View source for Pholcodine

{{Short description|Chemical compound}}
{{Use dmy dates|date=May 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| image              = Pholcodine2DCSD.svg
| image_class        = skin-invert-image
| width              = 300
| alt               = 
| image2             = Pholcodine3DanJ.gif
| width2             = 250
| alt2              = 

<!-- Clinical data -->
| pronounce         = 
| tradename          = Logicin, others
| Drugs.com          = {{drugs.com|international|pholcodine}}
| MedlinePlus       = 
| DailyMedID        = <!-- DailyMed may use generic or brand name (generic name preferred) -->
| pregnancy_AU      = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU_comment = 
| pregnancy_category = 
| dependency_liability = 
| addiction_liability = High
| routes_of_administration = [[By mouth]]
| class             = 
| ATC_prefix         = R05
| ATC_suffix         = DA08
| ATC_supplemental   = 

<!-- Legal status -->
| legal_AU          = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment  = 
| legal_BR           = A2
| legal_BR_comment   = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=3 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| legal_CA           = Schedule I
| legal_CA_comment  = 
| legal_DE          = Anlage II
| legal_DE_comment  = 
| legal_NZ          = <!-- Class A, B, C -->
| legal_NZ_comment  = 
| legal_UK           = Class B
| legal_UK_comment  = 
| legal_US           = Schedule I
| legal_US_comment  = 
| legal_EU          = 
| legal_EU_comment  = 
| legal_UN          = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment  = 
| legal_status      = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability    = Maximum plasma conc. attained 4-8 hours after oral dose.
| protein_bound      = 23.5%
| metabolism         = [[Liver]]
| metabolites       = 
| onset             = 
| elimination_half-life = 32-43 hours; volume of distribution is 36-49L/kg.
| duration_of_action = 
| excretion          = [[Kidney]]

<!-- Identifiers -->
| CAS_number         = 509-67-1
| CAS_supplemental  = 
| PubChem            = 5311356
| IUPHAR_ligand     = 
| DrugBank           = DB09209
| ChemSpiderID       = 4470854
| UNII               = LPP64AWZ7L
| KEGG               = D07385
| ChEBI              = 53579
| ChEMBL             = 2105224
| NIAID_ChemDB      = 
| PDB_ligand        = 
| synonyms          = 

<!-- Chemical and physical data -->
| IUPAC_name         = 7,8-Didehydro-4,5α-epoxy-17-methyl-3-[2-(morpholin-4-yl)ethoxy]morphinan-6α-ol
| C                  = 23
| H                  = 30
| N                  = 2
| O                  = 4
| SMILES             = O(c5ccc4c1c5O[C@H]3[C@@H](O)\C=C/[C@H]2[C@H](N(C)CC[C@@]123)C4)CCN6CCOCC6
| StdInChI           = 1S/C23H30N2O4/c1-24-7-6-23-16-3-4-18(26)22(23)29-21-19(5-2-15(20(21)23)14-17(16)24)28-13-10-25-8-11-27-12-9-25/h2-5,16-18,22,26H,6-14H2,1H3/t16-,17+,18-,22-,23-/m0/s1
| StdInChI_comment  = 
| StdInChIKey        = GPFAJKDEDBRFOS-FKQDBXSBSA-N
| density           = 
| density_notes     = 
| melting_point     = 
| melting_high      = 
| melting_notes     = 
| boiling_point     = 
| boiling_notes     = 
| solubility        = 
| sol_units         = 
| specific_rotation = 
}}

'''Pholcodine''' is an [[opioid]] [[cough suppressant]] (antitussive). It helps suppress unproductive [[cough]]s and also has a mild [[sedative]] effect, but has little or no [[analgesic]] effects. It is also known as morpholinylethylmorphine and homocodeine.

Pholcodine is found in certain cough [[Throat lozenge|lozenges]],<ref>{{cite web | title = Potter's Pholcodine cough pastilles | url = http://www.lloydspharmacy.com/en/potters-pholcodine-cough-pastilles | publisher = Lloyds Pharmacy | access-date = 29 February 2020 | archive-date = 29 February 2020 | archive-url = https://web.archive.org/web/20200229091624/http://www.lloydspharmacy.com/en/potters-pholcodine-cough-pastilles | url-status = live }}</ref> and more commonly as an oral solution, typically 5&nbsp;mg / 5 ml. Adult dosage is 5-10 ml up to 3-4 times daily.<ref>{{cite book | date = 2007 | title = British National Formulary 54 | publisher = BMJ Publishing Group Ltd., RPS Publishing | location = London | page = 175 }}</ref> Pholcodine now largely replaces the previously more common [[codeine]] linctus, as it has a much lower potential for dependence.

