View source for Codeine

{{Short description|Opiate and prodrug of morphine used to treat pain}}
{{Other uses}}
{{Use dmy dates|date=June 2023}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 456481929
| image = Codeine Structure.svg
| image_class = skin-invert-image
| width = 175px
| alt = Skeletal formula
| image2 = Codeine molecule ball.png
| width2 = 
| alt2 = Ball-and-stick model
| caption = <!-- Clinical data -->
| pronounce = {{IPAc-en|ˈ|k|oʊ|d|iː|n}}
| tradename = 
| Drugs.com = {{drugs.com|monograph|codeine}}
| MedlinePlus = a682065
| DailyMedID = Codeine
| pregnancy_AU = A
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Codeine Use During Pregnancy | website=Drugs.com | date=3 February 2020 | url=https://www.drugs.com/pregnancy/codeine.html | access-date=7 February 2020 | archive-date=30 December 2019 | archive-url=https://web.archive.org/web/20191230164005/https://www.drugs.com/pregnancy/codeine.html | url-status=live }}</ref>
| pregnancy_category = 
| dependency_liability = High
| addiction_liability = High<ref>{{cite book |vauthors=Bonewit-West K, Hunt SA, Applegate E |title=Today's Medical Assistant: Clinical and Administrative Procedures |date=2012 |page=571 |publisher=Elsevier Health Sciences |isbn=9781455701506 |url=https://books.google.com/books?id=YalYPI1KqTQC&pg=PA571 |access-date=20 August 2019 |archive-date=10 January 2023 |archive-url=https://web.archive.org/web/20230110030031/https://books.google.com/books?id=YalYPI1KqTQC&pg=PA571 |url-status=live }}</ref>
| routes_of_administration = [[Oral administration|By mouth]], [[rectal administration|rectal]], [[subcutaneous injection|subcutaneous]], [[intramuscular injection|intramuscular]]
| class = {{ubli|[[Opiate]];|[[Antitussive]]}}
| ATC_prefix = R05
| ATC_suffix = DA04
| ATC_supplemental = Combinations: {{ATC|N02|AA59}}, {{ATC|N02|AA79}}, {{ATC|N02|AJ08}}, {{ATC|N02|AJ06}}, {{ATC|N02|AJ07}}
        
<!-- Legal status -->| legal_AU = S8
| legal_AU_comment = / S4 (Prescription only){{efn|S4 only if in drug combinations; see [[#Legal status]].}}
| legal_BR = A2
| legal_BR_comment = / [[Brazilian Controlled Drugs and Substances Act|Class C1]]{{efn|Class C1 only for low doses; see exemptions on [[Brazilian Controlled Drugs and Substances Act|Portaria SVS/MS 344/98]].}}
| legal_CA = Schedule I
| legal_CA_comment = 
| legal_DE = Anlage III
| legal_DE_comment = 
| legal_NZ = Class C
| legal_NZ_comment = 
| legal_UK = Class B
| legal_UK_comment = / [[Pharmacy medicine]]{{efn|Pharmacy medicine if purchased in a low dose from a licensed pharmacy or in low dose drug combination; see [[#Legal status]].}}
| legal_US = Schedule II
| legal_US_comment = / Schedule III–V{{efn|Schedule III-V only if in drug combination; see [[#Legal status]].}}
| legal_UN = N II
| legal_UN_comment = / Narcotic Schedule III{{efn|Schedule III only if in drug combination; see [[#Legal status]].}}
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->| bioavailability = c. 60% (by mouth)<ref name="FiresteinBudd2016">{{cite book| vauthors= Polsten GR, Wallace MS | chapter = Analgesic Agents in Rheumatic Disease | veditors = Firestein GS, Budd R, Gabriel SE, McInnes IB, O'Dell JR |title=Kelley and Firestein's Textbook of Rheumatology | chapter-url = https://books.google.com/books?id=kBZ6DAAAQBAJ&pg=PA1081 |date=21 June 2016|publisher=Elsevier Health Sciences|isbn=978-0-323-41494-4|pages=1081–}}</ref>
| protein_bound = 
| metabolism = [[Liver]]: [[CYP2D6]] (to [[morphine]]), [[CYP3A4]] (to [[norcodeine]]), [[UGT2B7]] (to 3- and 6-[[glucuronide]]s of codeine, norcodeine, and morphine)<ref name="pmid17470523">{{cite journal | vauthors = Shen H, He MM, Liu H, Wrighton SA, Wang L, Guo B, Li C | title = Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17 | journal = Drug Metabolism and Disposition | volume = 35 | issue = 8 | pages = 1292–1300 | date = August 2007 | pmid = 17470523 | doi = 10.1124/dmd.107.015354 | s2cid = 2322678 }}</ref>
| metabolites = *[[Morphine]]
* [[Norcodeine]]
* Others (e.g., [[conjugation (biochemistry)|conjugate]]s)
| onset = 15–30 minutes<ref name=AHFS2016 />
| elimination_half-life = 2.5–3 hours
| duration_of_action = 4–6 hours<ref name=AHFS2016 />
| excretion = <!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 76-57-3
| CAS_supplemental = 
| PubChem = 5284371
| IUPHAR_ligand = 1673
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00318
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4447447
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = UX6OWY2V7J
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C06174
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = 
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 16714
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 485
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = 3-Methylmorphine

<!-- Chemical and physical data -->| IUPAC_name = (5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol
| C = 18
| H = 21
| N = 1
| O = 3
| SMILES = CN1CC[C@]23[C@@H]4[C@H]1CC5=C2C(=C(C=C5)OC)O[C@H]3[C@H](C=C4)O
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C18H21NO3/c1-19-8-7-18-11-4-5-13(20)17(18)22-16-14(21-2)6-3-10(15(16)18)9-12(11)19/h3-6,11-13,17,20H,7-9H2,1-2H3/t11-,12+,13-,17-,18-/m0/s1
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OROGSEYTTFOCAN-DNJOTXNNSA-N
| density = 
| density_notes = 
| melting_point = 
| melting_high = 
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}

<!-- Definition and medical uses -->
'''Codeine''' is an [[opiate]] and [[prodrug]] of [[morphine]] mainly used to treat [[pain]], [[cough medicine|coughing]], and [[diarrhea]]. It is also commonly used as a [[recreational drug]]. It is found naturally in the sap of the [[opium poppy]], ''Papaver somniferum''.<ref name=AHFS2016>{{cite web|title=Codeine |url=https://www.drugs.com/monograph/codeine.html |publisher=The American Society of Health-System Pharmacists |access-date=5 January 2016|url-status=live|archive-url=https://web.archive.org/web/20160118164241/http://www.drugs.com/monograph/codeine.html|archive-date=18 January 2016}}</ref><ref>{{cite journal | vauthors = Prommer E | title = Role of codeine in palliative care | journal = Journal of Opioid Management | volume = 7 | issue = 5 | pages = 401–406 | date = 2010 | pmid = 22165039 | doi = 10.5055/jom.2011.0081 }}</ref> It is typically used to treat mild to moderate degrees of pain.<ref name=AHFS2016 />{{Failed verification |date=March 2024 |reason=Recommended for that use in one country, nothing said about typical usage.}} Greater benefit may occur when combined with [[paracetamol]] (acetaminophen) as [[codeine/paracetamol]] or a [[nonsteroidal anti-inflammatory drug]] (NSAID) such as [[aspirin]] or [[ibuprofen]].<ref name=AHFS2016 /> Evidence does not support its use for acute cough suppression in children.<ref name="paul-im-2012">{{cite journal | vauthors = Paul IM | title = Therapeutic options for acute cough due to upper respiratory infections in children | journal = Lung | volume = 190 | issue = 1 | pages = 41–44 | date = February 2012 | pmid = 21892785 | doi = 10.1007/s00408-011-9319-y | s2cid = 23865647 }}</ref><ref>{{cite journal |vauthors=Smith SM, Schroeder K, Fahey T |date=November 2014 |title=Over-the-counter (OTC) medications for acute cough in children and adults in community settings |journal=The Cochrane Database of Systematic Reviews |volume=2014 |issue= 11|pages= CD001831|doi=10.1002/14651858.CD001831.pub5 |pmid=25420096|pmc=7061814 }}</ref> In Europe, it is not recommended as a cough medicine for those under 12 years of age.<ref name=AHFS2016 /> It is generally taken by mouth.<ref name=AHFS2016 /> It typically starts working after half an hour, with maximum effect at two hours.<ref name=AHFS2016 /> Its effects last for about four to six hours. Codeine exhibits abuse potential similar to other [[opioid]] medications, including a risk of [[addiction]] and [[Opioid overdose|overdose]].<ref name=AHFS2016 /> 

<!-- Side effects and mechanism -->
Common side effects include [[nausea]], [[vomiting]], [[constipation]], [[pruritis|itchiness]], [[lightheadedness]], and [[drowsiness]].<ref name=AHFS2016 /> Serious side effects may include breathing difficulties and addiction.<ref name=AHFS2016 /> Whether its use in [[pregnancy]] is safe is unclear.<ref name=AHFS2016 /> Care should be used during [[breastfeeding]], as it may result in [[opiate toxicity]] in the baby.<ref name=AHFS2016 /> Its use as of 2016 is not recommended in children.<ref name=Peds2016>{{cite journal | vauthors = Tobias JD, Green TP, Coté CJ | title = Codeine: Time to Say "No" | journal = Pediatrics | volume = 138 | issue = 4 | pages = e20162396 | date = October 2016 | pmid = 27647717 | doi = 10.1542/peds.2016-2396 | doi-access = free }}</ref> Codeine works following being broken down by the liver into morphine; how quickly this occurs depends on a person's [[genetics]].<ref name=AHFS2016 />

<!-- History, society, and culture -->
Codeine was discovered in 1832 by [[Pierre Jean Robiquet]].<ref name=New2015>{{cite book| vauthors = Newton D |title= Prescription Drug Abuse: A Reference Handbook |date=2015 |publisher=ABC-CLIO |isbn=978-1-4408-3979-5 |page=20 |url=https://books.google.com/books?id=mcAnCwAAQBAJ&pg=PA20|url-status=live|archive-url= https://web.archive.org/web/20170204073214/https://books.google.com/books?id=mcAnCwAAQBAJ&pg=PA20 |archive-date=4 February 2017}}</ref> In 2013, about 361,000&nbsp;kg (795,000 lb) of codeine were produced while 249,000&nbsp;kg (549,000 lb) were used, which made it the most commonly taken opiate.<ref name=UN2015>{{cite book|title=Narcotic Drugs 2014|date=2015|publisher=International Narcotics Control Board|isbn=9789210481571|page=21|url=https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2014/Narcotic_Drugs_Report_2014.pdf|url-status=live|archive-url=https://web.archive.org/web/20150602192211/https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2014/Narcotic_Drugs_Report_2014.pdf|archive-date=2 June 2015}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> Codeine occurs naturally and makes up about 2% of [[opium]].<ref name=New2015 />
{{TOC limit}}

