.who.int/selection_medicines/list/en/) presents those medicines deemed necessary to
meet priority health needs. The local implementation of essential medicines policies is associated
with improved quality use of medicines [79, 80].

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The World Health Organisation has placed codeine on ‘step 2’ of its pain ladder. Codeine is a weak
opioid that was endorsed by the World Health Organization as the second step on the analgesic
ladder for cancer pain and has been used routinely for postoperative and for breakthrough pain in
chronic sufferers. Dihydrocodeine similarly is on step two of the analgesic ladder for example for
musculoskeletal pain (https://bpac.org.nz/BPJ/2008/December/docs/
bpj18_who_ladder_pages_20-23.pdf).

11. Marketing Authorizations (as a Medicinal Product)

Many companies hold marketing authorisations for codeine as a medicine. Some examples include,
Actacode (Sigma), Bisoltus (Boehringer Ingelheim), Bromophar (Qualiphar), Bronchicum (Sanofi-Aventis),
Bronchodine (Pharmacobel), Codant (Antigen), Codedrill (Pierre Fabre), Codein (Cristália), Codeisan (Belmac),
Coderpina (Frycia Centro América), Codicalm (Welti), Codicept, Codinex (Pinewood), Coducept, Cougel
(Hwang's), Coutan (Mey See), Dinco (Center), Farmacod (Farmacom), Galcodine (Thornton & Ross), Pectoral
(Siphat) and Tussoret (MaxMedic).

In Ireland codeine medicines are currently authorised for the relief of pain in such conditions as
rheumatic and muscular pain, migraine, headache, menstrual pain, toothache, backache and for
symptoms of the common cold and influenza and the majority are available as non-prescription
medicines, from retail pharmacy businesses only [81].

12. Industrial Use

Industrial use of preparations listed in Schedule lll of the 1961 Single Convention on Narcotic Drugs
include is not reported

13. Non-Medical Use, Abuse and Dependence

It is difficult to estimate the prevalence of non-medical use of the preparations listed in Schedule lll
of the 1961 Single Convention on Narcotic Drugs. However, it is known that the abuse of over the
counter (OTC) antitussive preparations is a continuing problem in the United States and throughout
the world [27]. Thought to be due to the increasing availability, social acceptance and the
perception, especially among the young that pharmaceutical drugs are safe. With legislative
activity, educational, and economic initiatives there may have been a shift to abuse of other more
readily available, and easily attainable cough and cold preparations, such as those containing
codeine. There seems to be a particular problem with codeine-promethazine hydrochloride cough
syrup (CPHCS), which is a growing public health problem [82].

In a study in the UK 16 adults (13 women and 3 men) who had used codeine in the last 12 months
other than as directed or as indicated were interviewed. Environments capable of producing harm
included: unsupervised and long-term codeine prescribing, poor access to non-pharmacological pain
treatments, barriers to provision of risk education of codeine related harm and breakdown in
structures to reduce the use of over the counter codeine other than as indicated [83].

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Nonmedical use of cough syrup (NUCS) has become an issue in some areas despite the well-
documented dangers of cough syrup abuse: Hou et al (2011) associated chronic codeine cough
syrup abuse to alterations in the dopaminergic system and the striatal dopamine transporter (DAT).
Striatal DAT, responsible for the active dopamine reuptake into the presynaptic neuron and the
regulation of striatal synaptic dopamine levels was significantly reduced in codeine syrup dependent
compared to healthy volunteers [49]. Codeine is often misused through oral administration of
combination tablets and tampering procedures which separate codeine from the accompanying
analgesics appears to be gaining popularity amongst certain codeine taking populations. Often
referred to as ‘cold water extraction’, the aim is to keep as much codeine as possible in the extracted
tampering products, while at the same time reducing the amount of non-opioid analgesics to non-
toxic levels [84].