Pholcodine has been widely used as an antitussive agent but by 2023 concerns over its association with [[anaphylaxis]] in some circumstances meant that it has been withdrawn from sale in many territories. Pholcodine is not prescribed in the United States where it is classed as a [[Controlled Substances Act#Schedule I controlled substances|Schedule I]] drug, the most highly controlled drug category.<ref>{{cite web | title = Legislation - Controlled Substances | url = https://www.fda.gov/RegulatoryInformation/Legislation/ucm148726.htm | archive-url = https://web.archive.org/web/20160204232926/https://www.fda.gov/RegulatoryInformation/Legislation/ucm148726.htm | archive-date = 4 February 2016 | publisher = U.S. [[Food and Drug Administration]] (FDA) | date = 11 June 2009 }}</ref>

Following the conclusion of a review of post-marketing safety data by the MHRA, all pholcodine-containing medicines are being recalled and withdrawn from the UK as a precaution.<ref>{{Cite web |date=23 March 2023 |title=Pholcodine-containing cough and cold medicines: withdrawal from UK market as a precautionary measure |url=https://www.gov.uk/drug-safety-update/pholcodine-containing-cough-and-cold-medicines-withdrawal-from-uk-market-as-a-precautionary-measure |access-date=11 November 2023 |website=GOV.UK |archive-date=11 November 2023 |archive-url=https://web.archive.org/web/20231111224838/https://www.gov.uk/drug-safety-update/pholcodine-containing-cough-and-cold-medicines-withdrawal-from-uk-market-as-a-precautionary-measure |url-status=live }}</ref> The available data has demonstrated that pholcodine use, particularly in the twelve months before general anesthesia with NMBAs (neuromuscular blocking agents), is a risk factor for developing an anaphylactic reaction to NMBAs. In December 2022, the [[European Medicines Agency]] recommended their withdrawal in the EU.<ref>{{cite web | title=EMA recommends withdrawal of pholcodine medicines from EU market | website=[[European Medicines Agency]] (EMA) | date=2 December 2022 | url=https://www.ema.europa.eu/en/news/ema-recommends-withdrawal-pholcodine-medicines-eu-market | access-date=8 February 2024 | archive-date=8 February 2024 | archive-url=https://web.archive.org/web/20240208063949/https://www.ema.europa.eu/en/news/ema-recommends-withdrawal-pholcodine-medicines-eu-market | url-status=live }}</ref> {{As of|2023|2}}, the Australian [[Therapeutic Goods Administration]] canceled the registration of pholcodine.<ref>{{cite web | title=Pholcodine | website=[[Therapeutic Goods Administration]] (TGA) | date=28 February 2023 | url=https://www.tga.gov.au/safety/product-recalls/pholcodine | access-date=18 May 2024 | archive-date=18 May 2024 | archive-url=https://web.archive.org/web/20240518060851/https://www.tga.gov.au/safety/product-recalls/pholcodine | url-status=live }}</ref><ref>{{cite web | title=About pholcodine cough medicines cancelled by the TGA and recalled from pharmacies for safety reasons | website=[[Therapeutic Goods Administration]] (TGA) | date=1 March 2023 | url=https://www.tga.gov.au/safety/information-about-specific-safety-alerts-and-recalls/about-pholcodine-cough-medicines-cancelled-tga-and-recalled-pharmacies-safety-reasons | access-date=18 May 2024 | archive-date=18 May 2024 | archive-url=https://web.archive.org/web/20240518060951/https://www.tga.gov.au/safety/information-about-specific-safety-alerts-and-recalls/about-pholcodine-cough-medicines-cancelled-tga-and-recalled-pharmacies-safety-reasons | url-status=live }}</ref>

==Mechanism of action==
Pholcodine is readily absorbed from the [[gastrointestinal tract]] and freely crosses the [[blood–brain barrier]]. It acts primarily on the [[central nervous system]] (CNS), causing depression of the [[cough reflex]], partly by a direct effect on the [[cough centre]] in the [[Medulla oblongata|medulla]]. It is metabolized in the [[liver]] and its action may be prolonged in individuals with [[hepatic]] insufficiency (i.e. liver problems). Its use is therefore contraindicated in patients with liver disease, while care is advised in patients with hepatic impairment.