==Medical uses==

===Pain===
Codeine is used to treat mild to moderate pain.<ref name=AHFS2016/> It is commonly used to treat post-surgical dental pain.<ref name="Macleod2002">{{cite journal | vauthors = Macleod AG, Ashford B, Voltz M, Williams B, Cramond T, Gorta L, Simpson JM | title = Paracetamol versus paracetamol-codeine in the treatment of post-operative dental pain: a randomized, double-blind, prospective trial | journal = Australian Dental Journal | volume = 47 | issue = 2 | pages = 147–151 | date = June 2002 | pmid = 12139269 | doi = 10.1111/j.1834-7819.2002.tb00319.x | doi-access = free }}</ref>

Weak evidence indicates that it is useful in [[cancer pain]], but it may have increased adverse effects, especially constipation, compared to other opioids.<ref>{{cite journal | vauthors = Straube C, Derry S, Jackson KC, Wiffen PJ, Bell RF, Strassels S, Straube S | title = Codeine, alone and with paracetamol (acetaminophen), for cancer pain | journal = The Cochrane Database of Systematic Reviews | volume = 9 | issue = 9 | pages = CD006601 | date = September 2014 | pmid = 25234029 | pmc = 6513650 | doi = 10.1002/14651858.CD006601.pub4 }}</ref> The [[American Academy of Pediatrics]] does not recommend its use in children due to side effects.<ref name=Peds2016/> The [[Food and Drug Administration]] (FDA) lists age under 12 years old as a contraindication to use.<ref>{{cite web | author = Office of the Commissioner|title=Press Announcements - FDA statement from Douglas Throckmorton, M.D., deputy center director for regulatory programs, Center for Drug Evaluation and Research, on new warnings about the use of codeine and tramadol in children & nursing mothers |url= https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm553285.htm|website=www.fda.gov|access-date=21 April 2017|language=en|url-status=dead|archive-url= https://web.archive.org/web/20170420225410/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm553285.htm|archive-date=20 April 2017}}</ref>

===Cough===
Codeine is used to relieve [[cough]]ing.<ref name=AHFS2016/> Evidence does not support its use for acute cough suppression in children.<ref name="paul-im-2012" /> In Europe, it is not recommended as a cough medicine for those under 12 years of age.<ref name=AHFS2016 /> Some tentative evidence shows it can reduce a chronic cough in adults.<ref>{{cite journal | vauthors = McCrory DC, Coeytaux RR, Yancy WS Jr, Schmit KM, Kemper AR, Goode A, Hasselblad V, Heidenfelder BL, Irvine RJ, Musty MD, Gray R, Sanders GD | title = Assessment and Management of Chronic Cough | journal = AHRQ Comparative Effectiveness Reviews | date = January 2013 | pmid = 23367526 }}</ref>

===Diarrhea===
It is used to treat diarrhea and diarrhea-predominant [[irritable bowel syndrome]], although [[loperamide]] (which is available [[Over-the-counter drug|without a prescription]] for milder diarrhea), [[diphenoxylate]], [[paregoric]], or even [[laudanum]] are more frequently used to treat severe diarrhea.<ref>{{cite book|title=Diarrhea: Diagnostic and Therapeutic Advances|publisher=Humana Press|date=8 November 2010|location=New York, USA|isbn=978-1-60761-182-0|page=452|url=https://books.google.com/books?id=BstHGdtpb9AC&q=Diarrhea:+Diagnostic+and+Therapeutic+Advances|vauthors=Guandalini S, Vaziri H|access-date=9 October 2020|archive-date=29 June 2023|archive-url=https://web.archive.org/web/20230629225027/https://books.google.com/books?id=BstHGdtpb9AC&q=Diarrhea:+Diagnostic+and+Therapeutic+Advances|url-status=live}}</ref>

===Formulations===
Codeine is marketed as both a single-ingredient drug and in combination preparations with paracetamol (as [[co-codamol]]: e.g., brands Paracod, Panadeine, and the Tylenol-with-codeine series, including [[Tylenol 3]] and 1, 2, and 4); with [[aspirin]] (as [[co-codaprin]]); or with [[ibuprofen]] (as [[Nurofen Plus]]). These combinations provide greater pain relief than either agent alone ([[drug synergy]])<ref>{{cite web |title=Codeine Formulations: A Comprehensive Review |date=2025 |url=https://doi.org/10.5281/zenodo.15459453 |doi=10.5281/zenodo.15459453 |access-date=2025-05-18 |author1=Medical Research Collective (pseudonym) }}</ref>.

Codeine is also commonly marketed in products containing codeine with other pain killers or muscle relaxers, as well as codeine mixed with [[phenacetin]] (Emprazil with codeine No. 1, 2, 3, 4, and 5), [[naproxen]], [[indomethacin]], [[diclofenac]], and others, as well as more complex mixtures, including such mixtures as aspirin + paracetamol + codeine ± caffeine ± antihistamines and other agents, such as those mentioned above.

Codeine-only products can be obtained with a prescription as a [[Modified-release dosage| time-release tablet]]. Codeine is also marketed in cough syrups with zero to a half-dozen other active ingredients, and a [[linctus]] (e.g., Paveral) for all of the uses for which codeine is indicated.

Injectable codeine is available for subcutaneous or intramuscular injection only; intravenous injection is contraindicated, as this can result in nonimmune mast-cell degranulation and resulting [[anaphylactoid]] reaction. Codeine suppositories are also marketed in some countries<ref>{{cite web |title=Codeine Formulations: A Comprehensive Review |date=2025 |url=https://doi.org/10.5281/zenodo.15459453 |doi=10.5281/zenodo.15459453 |access-date=2025-05-18 |author1=Medical Research Collective (pseudonym) }}</ref>.

==Side effects==
Common adverse effects associated with the use of codeine include [[drowsiness]] and [[constipation]]. Less common are [[itching]], [[nausea]], [[vomiting]], [[dry mouth]], [[miosis]], [[orthostatic hypotension]], [[urinary retention]], [[euphoria]], and [[dysphoria]]. Rare adverse effects include [[anaphylaxis]], [[Epileptic seizure|seizure]], [[acute pancreatitis]], and [[respiratory depression]].<ref>{{cite web|publisher=WebMD LLC.|title=Codeine – adverse effects|url=http://reference.medscape.com/drug/codeine-343310#4|work=Medscape reference – Drugs, Diseases & Procedures|access-date=27 September 2012|url-status=live|archive-url=https://web.archive.org/web/20120818214647/http://reference.medscape.com/drug/codeine-343310#4|archive-date=18 August 2012}}</ref> As with all opiates, long-term effects can vary, but can include diminished libido, apathy, and memory loss. Some people may have allergic reactions to codeine, such as the swelling of the skin and rashes.<ref name=AHFS2016/>

Tolerance to many of the effects of codeine, including its therapeutic effects, develops with prolonged use. This occurs at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance.

As with other opioids, a potentially serious adverse drug reaction is respiratory depression. This depression is dose-related and is a mechanism for the potentially fatal consequences of overdose. As codeine is metabolized to morphine, morphine can be passed through breast milk in potentially lethal amounts, fatally depressing the respiration of a breastfed baby.<ref>CTV News, [https://www.ctvnews.ca/codeine-use-while-breastfeeding-may-be-dangerous-1.317673 Codeine use while breastfeeding may be dangerous] {{webarchive|url=https://web.archive.org/web/20080901210431/http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20080820/tylenol_3_breastfeeding_080820/20080820?hub=Canada |date=1 September 2008 }}, Wed. 20 August 2008</ref><ref name="koren etal">{{cite journal | vauthors = Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ | title = Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother | journal = Lancet | volume = 368 | issue = 9536 | pages = 704 | date = August 2006 | pmid = 16920476 | doi = 10.1016/S0140-6736(06)69255-6 | s2cid = 46339578 }}</ref>
In August 2012, the United States Food and Drug Administration issued a warning about deaths in pediatric patients less than 6 years old after ingesting "normal" doses of paracetamol with codeine after tonsillectomy; this warning was upgraded to a black box warning in February 2013.<ref>{{cite web|title=Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy|url=https://www.fda.gov/Drugs/DrugSafety/ucm339112.htm|publisher=FDA|date=20 February 2013|url-status=dead|archive-url=https://web.archive.org/web/20140904133820/https://www.fda.gov/drugs/drugsafety/ucm339112.htm|archive-date=4 September 2014}}</ref>

Some patients are very effective converters of codeine to its active form, morphine, resulting in lethal blood levels. The FDA is presently recommending very cautious use of codeine in young tonsillectomy patients; the drug should be used in the lowest amount that can control the pain, "as needed" and not "around the clock", and immediate medical attention is needed if the user responds negatively.

===Withdrawal and dependence===
As with other opiates, chronic use of codeine can cause [[physical dependence]] which can lead to severe [[drug withdrawal|withdrawal symptoms]] if a person suddenly stops the medication. Withdrawal symptoms include drug craving, runny nose, yawning, sweating, insomnia, weakness, stomach cramps, nausea, vomiting, diarrhea, muscle spasms, chills, irritability, and pain. These side effects also occur in acetaminophen/aspirin combinations, though to a lesser extent. To minimize withdrawal symptoms, long-term users should gradually reduce their codeine medication under the supervision of a healthcare professional.<ref>{{cite web|title=Opioids: Information for Health Professionals|url=http://www.albertahealthservices.ca/assets/info/res/mhr/if-res-mhr-hp-opioid-info.pdf|publisher=Alberta Health Services|access-date=9 March 2017|url-status=live|archive-url=https://web.archive.org/web/20170312032436/http://www.albertahealthservices.ca/assets/info/res/mhr/if-res-mhr-hp-opioid-info.pdf|archive-date=12 March 2017}}</ref>