In Europe, the misuse of codeine-containing medicines in combination with new psychoactive

substances (NPS) has been noted. Consuming codeine extracted from combination tablets
(OR = 16.79, 95% CI [8.67, 32.51]); obtaining codeine from friends, family, and acquaintances
(OR = 3.98, 95% CI [1.82, 8.7]); use of illicit controlled drugs (OR = 34.99, 95% CI [8.39, 145.94]) and;
use of codeine to experience euphoria (OR = 6.41, 95% CI [3.42, 12.04]) [85] were all significantly
more likely to predict NPS use. Tampering of codeine appeals to recreational users consuming high
amounts of codeine to induce opioid euphoria, to codeine dependent concerned with the toxicity
of non-opioid analgesics, and to those unable to obtain potent prescription opioids who may turn
to codeine to prevent withdrawal and cravings [84].

14. Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and
Dependence
The rapid rise of prescription opioid misuse has been identified as a key public health problem in
the United States. Representations of codeine misuse through analysis of public posts on Instagram
to identify text phrases related to misuse found that codeine misuse images were being glamorised
through co-ingestion with soda (street name: lean) and alcohol, and popular culture imagery. There
was concern that such activity holds the potential to normalise, increase codeine misuse, and
overdose. This has led to calls for more Public health efforts to better understand the relationship
between the potential normalisation, ritualisation, and commercialisation of codeine misuse [86].

The harmful effects of codeine misuse and dependence have long since been recognised by the
medical community [87]. Misuse of codeine can occur in pill or syrup form has been well
documented previously in the USA [88] India [89], Hong Kong [90] and elsewhere mixed with
caffeine amongst other ingredients [64, 91]. Further detail can be found in a comprehensive review
by Van Hout (2014) [91].

15. Licit Production, Consumption and International Trade

Most of the codeine currently manufactured globally comes from morphine through a semisynthetic
process. There has been an increase in the cultivation of the opium poppy variety that is rich in
codeine and in the manufacture of poppy straw concentrate rich in codeine, used for the extraction
of codeine. Due to uncertain social, political, and climatic conditions in some producing regions,
high-yielding methods for the chemical synthesis of opium alkaloids remain popular [9]. In searching

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for high-yielding methods Geffe et al, (2014) reported on a short and high-yielding enantioselective
synthesis of the –dihydrocodeine through the α-benzylation of a deprotonated bicyclic α-
aminonitrile, followed by Noyori’s asymmetric transfer hydrogenation combined with the Grewe
cyclization onto a symmetrical A-ring precursor [9].

The demand for codeine remains high and continues to rise (INCB, 2012). Both exports and
manufacture of codeine have also seen a rising trend [71]. Codeine is used mainly for the
manufacture of preparations in Schedule III of the 1961 Convention, while a smaller quantity is used
for the manufacture of other narcotic drugs, such as dihydrocodeine and hydrocodone [92]. In 2011,
figures show that the UK was the highest codeine manufacturer globally representing 22%, followed
by France (21%), US (17%) and Australia (8%). Over-the-counter sales of codeine containing
medications are not easy to determine despite supervision by a pharmacist being generally required
(European Medicines Agency, 2013) [71]

16. Illicit Manufacture and Traffic and Related Information

In the 1980s, a large number of small-scale illicit laboratories producing morphine and heroin from
commercially available, codeine-based pharmaceutical products were reported in New Zealand. The
codeine demethylation procedure was based on the use of pyridine hydrochloride and was
synthesised by people with little or no chemical background, following a recipe-like procedure
known as 'homebake' [19].

A short and high-yielding enantioselective synthesis of (-)-dihydrocodeine has been published

involving the α-benzylation of a deprotonated bicyclic α-aminonitrile, followed by Noyori's
asymmetric transfer hydrogenation combined with the Grewe cyclization onto a symmetrical A-ring
precursor. This compound can be converted to (-)-thebaine in high yield by known transformations,
while (-)-codeine and (-)-morphine are available from an advanced intermediate [9].