==Metabolism and excretion==
Pholcodine is slowly biotransformed in the body via oxidation and conjugation to a series of metabolites that are eliminated primarily in the urine. With an average half-life of approximately 2.3 days, steady-state in someone taking the drug chronically would not be reached for nearly 2 weeks. Nearly one-half of a single dose is eventually excreted as free or conjugated parent drug. The most important urinary metabolite is [[Drug metabolism|conjugated]] [[morphine]], which may be detectable for days or weeks after the last dose. This could trigger a positive result for opiates in a [[urine drug test]]ing program.<ref>{{cite journal | vauthors = Maurer HH, Fritz CF | title = Toxicological detection of pholcodine and its metabolites in urine and hair using radio immunoassay, fluorescence polarisation immunoassay, enzyme immunoassay, and gas chromatography-mass spectrometry | journal = International Journal of Legal Medicine | volume = 104 | issue = 1 | pages = 43–6 | date = December 1990 | pmid = 11453092 | doi = 10.1007/BF01816483 | s2cid = 5935454 }}</ref><ref>{{cite book | vauthors = Baselt R | title = Disposition of Toxic Drugs and Chemicals in Man | edition = 8th | publisher = Biomedical Publications | location = Foster City, CA | date = 2008 | pages = 1258–1260 }}</ref>

==Side effects==
Side effects are rare and may include [[dizziness]] and [[gastrointestinal disturbance]]s such as [[nausea]] or [[vomiting]]. Adverse effects such as [[constipation]], [[drowsiness]], [[Psychomotor agitation|excitation]], [[ataxia]] and [[respiratory depression]] have been reported occasionally or after large doses. The primary safety concerns with pholcodine revolve around death during general anaesthesia.<ref>{{cite journal | journal = The Pharmaceutical Journal | publisher = Royal Pharmaceutical Society | date = 17 January 2015 | vauthors = Andalo D | url = http://www.pharmaceutical-journal.com/news-and-analysis/anaesthetists-campaign-for-pholcodine-cough-medicines-to-become-prescription-only-products/20067520.article | title = Anaesthetists campaign for pholcodine cough medicines to become prescription-only products | access-date = 17 September 2016 | archive-date = 17 September 2016 | archive-url = https://web.archive.org/web/20160917162651/http://www.pharmaceutical-journal.com/news-and-analysis/anaesthetists-campaign-for-pholcodine-cough-medicines-to-become-prescription-only-products/20067520.article | url-status = live }}</ref>

==Anaphylaxis during general anaesthesia==
Administration of pholcodine causes production of antibodies linked with fatalities during surgery, when essential [[neuromuscular blocking agents]] (NMBAs) are administered to prevent patient movement under [[general anaesthesia]].<ref>{{cite journal | vauthors = Florvaag E, Johansson SG | title = The pholcodine story | journal = Immunology and Allergy Clinics of North America | volume = 29 | issue = 3 | pages = 419–27 | date = August 2009 | pmid = 19563989 | doi = 10.1016/j.iac.2009.04.002 }}</ref> These antibody levels gradually fall to low levels several years after last dose of pholcodine. However, the presence of these antibodies causes a 300-fold increase in risk of [[anaphylaxis]] during anaesthesia.<ref name=pmid23283141>{{cite journal | vauthors = Florvaag E, Johansson SG | title = The Pholcodine Case. Cough Medicines, IgE-Sensitization, and Anaphylaxis: A Devious Connection | journal = The World Allergy Organization Journal | volume = 5 | issue = 7 | pages = 73–8 | date = July 2012 | pmid = 23283141 | pmc = 3651177 | doi = 10.1097/WOX.0b013e318261eccc }}</ref>

The link was suspected when neighbouring Norway and Sweden were found to have tenfold differences of surgical anaphylaxis deaths. Sweden had no products approved containing pholcodine, whereas 40% of the population in Norway had consumed the single approved pholcodine product.<ref name=pmid23283141/> Norway withdrew pholcodine from the market in 2007, and the prevalence of anti-suxamethonium antibodies fell by over 80% in two years.<ref>{{cite journal | vauthors = Florvaag E, Johansson SG, Irgens Å, de Pater GH | title = IgE-sensitization to the cough suppressant pholcodine and the effects of its withdrawal from the Norwegian market | journal = Allergy | volume = 66 | issue = 7 | pages = 955–60 | date = July 2011 | pmid = 21241314 | doi = 10.1111/j.1398-9995.2010.02518.x | s2cid = 21048759 }}</ref> A corresponding fall in anaesthesia deaths followed.<ref name=pmid23283141/>