Also, no evidence indicates that [[CYP2D6]] inhibition is useful in treating codeine dependence,<ref>{{cite journal | vauthors = Fernandes LC, Kilicarslan T, Kaplan HL, Tyndale RF, Sellers EM, Romach MK | title = Treatment of codeine dependence with inhibitors of cytochrome P450 2D6 | journal = Journal of Clinical Psychopharmacology | volume = 22 | issue = 3 | pages = 326–329 | date = June 2002 | pmid = 12006904 | doi = 10.1097/00004714-200206000-00014 | s2cid = 30804655 }}</ref> though the metabolism of codeine to morphine (and hence further metabolism to glucuronide morphine conjugates) does have an effect on the abuse potential of codeine.<ref>{{cite journal | vauthors = Kathiramalainathan K, Kaplan HL, Romach MK, Busto UE, Li NY, Säwe J, Tyndale RF, Sellers EM | title = Inhibition of cytochrome P450 2D6 modifies codeine abuse liability | journal = Journal of Clinical Psychopharmacology | volume = 20 | issue = 4 | pages = 435–444 | date = August 2000 | pmid = 10917405 | doi = 10.1097/00004714-200008000-00008 }}</ref> However, CYP2D6 has been implicated in the toxicity and death of neonates when codeine is administered to lactating mothers, particularly those with increased enzyme activity ("ultra-rapid" metabolizers).<ref name="koren etal" /><ref>{{cite journal | vauthors = Willmann S, Edginton AN, Coboeken K, Ahr G, Lippert J | title = Risk to the breast-fed neonate from codeine treatment to the mother: a quantitative mechanistic modeling study | journal = Clinical Pharmacology and Therapeutics | volume = 86 | issue = 6 | pages = 634–643 | date = December 2009 | pmid = 19710640 | doi = 10.1038/clpt.2009.151 | s2cid = 37771918 }}</ref>

In 2019 Ireland was said to be on the verge of a codeine addiction epidemic, according to a paper in the [[Irish Medical Journal]]. Under Irish law, codeine can be bought over the counter under the supervision of a pharmacist, but there is no mechanism to detect patients travelling to different pharmacies to purchase codeine.<ref>{{cite news |title=Ireland on the verge of a codeine addiction epidemic, Irish Medical Journal warns |url=https://www.irishexaminer.com/news/arid-30911037.html |access-date=16 November 2022 |publisher=Irish Examiner |date=14 March 2019 |archive-date=16 November 2022 |archive-url=https://web.archive.org/web/20221116102257/https://www.irishexaminer.com/news/arid-30911037.html |url-status=live }}</ref>

==Pharmacology==

===Pharmacodynamics===
{| class="wikitable floatright" style="text-align: center;"
|+ Codeine (and metabolite) at opioid receptors
|-
! rowspan="2" | Compound || colspan="3" | [[Binding affinity|Affinities]] ({{abbrlink|K<sub>i</sub>|Inhibitor constant}}) || Ratio || rowspan="2" | Ref
|-
! {{abbrlink|MOR|μ-Opioid receptor}} !! {{abbrlink|DOR|δ-Opioid receptor}} !! {{abbrlink|KOR|κ-Opioid receptor}} !! MOR:DOR:KOR
|-
| Codeine || 79 nM || >1,000 nM || >1,000 nM || {{abbr|ND|No data}} || <ref name="pmid8114680">{{cite journal | vauthors = Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T | title = Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors | journal = Molecular Pharmacology | volume = 45 | issue = 2 | pages = 330–334 | date = February 1994 | doi = 10.1016/S0026-895X(25)09932-8 | pmid = 8114680 | url = http://molpharm.aspetjournals.org/content/45/2/330.long | access-date = 22 June 2018 | archive-date = 2 December 2020 | archive-url = https://web.archive.org/web/20201202161012/https://molpharm.aspetjournals.org/content/45/2/330.long | url-status = live | url-access = subscription }}</ref>
|-
| Morphine || 1.8 nM || 90 nM || 317 nM || 1:50:176 || <ref name="CorbettPaterson1993">{{cite book |vauthors=Corbett AD, Paterson SJ, Kosterlitz HW |veditors=Herz A, Akil H, Simon EJ |title=Opioids |volume=104 / 1 |year=1993 |pages=645–679 |issn=0171-2004 |doi=10.1007/978-3-642-77460-7_26 |chapter=Selectivity of Ligands for Opioid Receptors |series=Handbook of Experimental Pharmacology |publisher=Springer Verlag |isbn=978-3-642-77462-1}}</ref>
|}

{| class="wikitable floatright"
|+ <br />[[Equianalgesic]] doses<ref name="King2010">{{cite book| vauthors = King TL, Miller EL | chapter = Analgesia and Anaesthesia | veditors = King TL, Brucker MC |title=Pharmacology for Women's Health| chapter-url= https://books.google.com/books?id=o_rHHCsIpckC&pg=PA332|date=25 October 2010|publisher=Jones & Bartlett Publishers|isbn=978-1-4496-1073-9|pages=332–}}</ref><ref name="ChestnutWong2014">{{cite book |vauthors=Flood P, Aleshi P |chapter=Postoperative and Chronic Pain: Systematic and Regional Analgesia Techniques |veditors=Chestnut DH, Wong CA, Tsen LC, Kee WD, Beilin Y, Mhyre J |title=Chestnut's Obstetric Anesthesia: Principles and Practice |chapter-url=https://books.google.com/books?id=FMU0AwAAQBAJ&pg=PA611 |date=28 February 2014 |publisher=Elsevier Health Sciences |isbn=978-0-323-11374-8 |pages=611– |access-date=22 June 2018 |archive-date=11 January 2023 |archive-url=https://web.archive.org/web/20230111005540/https://books.google.com/books?id=FMU0AwAAQBAJ&pg=PA611 |url-status=live }}</ref><ref name="Tiziani2013">{{cite book|vauthors=Tiziani AP|title=Havard's Nursing Guide to Drugs|url=https://books.google.com/books?id=XpzQAgAAQBAJ&pg=PA933|date=1 June 2013|publisher=Elsevier Health Sciences|isbn=978-0-7295-8162-2|pages=933–|access-date=22 June 2018|archive-date=11 January 2023|archive-url=https://web.archive.org/web/20230111005617/https://books.google.com/books?id=XpzQAgAAQBAJ&pg=PA933|url-status=live}}</ref>
|-
! Compound !! [[Route of administration|Route]] !! [[Dose (biochemistry)|Dose]]
|-
| Codeine || {{abbr|PO|Oral administration}} || 200&nbsp;mg
|-
| [[Hydrocodone]] || {{abbr|PO|Oral administration}} || 20–30&nbsp;mg
|-
| [[Hydromorphone]] || {{abbr|PO|Oral administration}} || 7.5&nbsp;mg
|-
| Hydromorphone || {{abbr|IV|Intravenous administration}} || 1.5&nbsp;mg
|-
| [[Morphine]] || {{abbr|PO|Oral administration}} || 30&nbsp;mg
|-
| Morphine || {{abbr|IV|Intravenous administration}} || 10&nbsp;mg
|-
| [[Oxycodone]] || {{abbr|PO|Oral administration}} || 20&nbsp;mg
|-
| Oxycodone || {{abbr|IV|Intravenous administration}} || 10&nbsp;mg
|-
| [[Oxymorphone]] || {{abbr|PO|Oral administration}} || 10&nbsp;mg
|-
| Oxymorphone || {{abbr|IV|Intravenous administration}} || 1&nbsp;mg
|}

Codeine is a nonsynthetic [[opioid]].<ref name="Moore2012">{{cite book | vauthors = Szucs-Reed RP, Gallagher RM | chapter = Chronic pain and opioids. | veditors =  Moore RJ |title=Handbook of Pain and Palliative Care: Biobehavioral Approaches for the Life Course| chapter-url=https://books.google.com/books?id=bpvcJiCQb1wC&pg=PA499|date=5 January 2012|publisher=Springer Science & Business Media|isbn=978-1-4419-1651-8|pages=499– | doi = 10.1007/978-1-4419-1651-8_29 | s2cid = 68670125 }}</ref> It is a [[binding selectivity|selective]] [[agonist]] of the [[μ-opioid receptor]] (MOR).<ref name="Moore2012" /> Codeine itself has relatively weak [[affinity (pharmacology)|affinity]] for the MOR.<ref name="Moore2012" /><ref name="pmid8114680" /> Instead of acting directly on the MOR, codeine functions as a [[prodrug]] of its major [[active metabolite]]s morphine and [[codeine-6-glucuronide]], which are far more [[potency (pharmacology)|potent]] MOR agonists in comparison.<ref name="Moore2012" /><ref name="CorbettPaterson1993" />

Codeine has been found as an endogenous compound, along with morphine, in the brains of nonhuman primates with depolarized neurons, indicating that codeine may function as a neurotransmitter or neuromodulator in the central nervous system.<ref>Neri C; Guama M; et al. Endogenous morphine and codeine in the brain of non human primate. Medical Science Montier 2004, 10, MS1-MS5.</ref> Like morphine, codeine causes TLR4 signaling which causes [[allodynia]] and [[hyperalgesia]].<ref name="pmid25386959">{{cite journal | vauthors = Johnson JL, Rolan PE, Johnson ME, Bobrovskaya L, Williams DB, Johnson K, Tuke J, Hutchinson MR | title = Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation | journal = Translational Psychiatry | volume = 4 | issue = 11 | pages = e482 | date = November 2014 | pmid = 25386959 | pmc = 4259992 | doi = 10.1038/tp.2014.121 }}</ref> It does not need to be converted to morphine to increase pain sensitivity.<ref name="pmid25386959"/>

===Mechanism of action===

Codeine is an opiate and an agonist of the [[μ-opioid receptor]] (MOR). It acts on the central nervous system to have an analgesic effect.<ref name="Codeine">{{cite book | vauthors = Papich MG | chapter = Codeine | title = Saunders Handbook of Veterinary Drugs | edition = fourth |date=1 January 2016 |pages=183–184 |doi=10.1016/b978-0-323-24485-5.00175-3 |publisher=W.B. Saunders|isbn=978-0-323-24485-5 }}</ref> It is metabolised in the liver to produce morphine which is ten times more potent against the MOR. Opioid receptors are [[G protein-coupled receptors]] that positively and negatively regulate synaptic transmission through downstream signalling. Binding of codeine or morphine to the μ-opioid receptor results in hyperpolarization of the neuron leading to the inhibition of the release of nociceptive neurotransmitters, causing an analgesic effect and increased pain tolerance due to reduced neuronal excitability.<ref name="Codeine"/><ref>{{cite book | vauthors = Hitchings A, Lonsdale D, Burrage D, Baker E |title=Top 100 drugs: clinical pharmacology and practical prescribing |date=2015 |isbn=978-0-7020-5516-4 |page=168 |publisher=Churchill Livingstone }}</ref>

===Pharmacokinetics===
The conversion of codeine to morphine occurs in the liver and is catalyzed by the [[cytochrome P450]] enzyme [[CYP2D6]].<ref name="St2012" /> [[CYP3A4]] produces [[norcodeine]], and [[UGT2B7]] conjugates codeine, norcodeine, and morphine to the corresponding 3- and 6-glucuronides. Srinivasan, Wielbo, and Tebbett speculate that codeine-6-glucuronide is responsible for a large percentage of the analgesia of codeine, and thus these patients should experience some analgesia.<ref name="Srinivasan V, Wielbo D, Tebbett IR 1997 185–90">{{cite journal | vauthors = Srinivasan V, Wielbo D, Tebbett IR | title = Analgesic effects of codeine-6-glucuronide after intravenous administration | journal = European Journal of Pain | volume = 1 | issue = 3 | pages = 185–190 | year = 1997 | pmid = 15102399 | doi = 10.1016/S1090-3801(97)90103-8 | s2cid = 23099329 }}</ref> Many of the adverse effects will still be experienced in poor metabolizers. Conversely, between 0.5% and 2% of the population are "extensive metabolizers"; multiple copies of the gene for 2D6 produce high levels of CYP2D6 and will metabolize drugs through that pathway more quickly than others.