17. Current International Controls and Their Impact

Preparations of codeine are listed in Schedule lll of the 1961 Single Convention on Narcotic Drugs

18. Current and Past National Controls

The legal status of codeine differs internationally. In Australia, Canada, New Zealand, Sweden,
the United Kingdom, the United States and many other countries, codeine is regulated under
various narcotic control laws2. In some countries, codeine is available without a medical
prescription and in combination preparations from licensed pharmacists in doses up to 20 mg, or
30 mg when sold combined with 500 mg paracetamol [93]. A brief summary follows:

Australia: Since February 1, 2018, preparations containing codeine have not been available without
a prescription. Preparations containing pure codeine (e.g., codeine phosphate tablets or codeine

2 https://web.archive.org/web/20120510002957/http://www.incb.org/pdf/e/list/46thedition.pdf

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phosphate linctus) are available on prescription and are considered S8 (Schedule 8, or "Controlled
Drug Possession without authority illegal").

Canada: Tablets containing 8 mg of codeine combined with 15 mg of caffeine and 300 mg of

acetaminophen are sold as T1s (Tylenol Number 1) without a prescription.

Denmark: Codeine is sold over the counter in dosages up to 9.6 mg (with aspirin, brand name
Kodimagnyl); anything stronger requires a prescription.

France: In 2017, the law was changed in France making mandatory a prescription for all codeine
products along with ethylmorphine.

Germany, Switzerland, and Austria. Dispensing of products containing codeine and similar drugs
(dihydrocooeine nicocodeine and ethylmorphine) generally requires a prescription or is at the
discretion of the pharmacist.

Greece: Codeine is an illegal drug in Greece, although it is available by prescription (Lonarid-N,

Lonalgal).

Hong Kong: Codeine is regulated under Laws of Hong Kong, Dangerous Drugs Ordinance, Chapter
134, Schedule 1. But is available under a prescription.

India: Codeine preparations require a prescription. Codeine containing cough medicine has been
banned in India since 2016.

Iran: Preparations of codeine in Iran are usually over-the-counter in combination with paracetamol
or guaifenesin. Codeine phosphate (30 mg tablets) can be purchased with a special permit.

Ireland: Codeine remains a semi non-prescriptive, over-the-counter drug up to a limit of 12.8 mg

per tablet, but these products "are not accessible to the public for self-selection". For medicines
with more than 12.8 mg codeine a prescription is required [94].

Italy: Codeine tablets or preparations require a prescription in Italy (Co-Efferailgen and

Tachidol).

Japan: Low dose codeine is available over the counter at pharmacies.

Romania: Codeine (Farmacod) requires a medical prescription. Doses do not exceed 15 mg.

South Africa: Codeine is freely available OTC and there is a low annual prevalence rate of opiate use
at 0.3% [94].

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Sri Lanka: Codeine preparations are available as OTC pharmacy medicines. The most common
preparation is Panadeine, which contains 500 mg of Paracetamol and 8 mg of Codeine. Cough syrup
containing codeine and promethazine is not permitted

United Arab Emirates: Medicines containing codeine are banned without a doctor's prescription
including visitors to the country.

United Kingdom: Codeine is a controlled substance or a Class A drug when prepared for injection.
Codeine use without a prescription is permitted with at least one other active or inactive ingredient
and that the dosage of each tablet, capsule, etc. does not exceed 100 mg or 2.5% concentration in
the case of liquid preparations.

United States: Codeine is a Schedule II controlled substance when used in products for pain-relief
(alone or more than 80 mg per dosage unit). Cough syrups are classed as Schedule III, IV or V,
depending on formulation.

19. Other Medical and Scientific Matters Relevant for a Recommendation on the
Scheduling of the Substance

None

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Annex 1: Report on WHO Questionnaire for Review of Psychoactive

Substances

Refer to separate Annex 1: Report on WHO questionnaire for review of psychoactive substances

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