A similar disparity exists between NMBA anaphylaxis rates in Australia, where pholcodine consumption is high and the US, where pholcodine is banned.<ref>{{cite journal | vauthors = Sadleir PH, Clarke RC, Bunning DL, Platt PR | title = Anaphylaxis to neuromuscular blocking drugs: incidence and cross-reactivity in Western Australia from 2002 to 2011 | journal = British Journal of Anaesthesia | volume = 110 | issue = 6 | pages = 981–7 | date = June 2013 | pmid = 23335568 | doi = 10.1093/bja/aes506 | doi-access = free }}</ref> In the US, anaphylaxis rates are so low that some anaesthetists question the existence of such reactions to NMBAs.<ref>{{cite journal | vauthors = Levy JH | title = Anaphylactic reactions to neuromuscular blocking drugs: are we making the correct diagnosis? | journal = Anesthesia and Analgesia | volume = 98 | issue = 4 | pages = 881–2 | date = April 2004 | pmid = 15041566 | doi = 10.1213/01.ANE.0000115146.70209.4B | doi-access = free }}</ref> Conversely, Australian anaesthetists have requested a ban on pholcodine<ref>{{cite journal | vauthors = Crilly H, Rose M |title=Anaphylaxis and anaesthesia–can treating a cough kill? |journal=Australian Prescriber |volume=37 |issue=3 |year=2014 |pages=74–76 |doi=10.18773/austprescr.2014.032 |doi-access=free }}</ref> due to the high anaphylaxis rate in the country.<ref>{{cite journal | vauthors = Katelaris CH, Kurosawa M, Moon HB, Borres M, Florvaag E, Johansson SG | title = Pholcodine consumption and immunoglobulin E-sensitization in atopics from Australia, Korea, and Japan | journal = Asia Pacific Allergy | volume = 4 | issue = 2 | pages = 86–90 | date = April 2014 | pmid = 24809013 | pmc = 4005347 | doi = 10.5415/apallergy.2014.4.2.86 }}</ref> However, the [[Therapeutic Goods Administration]] declined the request in January 2015,<ref>{{cite web | first = Julia | last = Medew | title = Cough medicine alert over surgery | work = The Age | date = 5 January 2015 | url = http://www.theage.com.au/national/health/cough-medicine-alert-over-surgery-20150105-12i8sq.html | access-date = 5 January 2015 | archive-date = 7 January 2015 | archive-url = https://web.archive.org/web/20150107181404/http://www.theage.com.au/national/health/cough-medicine-alert-over-surgery-20150105-12i8sq.html | url-status = live }}</ref> pending further reviews to follow. In February 2023, the Therapeutic Goods Administration reversed its previous decision and banned products containing pholcodine.<ref>{{Cite web |title=Pholcodine cough medicines cancelled by the TGA and recalled from pharmacies for safety reasons |url=https://www.tga.gov.au/news/media-releases/pholcodine-cough-medicines-cancelled-tga-and-recalled-pharmacies-safety-reasons |access-date=28 February 2023 |website=Therapeutic Goods Administration |archive-date=28 February 2023 |archive-url=https://web.archive.org/web/20230228033656/https://www.tga.gov.au/news/media-releases/pholcodine-cough-medicines-cancelled-tga-and-recalled-pharmacies-safety-reasons |url-status=live }}</ref>

In contrast, the [[European Medicines Agency]]'s 2012 "Assessment report for Pholcodine containing medicinal products" concludes this:
The Committee considered that evidence of an association between pholcodine use and development of
NMBA-related anaphylaxis is circumstantial, not entirely consistent and therefore does not support the
conclusion that there is a significant risk of cross-sensitisation to NMBAs and subsequent development
of anaphylaxis during surgery.<ref>{{cite web | title = Assessment report for Pholcodine containing medicinal products | url = http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Pholcodine_31/WC500124716.pdf?UNLID=559983127201732412541 | work = European Medicines Agency | date = 17 February 2012 | access-date = 24 March 2017 | archive-date = 16 December 2017 | archive-url = https://web.archive.org/web/20171216034453/http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Pholcodine_31/WC500124716.pdf?UNLID=559983127201732412541 | url-status = dead }}</ref>