Some medications are CYP2D6 inhibitors and reduce or even completely block the conversion of codeine to morphine. The best-known of these are two of the [[selective serotonin reuptake inhibitor]]s, [[paroxetine]] (Paxil) and [[fluoxetine]] (Prozac), as well as the antihistamine [[diphenhydramine]] (Benadryl) and the antidepressant [[bupropion]] (Wellbutrin, also known as Zyban). Other drugs, such as [[rifampicin]] and [[dexamethasone]], induce CYP450 isozymes and thus increase the conversion rate.

CYP2D6 converts codeine into morphine, which then undergoes glucuronidation. Life-threatening intoxication, including respiratory depression requiring intubation, can develop over a matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultrarapid metabolism of opioids such as codeine into morphine.<ref>{{cite journal | vauthors = Lurcott G | title = The effects of the genetic absence and inhibition of CYP2D6 on the metabolism of codeine and its derivatives, hydrocodone and oxycodone | journal = Anesthesia Progress | volume = 45 | issue = 4 | pages = 154–156 | year = 1998 | pmid = 10483388 | pmc = 2148980 }}</ref><ref>{{cite journal | vauthors = Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J | title = Codeine intoxication associated with ultrarapid CYP2D6 metabolism | journal = The New England Journal of Medicine | volume = 351 | issue = 27 | pages = 2827–2831 | date = December 2004 | pmid = 15625333 | doi = 10.1056/NEJMoa041888 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Caraco Y | title = Genes and the response to drugs | journal = The New England Journal of Medicine | volume = 351 | issue = 27 | pages = 2867–2869 | date = December 2004 | pmid = 15625340 | doi = 10.1056/NEJMe048278 }}</ref>

Studies on codeine's analgesic effect are consistent with the idea that metabolism by CYP2D6 to morphine is important, but some studies show no major differences between those who are poor metabolizers and extensive metabolizers. Evidence supporting the hypothesis that ultrarapid metabolizers may get greater analgesia from codeine due to increased morphine formation is limited to case reports.<ref>{{cite journal | vauthors = Gardiner SJ, Begg EJ | title = Pharmacogenetics, drug-metabolizing enzymes, and clinical practice | journal = Pharmacological Reviews | volume = 58 | issue = 3 | pages = 521–590 | date = September 2006 | pmid = 16968950 | doi = 10.1124/pr.58.3.6 | s2cid = 25747320 }}</ref>

Due to the increased metabolism of codeine to morphine, ultrarapid metabolizers (those possessing more than two functional copies of the CYP2D6 allele) are at increased risk of adverse drug effects related to morphine toxicity. Guidelines released by the Clinical Pharmacogenomics Implementation Consortium (CPIC) advise against administering codeine to ultrarapid metabolizers, where this genetic information is available. The CPIC also suggests that codeine use be avoided in poor metabolizers, due to its lack of efficacy in this group.<ref>{{cite journal | vauthors = Crews KR, Gaedigk A, Dunnenberger HM, Leeder JS, Klein TE, Caudle KE, Haidar CE, Shen DD, Callaghan JT, Sadhasivam S, Prows CA, Kharasch ED, Skaar TC | title = Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update | journal = Clinical Pharmacology and Therapeutics | volume = 95 | issue = 4 | pages = 376–382 | date = April 2014 | pmid = 24458010 | pmc = 3975212 | doi = 10.1038/clpt.2013.254 }}</ref>

Codeine and its salts are readily absorbed from the gastrointestinal tract, and ingestion of codeine phosphate produces peak plasma concentrations in about one hour. Plasma half life is between 3 and 4 hours, and oral/intramuscular analgesic potency ratio is approximately equal to 1:1.5. The most common conversion ratio, given on equianalgesia charts used in the United States, Canada, the UK, Republic of Ireland, the European Union, Russia and elsewhere as 130&nbsp;mg IM equals 200&nbsp;mg PO—both of which are equivalent to 10&nbsp;mg of morphine sulphate IV and 60&nbsp;mg of morphine sulphate PO. The salt:freebase ratio of the salts of both drugs in use are roughly equivalent, and do not generally make a clinical difference.<ref>The Merck Index, 13th Edition: Morphine Hydrochloride</ref>

Codeine is metabolised by ''O''- and ''N''-demethylation in the liver to morphine and norcodeine. [[Hydrocodone]] is also a metabolite of codeine in humans.<ref name="pmid37301">{{cite journal | vauthors = Cone EJ, Darwin WD, Gorodetzky CW | title = Comparative metabolism of codeine in man, rat, dog, guinea-pig and rabbit: identification of four new metabolites | journal = The Journal of Pharmacy and Pharmacology | volume = 31 | issue = 5 | pages = 314–317 | date = May 1979 | pmid = 37301 | doi = 10.1111/j.2042-7158.1979.tb13507.x | s2cid = 42128300 }}</ref> Codeine and its metabolites are mostly removed from the body by the kidneys, primarily as conjugates with glucuronic acid.<ref>{{cite web |title=Codeine Phosphate Tablets 30mg - Summary of Product Characteristics (SmPC) - (emc) |url=http://www.medicines.org.uk/emc/medicine/23910#PHARMACOKINETIC_PROPS |url-status=dead |archive-url=https://web.archive.org/web/20220123193235/https://www.medicines.org.uk/emc/medicine/23910 |archive-date=23 January 2022 |access-date=29 December 2019 |website=www.medicines.org.uk}}</ref>

The active metabolites of codeine, notably morphine, exert their effects by binding to and activating the [[μ-opioid receptor]]. In people that can extensively metabolize the codeine, a 30 mg dose could yield up to 4 mg of morphine.<ref>{{cite web | url=https://medsafe.govt.nz/profs/PUArticles/June2018/SpotlightOnCodeine.htm#:~:text=Extensive%20metabolisers%20convert%205%E2%80%9315,to%204.5%20mg%20of%20morphine | title=Spotlight on Codeine }}</ref>

==Chemistry==

While codeine can be directly extracted from opium, its source, most codeine is synthesized from the much more abundant [[morphine]] through the process of O-[[methylation]],<ref name="sciencedaily" /><ref>{{cite web |title=Virtual ChemBook |url=http://www.elmhurst.edu/~chm/vchembook/674narcotic.html |website=chemistry.elmhurst.edu |access-date=29 December 2019 |archive-date=29 July 2003 |archive-url=https://web.archive.org/web/20030729104518/http://www.elmhurst.edu/~chm/vchembook/674narcotic.html |url-status=dead }}</ref> through a process first completed in the late 20th century by Robert C. Corcoran and Junning Ma.<ref>{{cite patent | country	= US | number = 6204337 | invent1	= Robert C. Corcoran | invent2	= Junning Ma | status = expired
| title	= Solid-phase synthesis of codeine from morphine | pubdate = 2001-03-20 | gdate = 2001-03-20 | fdate = 1999-09-03 | pridate = 1999-09-03 | assign1 = University and Community College System of Nevada UCCSN }}</ref>

===Relation to other opioids===
Codeine has been used in the past as the starting material and prototype of a large class of mainly mild to moderately strong opioids, such as [[hydrocodone]] (1920 in Germany), [[oxycodone]] (1916 in Germany), [[dihydrocodeine]] (1908 in Germany), and its derivatives such as [[nicocodeine]] (1956 in Austria).{{Citation needed|date=May 2013}} However, these [[opioids]] are no longer synthesized from codeine and are usually synthesized from other [[opium]] alkaloids, specifically [[thebaine]].<ref>{{Cite news |title=How Johnson & Johnson companies used a 'super poppy' to make narcotics for America's most abused opioid pills |url=https://www.washingtonpost.com/graphics/2020/business/opioid-crisis-johnson-and-johnson-tasmania-poppy/ |access-date=20 April 2022 |newspaper=The Washington Post |language=en |archive-date=15 May 2022 |archive-url=https://web.archive.org/web/20220515213704/https://www.washingtonpost.com/graphics/2020/business/opioid-crisis-johnson-and-johnson-tasmania-poppy/ |url-status=live }}</ref> Other series of codeine derivatives include [[isocodeine]] and its derivatives, which were developed in Germany starting around 1920. In general, the various classes of morphine derivatives such as ketones, semisynthetics like [[dihydromorphine]], halogeno-morphides, esters, ethers, and others have codeine, dihydrocodeine, and isocodeine analogues.<ref>Report of Committee on drug addiction, 1929–1941. National Research Council (US).</ref> The codeine ester [[acetylcodeine]] is a common active impurity in street [[heroin]] as some codeine tends to dissolve with the morphine when it is extracted from [[opium]] in underground heroin and morphine base labs.

As an analgesic, codeine [[opiate comparison|compares weakly to other opiates]]. Related to codeine in other ways are [[codoxime]], [[thebacon]], [[codeine-N-oxide|codeine-''N''-oxide]] (genocodeine), related to the nitrogen morphine derivatives as is codeine methobromide, and [[heterocodeine]], which is a drug six times stronger than morphine and 72 times stronger than codeine due to a small re-arrangement of the molecule, namely moving the methyl group from the 3 to the 6 position on the morphine carbon skeleton.

Drugs bearing resemblance to codeine in effects due to close structural relationship are variations on the methyl groups at the 3 position including [[ethylmorphine]], also known as codethyline (Dionine), and [[benzylmorphine]] (Peronine). While having no narcotic effects of its own, the important opioid precursor [[thebaine]] differs from codeine only slightly in structure. Pseudocodeine and some other similar alkaloids not currently used in medicine are found in trace amounts in opium as well.

==History==
Codeine, or 3-methylmorphine, is an [[alkaloid]] found in the [[opium poppy]], ''Papaver somniferum'' var. ''album'', a plant in the family [[Papaveraceae]]. Opium poppy has been cultivated and utilized throughout human history for a variety of medicinal (analgesic, [[anti-tussive]] and [[anti-diarrheal]]) and hypnotic properties linked to the diversity of its active components, which include morphine, codeine and [[papaverine]].

Codeine is found in concentrations of 1% to 3% in opium prepared by the latex method from unripe pods of ''Papaver somniferum''. The name codeine is derived from the [[Ancient Greek]] {{lang|grc|κώδεια}} ({{lang|grc-Latn|kṓdeia}}, "poppy head"). The relative proportion of codeine to morphine, the most common opium alkaloid at 4% to 23%, tends to be somewhat higher in the [[poppy straw]] method of preparing opium alkaloids.

Until the beginning of the 19th century, raw opium was used in diverse preparations known as [[laudanum]] (see [[Thomas de Quincey]]'s ''[[Confessions of an English Opium-Eater]]'', 1821) and [[paregoric]] [[elixir]]s, several which were popular in England since the beginning of the 18th century; the original preparation seems to have been elaborated in [[Leiden]], the [[Netherlands]] around 1715 by a chemist Jakob Le Mort; in 1721 the ''London Pharmacopoeia'' mentions an Elixir Asthmaticum, replaced by the term Elixir Paregoricum ("pain soother") in 1746.

The progressive isolation of opium's several active components opened the path to improved selectivity and safety of the opiates-based pharmacopeia.

Morphine had already been isolated in Germany by {{lang|de|[[Friedrich Sertürner]]|italic=no}} in 1804.<ref>{{cite book | vauthors = Hayes AN, Gilbert SG | chapter = Historical milestones and discoveries that shaped the toxicology sciences | chapter-url = https://books.google.com/books?id=MtOiLVWBn8cC&pg=PA20|page=20|title=Molecular, clinical and environmental toxicology| veditors = Luch A |publisher=Springer|year=2009|isbn=978-3-7643-8335-0}}</ref> Codeine was first isolated in 1832 in France by {{lang|fr|[[Pierre Jean Robiquet|Pierre Robiquet]]|italic=no}}, already famous for the discovery of [[alizarin]], the most widespread red dye, while working on refined morphine extraction processes.<ref name=":0">{{Cite journal|date=1 March 2013|title=Pierre-Jean Robiquet|journal=Educación Química|language=en|volume=24|pages=139–149|doi=10.1016/S0187-893X(13)72507-2|issn=0187-893X| vauthors = Wisniak J |doi-access=free}}</ref> Robiquet is also credited with discovering [[caffeine]] independently of Pelletier, Caventou, and Runge.<ref name=":0" /> [[Thomas Anderson (chemist)|Thomas Anderson]] determined the correct composition in 1853 but a chemical structure was proposed only in 1925 by J. M. Gulland and [[Robert Robinson (chemist)|Robert Robinson]].<ref name="Gen 2022">{{cite journal | vauthors = Li G, Lou M, Qi X | title=A brief overview of classical natural product drug synthesis and bioactivity | journal=Organic Chemistry Frontiers | volume=9 | issue=2 | year=2022 | issn=2052-4129 | doi=10.1039/d1qo01341f | pages=517–571| s2cid=244465703 }}</ref> The first crystal structure would have to wait until 1954.<ref>{{cite journal | vauthors = Lindsey J, Barnes WH |title=The Crystal and Molecular Structure of Codeine Hydrobromide Dihydrate |journal=Acta Crystallographica | date = April 1955 |volume=8 |issue=4 |page=227 |doi=10.1107/S0365110X55000753 |bibcode=1955AcCry...8..227L }}</ref>

Codeine and morphine, as well as opium, were used in an attempt to treat diabetes in the 1880s and thereafter, as recently as the 1950s.<ref>{{cite journal | vauthors = Fraser TR | title = The Relative Value of Opium, Morphine, and Codeine in Diabetes Mellitus | journal = British Medical Journal | volume = 1 | issue = 1464 | pages = 118–119 | date = January 1889 | pmid = 20752554 | pmc = 2154578 | doi = 10.1136/bmj.1.1464.118 }}</ref>

Numerous codeine salts have been prepared since the drug was discovered.  The most commonly used are the hydrochloride (freebase conversion ratio 0.805, i.e. 10&nbsp;mg of the hydrochloride salt is equivalent in effect to 8.05&nbsp;mg of the freebase form), phosphate (0.736), sulphate (0.859), and citrate (0.842). Others include a [[salicylate]] [[NSAID]], codeine salicylate (0.686), a [[bromide]] ([[codeine methylbromide]], 0.759), and at least five codeine-based [[barbiturates]], the [[phenobarbital|phenylethylbarbiturate]] (0.56), [[cyclobarbital|cyclohexenylethylbarbiturate]] (0.559), [[cyclopentobarbital|cyclopentenylallylbarbiturate]] (0.561), {{chem name|[[allobarbital|diallylbarbiturate]]}} (0.561), and [[veronal|diethylbarbiturate]] (0.619). The latter was introduced as Codeonal in 1912, indicated for pain with nervousness.<ref>{{Cite book|url=https://books.google.com/books?id=KjtYAAAAMAAJ&q=codeonal&pg=PA240|title=The American Practitioner|year=1912|access-date=9 October 2020|archive-date=29 June 2023|archive-url=https://web.archive.org/web/20230629225033/https://books.google.com/books?id=KjtYAAAAMAAJ&q=codeonal&pg=PA240|url-status=live}}</ref> Codeine methylbromide is also considered a separate drug for various purposes.<ref>DEA, ibid</ref>

==Society and culture==

Codeine is the most widely used opiate in the world,<ref name="sciencedaily">{{cite web |title=Unlocking the opium poppy's biggest secret: Genes that make codeine, morphine |url=https://www.sciencedaily.com/releases/2010/03/100314150916.htm |website=ScienceDaily |access-date=29 December 2019 |language=en |archive-date=9 September 2017 |archive-url=https://web.archive.org/web/20170909095024/https://www.sciencedaily.com/releases/2010/03/100314150916.htm |url-status=live }}</ref> and is one of the most commonly used drugs overall according to numerous reports by organizations including the World Health Organization and its [[League of Nations]] predecessor agency.

===Names===
It is often sold as a salt in the form of either codeine sulfate or codeine phosphate in the United States, United Kingdom, and Australia. Codeine hydrochloride is more common worldwide and the citrate, hydroiodide, hydrobromide, tartrate, and other salts are also seen.<ref>Merck Index</ref> The chemical name for codeine is morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-, (5α,6α)-<ref>Anonymous Codeine. In The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals; O'Neil, M. J., Ed.; Merck: Whitehouse Station, NJ, 2006; pp 2417.</ref>

===Recreational use===
[[File:Coughsyrup-promethcode.jpg|thumb|right|The recreational drug [[Lean_(drug)|lean]] can be created with codeine syrup (pictured).]]
A [[heroin]] (diamorphine) or other [[opiate]]/[[opioid]] addict may use codeine to ward off the effects of [[Drug withdrawal|withdrawal]] during periods where their preferred drug is unavailable or unaffordable.<ref>{{Cite book | vauthors = van Solinge TB | title = L'héroïne, la cocaïne et le crack en France. Trafic, usage et politique | publisher = CEDRO Centrum voor Drugsonderzoek, Universiteit van Amsterdam | location = Amsterdam | language = fr | pages = 247–262 | chapter = 7. La politique de soins des années quatre-vingt-dix | chapter-url = http://www.cedro-uva.org/lib/boekhout.heroine.fr.7.html | year = 1996 | access-date = 26 April 2006 | archive-date = 25 February 2021 | archive-url = https://web.archive.org/web/20210225064644/http://www.cedro-uva.org/lib/boekhout.heroine.fr.7.html | url-status = live }}</ref>

Codeine is also available in conjunction with the anti-nausea medication [[promethazine]] in the form of a syrup. Brand named as Phenergan with Codeine or in generic form as promethazine with Codeine, it began to be mixed with soft drinks in the 1990s as a recreational drug, called "syrup", "lean", or "[[purple drank]]".<ref>{{cite news |newspaper = [[USA Today]] | vauthors = Leinwand D |title = DEA warns of soft drink-cough syrup mix |url = https://www.usatoday.com/news/nation/2006-10-18-lean_x.htm?csp=34 |date = 18 October 2006 |access-date = 23 October 2006 |url-status = live |archive-url = https://web.archive.org/web/20061128201409/http://www.usatoday.com/news/nation/2006-10-18-lean_x.htm?csp=34 |archive-date = 28 November 2006 |df = dmy-all }}</ref> Rapper [[Pimp C]], from the group [[UGK]], died from an overdose of this combination.<ref>{{cite news |url=http://www.chron.com/entertainment/music/article/Pimp-C-s-death-caused-by-overdose-and-sleep-1629962.php |title=Pimp C's death caused by overdose and sleep condition – Houston Chronicle |publisher=Chron.com |date=4 February 2008 |access-date=12 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20131231063510/http://www.chron.com/entertainment/music/article/Pimp-C-s-death-caused-by-overdose-and-sleep-1629962.php |archive-date=31 December 2013  }}</ref>

Codeine is used in [[clandestine chemistry|illegal drug laboratories]] to make morphine.<ref>{{Cite book| vauthors = Hogshire J | author-link = Jim Hogshire | title = Pills-A-Go-Go: A Fiendish Investigation into Pill Marketing, Art, History & Consumption | publisher = Feral House |date=June 1999 | location = Los Angeles | pages = 216–223 | isbn = 978-0-922915-53-8}}</ref><ref>{{cite journal |pages=361–70 |doi=10.1134/S1061934808040096 |title=Chromatographic study of expert and biological samples containing desomorphine |year=2011 | vauthors = Savchuk SA, Barsegyan SS, Barsegyan IB, Kolesov GM |journal=Journal of Analytical Chemistry |volume=63 |issue=4|s2cid=54546428 }}</ref>