In September 2022, the European Medicines Agency (EMA) started reviewing its position<ref>{{cite web |title=Review of pholcodine medicines started |url=https://www.ema.europa.eu/en/news/review-pholcodine-medicines-started |date=9 February 2022 |work=European Medicines Agency |access-date=13 October 2022 |archive-date=13 October 2022 |archive-url=https://web.archive.org/web/20221013190603/https://www.ema.europa.eu/en/news/review-pholcodine-medicines-started |url-status=live }}</ref> at the request of the French [[Agence_nationale_de_sécurité_du_médicament_et_des_produits_de_santé|ANSM]], which withdrew all pholcodine-containing medicines<ref>{{cite web | language=french | title=Pholcodine: Suspension des autorisations de mise sur le marché et retrait de toutes les boîtes de sirop contenant de la pholcodine en raison d'un risque d'allergie croisée avec les curares | trans-title=Pholcodine: Suspension of marketing authorizations and withdrawal of all boxes of syrup containing pholcodine due to a risk of cross allergy with curares | work=Agence nationale de sécurité du médicament et des produits de santé (ANSM) | trans-work=National Agency for the Safety of Medicines and Health Products | url=https://ansm.sante.fr/informations-de-securite/pholcodine-suspension-des-autorisations-de-mise-sur-le-marche-et-retrait-de-toutes-les-boites-de-sirop-contenant-de-la-pholcodine-en-raison-dun-risque-dallergie-croisee-avec-les-curares | access-date=13 October 2022 | archive-date=13 October 2022 | archive-url=https://web.archive.org/web/20221013190555/https://ansm.sante.fr/informations-de-securite/pholcodine-suspension-des-autorisations-de-mise-sur-le-marche-et-retrait-de-toutes-les-boites-de-sirop-contenant-de-la-pholcodine-en-raison-dun-risque-dallergie-croisee-avec-les-curares | url-status=live }}</ref> after preliminary results from a local study showed an increased risk of anaphylaxis after pholcodine use.<ref>{{cite web |title=Rationale for the Triggering of Procedure Under Article 107i of Directive 2001/83/EE on Pholcodine |url=https://www.ema.europa.eu/en/documents/referral/pholcodine-containing-medicinal-products-article-107i-referral-rationale-triggering_en.pdf |date=August 2022 |work=French Competent Authority (ANSM - French National Agency for Medicines and Health Products Safety) Agence nationale de sécurité du médicament et des produits de santé |access-date=13 October 2022 |archive-date=12 October 2022 |archive-url=https://web.archive.org/web/20221012144745/https://www.ema.europa.eu/en/documents/referral/pholcodine-containing-medicinal-products-article-107i-referral-rationale-triggering_en.pdf |url-status=live }}</ref> The EMA review concluded on 14 December 2022 with the recommendation that pholcodine be withdrawn from the EU market.<ref>{{cite web |title=EMA recommends withdrawal of pholcodine medicines from EU market |url=https://www.ema.europa.eu/en/medicines/human/referrals/pholcodine-containing-medicinal-products |work=European Medicines Agency |date=1 December 2022 |access-date=20 December 2022 |archive-date=20 December 2022 |archive-url=https://web.archive.org/web/20221220090630/https://www.ema.europa.eu/en/medicines/human/referrals/pholcodine-containing-medicinal-products |url-status=live }}</ref> This decision was ratified by the European Commission in March 2023.<ref>{{Cite web | title = Pholcodine medicines withdrawn from EU market | date = 6 March 2023 | work = European Medicines Agency | url = https://www.ema.europa.eu/en/documents/referral/pholcodine-medicines-withdrawn-eu-market_en.pdf | access-date = 3 July 2023 | archive-date = 5 April 2023 | archive-url = https://web.archive.org/web/20230405232436/https://www.ema.europa.eu/en/documents/referral/pholcodine-medicines-withdrawn-eu-market_en.pdf | url-status = live }}</ref> The UK government recalled all products containing pholcodine in March 2023.<ref>{{cite web |url=https://www.gov.uk/drug-device-alerts/class-2-medicines-recall-various-marketing-authorisation-holders-pholcodine-containing-products-el-23-a-slash-09 |date=14 March 2023 |author=Medicines and Healthcare products Regulatory Agency |title=Class 2 Medicines Recall: Various Marketing Authorisation Holders, pholcodine-containing products, EL (23)A/09 |access-date=14 March 2023 |archive-date=14 March 2023 |archive-url=https://web.archive.org/web/20230314111152/https://www.gov.uk/drug-device-alerts/class-2-medicines-recall-various-marketing-authorisation-holders-pholcodine-containing-products-el-23-a-slash-09 |url-status=live }}</ref>

== References ==
{{Reflist}}

{{Cough and cold preparations}}
{{Opioidergics}}
{{Portal bar | Medicine}}
{{Authority control}}

[[Category:Semisynthetic opioids]]
[[Category:Antitussives]]
[[Category:4,5-Epoxymorphinans]]
[[Category:4-Morpholinyl compounds]]
[[Category:Phenol ethers]]
[[Category:Secondary alcohols]]
[[Category:Heterocyclic compounds with 5 rings]]
[[Category:Withdrawn drugs]]