===Detection===
Codeine and its major metabolites may be quantitated in [[blood]], [[Blood plasma|plasma]], or [[urine]] to monitor therapy, confirm a diagnosis of poisoning, or assist in a medico-legal death investigation. [[Drug abuse]] screening programs generally test [[urine]], [[hair]], [[sweat]] or [[saliva]]. Many commercial opiate screening tests directed at morphine cross-react appreciably with codeine and its metabolites, but chromatographic techniques can easily distinguish codeine from other opiates and opioids. It is important to note that codeine usage results in significant amounts of morphine as an excretion product. Furthermore, [[heroin]] contains codeine (or acetyl codeine) as an impurity and its use will result in the excretion of small amounts of codeine. [[Poppy seed]] foods represent yet another source of low levels of codeine in one's [[biofluids]]. Blood or plasma codeine concentrations are typically in the 50–300&nbsp;μg/L range in persons taking the drug therapeutically, 700–7,000&nbsp;μg/L in chronic users, and 1,000–10,000&nbsp;μg/L in cases of acute fatal over dosage.<ref>{{cite journal | vauthors = Thevis M, Opfermann G, Schänzer W | title = Urinary concentrations of morphine and codeine after consumption of poppy seeds | journal = Journal of Analytical Toxicology | volume = 27 | issue = 1 | pages = 53–56 | year = 2003 | pmid = 12587685 | doi = 10.1093/jat/27.1.53 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cone EJ, Welch P, Paul BD, Mitchell JM | title = Forensic drug testing for opiates, III. Urinary excretion rates of morphine and codeine following codeine administration | journal = Journal of Analytical Toxicology | volume = 15 | issue = 4 | pages = 161–166 | year = 1991 | pmid = 1943064 | doi = 10.1093/jat/15.4.161 }}</ref><ref>{{cite book |vauthors=Baselt R |title=Disposition of Toxic Drugs and Chemicals in Man |publisher=Biomedical Publications |location=Foster City CA |year=2008 |pages=355–360 |edition=8th }}</ref>

Codeine is produced in the human body along the [[Morphine#Human biosynthesis|same biosynthetic pathway as morphine]].<ref name="St2012">{{cite journal | vauthors = Stefano GB, Ptáček R, Kuželová H, Kream RM | title = Endogenous morphine: up-to-date review 2011 | journal = Folia Biologica | volume = 58 | issue = 2 | pages = 49–56 | date = 2012 | doi = 10.14712/fb2012058020049 | pmid = 22578954 | url = http://fb.cuni.cz/file/5635/FB2012A0008.pdf | url-status = live | quote = Positive evolutionary pressure has apparently preserved the ability to synthesize chemically authentic morphine, albeit in homeopathic concentrations, throughout animal phyla. | df = dmy-all | archive-url = https://web.archive.org/web/20160824130751/http://fb.cuni.cz/file/5635/FB2012A0008.pdf | archive-date = 24 August 2016 }}</ref> Urinary concentrations of endogenous codeine and morphine have been found to significantly increase in individuals taking [[L-DOPA]] for the treatment of [[Parkinson's disease]].<ref name="St2012" />

===Legal status===
Around the world, codeine is, contingent on its concentration, a Schedule II and III drug under the [[Single Convention on Narcotic Drugs]].<ref name="INCB-Yellow">{{cite web | author =International Narcotics Control Board | author-link =International Narcotics Control Board | url =http://www.incb.org/pdf/e/list/46thedition.pdf | title =List of Narcotic Drugs under International Control | access-date =24 May 2006 | url-status =dead | archive-url =https://web.archive.org/web/20120510002957/http://www.incb.org/pdf/e/list/46thedition.pdf | archive-date =10 May 2012 | df =dmy-all }}</ref> In [[Australia]], [[Canada]], [[New Zealand]], [[Sweden]], the [[United Kingdom]], the [[United States]] and many other countries, codeine is regulated under various [[Drug prohibition law#List by jurisdiction of principal drug prohibition laws|narcotic control laws]]. In some countries, it is available without a medical prescription in combination preparations from licensed pharmacists in doses up to 20&nbsp;mg, or 30&nbsp;mg when sold combined with 500&nbsp;mg paracetamol.

As of 2015, of the European Union member states, 11 countries (Bulgaria, Cyprus, Denmark, Estonia, Ireland, Latvia, Lithuania, Malta, Poland, Romania, and Slovenia) allow the sale of OTC codeine solid dosage forms.<ref name="academia.edu">{{cite journal | vauthors = Foley M, Harris R, Rich E, Rapca A, Bergin M, Norman I, Van Hout MC | title = The availability of over-the-counter codeine medicines across the European Union | journal = Public Health | volume = 129 | issue = 11 | pages = 1465–1470 | date = November 2015 | pmid = 26215740 | doi = 10.1016/j.puhe.2015.06.014 | url = https://www.academia.edu/19659390 | access-date = 8 July 2020 | url-status = live | archive-url = https://web.archive.org/web/20200709021531/https://www.academia.edu/19659390/The_availability_of_over-the-counter_codeine_medicines_across_the_European_Union | archive-date = 9 July 2020 }}</ref>

====Australia====
In Australia, since 1 February 2018, preparations containing codeine are not available without a prescription.<ref>{{cite web|title=Over-the-counter Codeine: The End Of An Era, And Preparing For The Changes Ahead|url=https://az659834.vo.msecnd.net/eventsairaueprod/production-ashm-public/d9f7d738c82e43fd97ca276f29b5b045|publisher=Australian and New Zealand Mental Health Association, and HealtheCare|access-date=11 July 2021|archive-date=11 July 2021|archive-url=https://web.archive.org/web/20210711061106/https://az659834.vo.msecnd.net/eventsairaueprod/production-ashm-public/d9f7d738c82e43fd97ca276f29b5b045|url-status=live}}</ref><ref>{{cite web | title = Painkillers with codeine won't be available over the counter from 2018 | publisher = ABC.net.au | url = http://www.abc.net.au/news/2016-12-20/codeine-painkillers-won't-be-available-over-the-counter-2018/8133996 | access-date = 20 December 2016 | url-status = live | archive-url = https://web.archive.org/web/20161221131240/http://www.abc.net.au/news/2016-12-20/codeine-painkillers-won't-be-available-over-the-counter-2018/8133996 | archive-date = 21 December 2016 | df = dmy-all | date = 19 December 2016 }}</ref>

Preparations containing pure codeine (e.g., codeine phosphate tablets or codeine phosphate [[linctus]]) are available on prescription and are considered S8 (Schedule 8, or "Controlled Drug Possession without authority illegal"). [[Standard for the Uniform Scheduling of Medicines and Poisons#Schedule 8 Controlled Drug (Possession without authority illegal)|Schedule 8]] preparations are subject to the strictest regulation of all medications available to consumers. 

Prior to 1 February 2018, Codeine was available over-the-counter (OTC).<ref>{{cite journal | vauthors = McCoy J, Bruno R, Nielsen S | title = Attitudes in Australia on the upscheduling of over-the-counter codeine to a prescription-only medication | journal = Drug and Alcohol Review | volume = 37 | issue = 2 | pages = 257–261 | date = February 2018 | pmid = 28597531 | doi = 10.1111/dar.12568 | s2cid = 26296460 }}</ref>

====Canada====
In Canada, codeine is regulated under the Narcotic Control Regulations (NCR), which falls under the [[Controlled Drugs and Substances Act]] (CDSA). Regulations state the pharmacists may, without a prescription, sell low-dose codeine products (containing up to 8&nbsp;mg of codeine per tablet or up to 20&nbsp;mg per 30 ml in liquid preparation) if the preparation contains at least two
additional medicinal ingredients other than a narcotic (S.36.1 NCR).<ref name="CPhA">{{cite web |title=Letter to Office of Legislative and Regulatory Affairs - Health Canada |url=https://www.pharmacists.ca/cpha-ca/assets/File/cpha-on-the-issues/CPhA%20Submission%20to%20HC%20Consultation_Modernizing%20NCR%2C%20BOTSR%2C%20FDR-Part%20G.pdf |publisher=Canadian Pharmacists Association |access-date=22 August 2019 |archive-date=22 September 2020 |archive-url=https://web.archive.org/web/20200922090701/https://www.pharmacists.ca/cpha-ca/assets/File/cpha-on-the-issues/CPhA%20Submission%20to%20HC%20Consultation_Modernizing%20NCR%2C%20BOTSR%2C%20FDR-Part%20G.pdf |url-status=live }}</ref><ref name="CADTH">{{cite web |vauthors=Chao YS, Severn M |title=Non-prescription Analgesic and Antitussive Medications Containing Codeine: A Review of Clinical Effectiveness and Safety |url=https://cadth.ca/sites/default/files/pdf/htis/2018/RC0994%20OTC%20Codeine%20Final.pdf |publisher=CADTH Canadian Agency for Drugs and Technologies in Health |access-date=20 June 2018 |archive-date=26 September 2020 |archive-url=https://web.archive.org/web/20200926052935/https://cadth.ca/sites/default/files/pdf/htis/2018/RC0994%20OTC%20Codeine%20Final.pdf |url-status=live }}</ref>

In Canada tablets containing 8&nbsp;mg of codeine combined with 15&nbsp;mg of caffeine and 300&nbsp;mg of acetaminophen are sold as T1s (Tylenol Number 1) without a prescription. A similar tablet called "A.C. & C." (which stands for Acetylsalicylic acid with Caffeine and Codeine) containing 325–375&nbsp;mg of [[acetylsalicylic acid]] (Aspirin) instead of acetaminophen is also available without a prescription. Codeine combined with an antihistamine, and often caffeine, is sold under various trade names and is available without a prescription. These products are kept behind the counter and must be dispensed by a pharmacist who may limit quantities.{{citation needed|date=February 2020}}

Names of many codeine and dihydrocodeine products in Canada tend to follow the narcotic content number system (Tylenol With Codeine No. 1, 2, 3, 4 &c) mentioned below in the section on the United States; it came to be in its current form with the Pure Food & Drug Act of 1906.{{citation needed|date=February 2020}}

Controlled Drugs and Substances Act (S.C. 1996, c. 19) effective 28 July 2020.<ref>{{Cite web| author = Legislative Services Branch |date=19 September 2019|title=Consolidated Federal Laws of Canada, Controlled Drugs and Substances Act|url=https://www.laws-lois.justice.gc.ca/eng/acts/C-38.8/page-13.html#h-95315|url-status=live|archive-url=https://web.archive.org/web/20200923072832/https://laws-lois.justice.gc.ca/eng/acts/c-38.8/page-13.html|archive-date=23 September 2020|access-date=27 September 2020|website=Justice Laws Website}}</ref> Codeine is now classified under Schedule 1, giving it a higher priority in the treatments of offenders of the law.

Codeine became a prescription-only medication in the province of Manitoba on 1 February 2016. The number of low-dose codeine tablets sold in Manitoba decreased by 94 percent from 52.5 million tablets sold in the year prior to the policy change to 3.3 million in the year after.<ref name="Manitoba">{{cite web |title=College of Pharmacists of Manitoba Newsletter Summer 2018 |url=https://cphm.ca/uploaded/web/Newsletters/Summer%202018/College-of-Pharmacists-of-Manitoba-Summer-2018-Newsletter-FINAL.pdf |publisher=CPHM |access-date=22 August 2019 |archive-date=21 July 2020 |archive-url=https://web.archive.org/web/20200721235959/https://cphm.ca/uploaded/web/Newsletters/Summer%202018/College-of-Pharmacists-of-Manitoba-Summer-2018-Newsletter-FINAL.pdf |url-status=dead }}</ref> A pharmacist may issue a prescription, and all purchases are logged to a central database to prevent overprescribing.<ref>{{Cite web|url=http://www.cbc.ca/news/canada/manitoba/tylenol-1-to-require-prescription-in-manitoba-in-february-2016-1.3370689|title=Tylenol 1 to require prescription in Manitoba in February 2016|website=www.cbc.ca|access-date=4 June 2016|url-status=live|archive-url=https://web.archive.org/web/20160531112759/http://www.cbc.ca/news/canada/manitoba/tylenol-1-to-require-prescription-in-manitoba-in-february-2016-1.3370689|archive-date=31 May 2016}}</ref> Saskatchewan's pharmacy college is considering enacting a similar ban to Manitoba's.<ref name="charges">{{cite news |vauthors=Taylor S |title='Opioid epidemic:' Pharmacists want to restrict low-dose codeine products like Tylenol 1 |url=https://nationalpost.com/news/canada/opioid-epidemic-pharmacists-call-for-stricter-access-to-low-dose-codeine |newspaper=National Post |access-date=22 August 2019 |archive-date=28 August 2021 |archive-url=https://web.archive.org/web/20210828043047/https://nationalpost.com/news/canada/opioid-epidemic-pharmacists-call-for-stricter-access-to-low-dose-codeine |url-status=live }}</ref><ref>{{cite web |title=Over-the-counter codeine should be limited in wake of 'opioid epidemic', says Sask. pharmacist |url=https://www.cbc.ca/news/canada/saskatchewan/codeine-limiting-opioid-crisis-1.5159395 |publisher=CBC |access-date=22 August 2019 |archive-date=24 October 2020 |archive-url=https://web.archive.org/web/20201024190904/https://www.cbc.ca/news/canada/saskatchewan/codeine-limiting-opioid-crisis-1.5159395 |url-status=live }}</ref>

On 9 May 2019, the [[Canadian Pharmacists Association]] wrote to [[Health Canada]] proposing regulations amending the NCR, the BOTSR, and the FDR - Part G, which included requiring that all products containing codeine be available by prescription only.<ref name="CPhA"/>

New safety measures were issued by [[Health Canada]] on 28 July 2016; "codeine should no longer be used (contraindicated) in patients under 18 years of age to treat pain after surgery to remove tonsils or adenoids, as these patients are more susceptible to the risk of serious breathing problems. Codeine (prescription and non-prescription) is already not recommended for children under the age of 12, for any use."<ref>{{cite web |title=Recalls and Safety Alerts |date=25 August 2021 |url=http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/59584a-eng.php |publisher=Government of Canada |access-date=22 August 2019 |archive-date=5 November 2020 |archive-url=https://web.archive.org/web/20201105162235/https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/59584a-eng.php |url-status=live }}</ref>

====Denmark====
In Denmark, codeine is sold over the counter in dosages up to 9.6&nbsp;mg (with aspirin, brand name Kodimagnyl); anything stronger requires a prescription.<ref>{{cite journal | vauthors = Foley M, Breindahl T, Hindersson P, Deluca P, Kimergård A | title = Misuse of 'over-the-counter' codeine analgesics: does formulation play a role? | journal = Public Health | volume = 130 | pages = 95–96 | date = January 2016 | pmid = 26612458 | doi = 10.1016/j.puhe.2015.10.006 }}</ref>

====Estonia====
Until 2023, in Estonia codeine was sold over the counter in dosages up to 8&nbsp;mg (with paracetamol, brand name Co-Codamol).<ref>{{Cite web | vauthors = Koppel K |date=2022-11-23 |title=Pharmacists welcome ban on OTC sale of painkillers containing codeine |url=https://news.err.ee/1608797869/pharmacists-welcome-ban-on-otc-sale-of-painkillers-containing-codeine |access-date=2023-11-08 |website=ERR |language=en}}</ref>

==== Ethiopia ====
Approximately 30% of the [[Ethiopia|Ethiopian]] population carry an extra copy of the gene ''[[CYP2D6]],'' and are classified as codeine ultrametabolizers. These individuals metabolize codeine to morphine at a dangerously fast rate, leading to adverse events and potentially death. As a consequence the Ethiopian Food, Medicine and Health Care Administration and Control Authority has entirely banned the use of codeine as unsafe for the general population.<ref>{{cite journal | vauthors = Baker JL, Shriner D, Bentley AR, Rotimi CN | title = Pharmacogenomic implications of the evolutionary history of infectious diseases in Africa | journal = The Pharmacogenomics Journal | volume = 17 | issue = 2 | pages = 112–120 | date = March 2017 | pmid = 27779243 | pmc = 5380847 | doi = 10.1038/tpj.2016.78 }}</ref>

====France====
In [[France]], most preparations containing codeine only began requiring a doctor's prescription in 2017. Products containing codeine include Néocodion (codeine and camphor), Tussipax ([[ethylmorphine]] and codeine), Paderyl (codeine alone), Codoliprane (codeine with [[paracetamol]]), Prontalgine and Migralgine (codeine, paracetamol and [[caffeine]]).<ref>{{cite web | title = vital list of codein | publisher = vidal.com | url = http://www.vidal.fr/Substance/codeine-1039.htm | access-date = 12 January 2011 | url-status = live | archive-url = https://web.archive.org/web/20110721024429/http://www.vidal.fr/Substance/codeine-1039.htm | archive-date = 21 July 2011 | df = dmy-all }}</ref> The 2017 law change made a prescription mandatory for all codeine products, along with those containing [[ethylmorphine]] and [[dextromethorphan]].<ref>{{cite web|url=http://www.otctoolbox.com/news/france-restricts-dextromethorphan-and-codeine.aspx|title=OTCToolbox - France restricts dextromethorphan and codeine| vauthors = Wilkes D |website=www.otctoolbox.com|access-date=28 October 2017|archive-date=16 January 2019|archive-url=https://web.archive.org/web/20190116200913/http://www.otctoolbox.com/news/france-restricts-dextromethorphan-and-codeine.aspx|url-status=dead}}</ref>

====Greece====
Codeine is classed as an illegal drug in Greece, and individuals possessing it could conceivably be arrested, even if they were legitimately prescribed it in another country. It is sold only with a doctor's prescription (Lonarid-N, Lonalgal).<ref>{{cite web | title = Pharmacies in Greece | work = About.com Travel | publisher = About.com | url = http://gogreece.about.com/od/planagreattriptogreece/a/greecepharmacy_2.htm | access-date = 10 October 2009 | url-status = live | archive-url = https://web.archive.org/web/20101006152215/http://gogreece.about.com/od/planagreattriptogreece/a/greecepharmacy_2.htm | archive-date = 6 October 2010 | df = dmy-all }}</ref>

====Hong Kong====
In Hong Kong, codeine is regulated under the Laws of the Hong Kong, Dangerous Drugs Ordinance, Chapter 134, Schedule 1. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without a prescription can be fined $10,000 ([[Hong Kong dollar|HKD]]). The maximum penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.

However, codeine is available without prescription from licensed pharmacists in doses up to 0.1%<ref name=LawsOfHongKongChapter134>Laws of Hong Kong, Dangerous Drugs Ordinance, Chapter 134 {{cite web |url=http://www.legislation.gov.hk/eng/home.htm |title=Hong Kong e-Legislation |access-date=16 October 2016 |url-status=dead |archive-url=https://web.archive.org/web/20121016064430/http://www.legislation.gov.hk/eng/home.htm |archive-date=16 October 2012  }}</ref>{{rp|Schedule 1, Part IV, paragraph 23}} (i.e. 5&nbsp;mg/5ml)<ref name=LawsOfHongKongChapter134 />{{rp|Section 3, (1) (a)}}

====India====
Codeine preparations require a prescription in India. A preparation of [[paracetamol]] and codeine is available in India. Codeine is also present in various cough syrups as codeine phosphate including chlorpheniramine maleate. Pure codeine is also available as codeine sulphate tablets. Codeine containing [[cough medicine]] has been banned in India with effect from 14 March 2016. The Ministry of Health and Family Welfare has found no proof of its efficacy against cough control.<ref>{{Cite news|url=http://economictimes.indiatimes.com/markets/stocks/news/pfizer-abbott-shares-tank-after-ban-on-corex-phensedyl-and-327-other-drugs/articleshow/51389151.cms|title=Pfizer, Abbott shares tank after ban on Corex, Phensedyl and 327 other drugs – The Economic Times|newspaper=The Economic Times|access-date=14 March 2016|url-status=live|archive-url=https://web.archive.org/web/20161117212043/http://economictimes.indiatimes.com/markets/stocks/news/pfizer-abbott-shares-tank-after-ban-on-corex-phensedyl-and-327-other-drugs/articleshow/51389151.cms|archive-date=17 November 2016|date=14 March 2016| vauthors = Mudgill A }}</ref>

====Ireland====
In [[Republic of Ireland|Ireland]], new regulations came into effect on 1 August 2010<ref>{{cite news | url = http://www.irishtimes.com/newspaper/health/2010/0824/1224277436013.html | newspaper = The Irish Times | date = 8 August 2010 | title = Codeine regulations cause a few headaches | url-status = live | archive-url = https://web.archive.org/web/20100903101512/http://www.irishtimes.com/newspaper/health/2010/0824/1224277436013.html | archive-date = 3 September 2010 | df = dmy-all }}</ref> concerning codeine, due to worries about the overuse of the drug. Codeine remains a semi non-prescriptive, over-the-counter drug up to a limit of 12.8&nbsp;mg per pill, but codeine products must be out of the view of the public to facilitate the legislative requirement that these products "are not accessible to the public for self-selection".<ref>[http://www.attorneygeneral.ie/esi/2008/B26511.pdf Office of The Attorney General, Regulation 5(1)(e) of the Regulation of Retail Pharmacy Businesses Regulations 2008 (S.I. 488 of 2008)] {{webarchive|url=https://web.archive.org/web/20110727031826/http://www.attorneygeneral.ie/esi/2008/B26511.pdf |date=27 July 2011 }}</ref> In practice, this means customers must ask pharmacists for the product containing codeine in name, and the pharmacist makes a judgement whether it is suitable for the patient to be using codeine, and that patients are fully advised of the correct use of these products. Products containing more than 12.8&nbsp;mg codeine are available on prescription only.<ref>{{Cite web | url = http://www.thepsi.ie/Libraries/Consultations/Draft_Codeine_Guidelines.sflb.ashx | title = Non-Prescription Medicinal Products Containing Codeine: Draft Guidance for Pharmacists | website= [[Pharmaceutical Society of Ireland]] | url-status = live | archive-url = https://web.archive.org/web/20130521074855/http://www.thepsi.ie/Libraries/Consultations/Draft_Codeine_Guidelines.sflb.ashx | archive-date = 21 May 2013 | df = dmy-all }}</ref>

====Italy====
Codeine tablets or preparations require a prescription in [[Italy]]. Preparations of [[paracetamol]] and codeine are available in Italy as ''Co-Efferalgan'' and ''Tachidol''.<ref>{{Cite web|title=Tachidol - Foglio Illustrativo|url=https://www.my-personaltrainer.it/Foglietti-illustrativi/Tachidol.html|access-date=3 February 2022|website=www.my-personaltrainer.it|language=it|archive-date=3 February 2022|archive-url=https://web.archive.org/web/20220203202451/https://www.my-personaltrainer.it/Foglietti-illustrativi/Tachidol.html|url-status=live}}</ref>

====Japan====
Codeine is available over the counter at pharmacies, allowing up to 50&nbsp;mg of codeine phosphate per day for adults.<ref>Aneton cough medicine package.</ref>

====Latvia====
In Latvia codeine is sold over the counter in dosages up to 8&nbsp;mg (with paracetamol, brand name Co-Codamol).<ref name="academia.edu"/>

====Nigeria====
Nigeria in 2018 plans to ban the manufacture and import of cough syrup that include codeine as an ingredient.<ref name=BBC2018>{{cite news|title=Nigeria bans all codeine cough syrup|url=https://www.bbc.com/news/world-africa-43961738|access-date=3 May 2018|work=BBC News Online|date=1 May 2018|archive-date=2 May 2018|archive-url=https://web.archive.org/web/20180502221300/http://www.bbc.com/news/world-africa-43961738|url-status=live}}</ref> This is due to concerns regarding its use to get intoxicated.<ref name=BBC2018/>

====South Africa====
Codeine is available over the counter in South Africa. Certain pharmacies require people to write down their name and address to ensure they are not buying too much over a short period although many do not require this at all. According to Lochan Naidoo, the former president of the National Narcotics Control Board, making the drugs more difficult to obtain could lead to even worse problems where people in withdrawal would turn to illicit drugs to get their fix.<ref>{{cite web |url=http://www.iol.co.za/news/south-africa/kwazulu-natal/sas-silent-codeine-addiction-uncovered-2071990 |title=SA's silent codeine addiction uncovered {{pipe}} IOL News |access-date=16 October 2016 |url-status=live |archive-url=https://web.archive.org/web/20161017035926/http://www.iol.co.za/news/south-africa/kwazulu-natal/sas-silent-codeine-addiction-uncovered-2071990 |archive-date=17 October 2016  }}</ref> Although codeine is freely available, South Africa has a fairly low annual prevalence rate of opiate use at 0.3% compared to the United States at 0.57% where all opiates are strictly regulated.

====United Arab Emirates====
The UAE takes an exceptionally strict line on medicines, with many common drugs, notably anything containing codeine being banned unless one has a notarized and authenticated doctor's prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned. The US Embassy to the UAE maintains an [https://web.archive.org/web/20130528033759/http://abudhabi.usembassy.gov/restricted_medication.html unofficial list] of what may not be imported.

====United Kingdom====
In the United Kingdom, the sale and possession of codeine are restricted separately under law.

Neat codeine and higher-strength codeine formulations are generally prescription-only medicines (POM) meaning that the sale of such products is restricted under the [[Medicines Act 1968]]. Lower-strength products containing combinations of up to 12.8&nbsp;mg of codeine per dosage unit, combined with [[paracetamol]], [[ibuprofen]] or [[aspirin]] are available over the counter at pharmacies. Codeine linctus cough syrups were banned from over-the-counter sale in 2024 due to concerns over addiction and recreational usage. They remain available under a prescription.<ref>{{cite web|
last1=Medicines & Healthcare products Regulatory Agency|date=20 February 2024|title=Codeine linctus (codeine oral solutions): reclassification to prescription-only medicine|url=https://www.gov.uk/drug-safety-update/codeine-linctus-codeine-oral-solutions-reclassification-to-prescription-only-medicine|access-date=20 June 2025|work=gov.uk}}</ref>

Under the Misuse of Drugs Act 1971 codeine is a Class B controlled substance or a Class A drug when prepared for injection.<ref>{{cite web |url=http://www.legislation.gov.uk/ukpga/1971/38/schedule/2 |title=Misuse of Drugs Act 1971 |publisher=Legislation.gov.uk |access-date=12 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20131108014958/http://www.legislation.gov.uk/ukpga/1971/38/schedule/2 |archive-date=8 November 2013  }}</ref><ref>{{cite web | title=List of most commonly encountered drugs currently controlled under the misuse of drugs legislation | website=GOV.UK | date=20 October 2016 | url=https://www.gov.uk/government/publications/controlled-drugs-list--2/list-of-most-commonly-encountered-drugs-currently-controlled-under-the-misuse-of-drugs-legislation | access-date=7 February 2020 | archive-date=8 December 2019 | archive-url=https://web.archive.org/web/20191208222115/https://www.gov.uk/government/publications/controlled-drugs-list--2/list-of-most-commonly-encountered-drugs-currently-controlled-under-the-misuse-of-drugs-legislation | url-status=live }}</ref> The possession of controlled substances without a prescription is a criminal offence.<ref>{{cite web |url=http://www.legislation.gov.uk/ukpga/1971/38/contents |title=Misuse of Drugs Act 1971 |publisher=Legislation.gov.uk |access-date=12 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20140128042930/http://www.legislation.gov.uk/ukpga/1971/38/contents |archive-date=28 January 2014  }}</ref> However, certain preparations of codeine are exempt from this restriction under Schedule 5 of the Misuse of Drugs Regulations 2001. It is thus legal to possess codeine without a prescription, provided that it is compounded with at least one other active or inactive ingredient and that the dosage of each tablet, capsule, etc. does not exceed 100&nbsp;mg or 2.5% [[concentration]] in the case of liquid preparations. The exemptions do not to apply to any preparation of codeine designed for injection.<ref>{{cite web |url=http://www.legislation.gov.uk/uksi/2001/3998/schedule/5/made |title=The Misuse of Drugs Regulations 2001 |publisher=Legislation.gov.uk |date=9 December 2013 |access-date=12 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20140129223606/http://www.legislation.gov.uk/uksi/2001/3998/schedule/5/made |archive-date=29 January 2014  }}</ref>

====United States====
In the United States, codeine is regulated by the [[Controlled Substances Act]]. Federal law dictates that codeine be a Schedule II controlled substance when used in products for pain relief that contain codeine alone or more than 80&nbsp;mg per dosage unit. Codeine without aspirin or acetaminophen (Tylenol) is very rarely available or prescribed to discourage abuse. Tablets of codeine in combination with aspirin or acetaminophen ([[paracetamol]]) and intended for pain relief are listed as Schedule III.

Cough syrups are classed as Schedule III, IV, or V, depending on formulation. For example, the acetaminophen/codeine antitussive liquid is a Schedule IV controlled substance.<ref name="Valeant Pharmaceuticals Prescribing Information for Capital with Codeine Oral Suspension">{{cite web | author =Valeant Pharmaceuticals | author-link =Valeant Pharmaceuticals | url =http://www.valeant.com/fileRepository/products/PI/Capital_with_Codeine_Suspension_120mg_PI_Aug04.pdf | title =Prescribing Information for Capital with Codeine (paracetamol with codeine) showing Schedule V designation | access-date =25 February 2011 | url-status =dead | archive-url =https://web.archive.org/web/20110717183303/http://www.valeant.com/fileRepository/products/PI/Capital_with_Codeine_Suspension_120mg_PI_Aug04.pdf | archive-date =17 July 2011 | df =dmy-all }}</ref>

Some states have chosen to reclassify codeine preparations at a more restrictive schedule to lower the instances of its abuse. Minnesota, for instance, has chosen to reclassify Schedule V some codeine preparations (e.g. [[Cheratussin]]) as a Schedule III controlled substance.<ref name="Minnesota; Schedules of controlled substances">{{cite web|title=152.02 Schedules Of Controlled Substances|url=https://www.revisor.mn.gov/statutes/?id=152.02|publisher=State of Minnesota|access-date=30 May 2013|url-status=live|archive-url=https://web.archive.org/web/20130730103623/https://www.revisor.mn.gov/statutes/?id=152.02|archive-date=30 July 2013}}</ref>

=====Schedule V controlled substances=====

Substances in this schedule have a low potential for abuse relative to substances listed in Schedule IV and consist primarily of preparations containing limited quantities of certain narcotics.

Examples of Schedule V substances include cough preparations containing not more than 200 milligrams of codeine per 100 milliliters or per 100 grams (Robitussin AC, Phenergan with Codeine).<ref>[https://www.deadiversion.usdoj.gov/schedules/ Controlled Substance Schedules.] {{Webarchive|url=https://web.archive.org/web/20201121231025/https://www.deadiversion.usdoj.gov/schedules/ |date=21 November 2020 }} U.S. DEPARTMENT OF JUSTICE, DRUG ENFORCEMENT ADMINISTRATION: Diversion Control Division.</ref>

==Veterinary use==
Codeine is not recommended as an analgesic in dogs and cats due to poor oral availability and lack of evidence to support the use of codeine over other analgesics.<ref>{{cite book | vauthors = Simon BT, Lizarraga I | chapter = Opioids | title = Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones | pages = 381 | isbn = 978-1-119-83027-6 | veditors = Lamont L, Grimm K, Robertson S, Love L, Schroeder C | publisher = Wiley Blackwell }}</ref>

== References ==
{{Reflist}}

==Notes==
{{Notelist}}

== Further reading ==
* {{cite book | title=Medical Genetics Summaries | chapter=Codeine Therapy and CYP2D6 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK100662/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2012 | pmid=28520350 | id=Bookshelf ID: NBK100662 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}

== External links ==
{{Commons category|Codeine}}

{{Components of Opium}}
{{Analgesics}}
{{Antidiarrheals, intestinal anti-inflammatory/anti-infective agents}}
{{Cough and cold preparations}}
{{Opioid receptor modulators}}
{{Glycine receptor modulators}}
{{Portal bar|Medicine}}
{{Authority control}}

[[Category:Benzylisoquinoline alkaloids]]
[[Category:Antidiarrhoeals]]
[[Category:Antitussives]]
[[Category:Catechol ethers]]
[[Category:4,5-Epoxymorphinans]]
[[Category:Glycine receptor antagonists]]
[[Category:Natural opium alkaloids]]
[[Category:Opiates]]
[[Category:Prodrugs]]
[[Category:Secondary metabolites]]
[[Category:World Health Organization essential medicines]]
[[Category:Wikipedia medicine articles ready to translate]]