Pholcodine is anopioidcough suppressant (antitussive). It helps suppress unproductivecoughs and also has a mildsedative effect, but has little or noanalgesic effects. It is also known as morpholinylethylmorphine and homocodeine.
Pholcodine is found in certain coughlozenges,[2] and more commonly as an oral solution, typically 5 mg / 5 ml. Adult dosage is 5-10 ml up to 3-4 times daily.[3] Pholcodine now largely replaces the previously more commoncodeine 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agent but by 2023 concerns over its association withanaphylaxis in some circumstances meant that it has been withdrawn from sale in many territories.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 aSchedule I drug, the most highly controlled drug category.[4]
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of a review of post-marketing safety data by the MHRA, all pholcodine-containing medicines are being recalled and withdrawn from the UK as a precaution.[5] The available data has demonstrated that pholcodine use, particularly in the twelve months before general anesthesia with NMBAs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, theEuropean Medicines Agency recommended their withdrawal in the EU.[6] As of February 2023[update], the AustralianTherapeutic Goods Administration canceled the registration of pholcodine.[7][8]
Pholcodine is readily absorbed from thegastrointestinal tract and freely crosses theblood–brain barrier. It acts primarily on thecentral nervous system (CNS), causing depression of thecough reflex, partly by a direct effect on thecough centre in themedulla. It is metabolized in theliver and its action may be prolonged in individuals withhepatic insufficiency (i.e. liver problems). Its use is therefore contraindicated in patients with liver disease, while care is advised in patients with hepatic impairment.
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 isconjugatedmorphine, which may be detectable for days or weeks after the last dose. This could trigger a positive result for opiates in aurine drug testing program.[9][10]
Administration of pholcodine causes production of antibodies linked with fatalities during surgery, when essentialneuromuscular blocking agents (NMBAs) are administered to prevent patient movement undergeneral anaesthesia.[12] 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 ofanaphylaxis during anaesthesia.[13]
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.[13] Norway withdrew pholcodine from the market in 2007, and the prevalence of anti-suxamethonium antibodies fell by over 80% in two years.[14] A corresponding fall in anaesthesia deaths followed.[13]
A similar disparity exists between NMBA anaphylaxis rates in Australia, where pholcodine consumption is high and the US, where pholcodine is banned.[15] In the US, anaphylaxis rates are so low that some anaesthetists question the existence of such reactions to NMBAs.[16] Conversely, Australian anaesthetists have requested a ban on pholcodine[17] due to the high anaphylaxis rate in the country.[18] However, theTherapeutic Goods Administration declined the request in January 2015,[19] pending further reviews to follow. In February 2023, the Therapeutic Goods Administration reversed its previous decision and banned products containing pholcodine.[20]
In contrast, theEuropean 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 ofNMBA-related anaphylaxis is circumstantial, not entirely consistent and therefore does not support theconclusion that there is a significant risk of cross-sensitisation to NMBAs and subsequent developmentof anaphylaxis during surgery.[21]
In September 2022, the European Medicines Agency (EMA) started reviewing its position[22] at the request of the FrenchANSM, which withdrew all pholcodine-containing medicines[23] after preliminary results from a local study showed an increased risk of anaphylaxis after pholcodine use.[24] The EMA review concluded on 14 December 2022 with the recommendation that pholcodine be withdrawn from the EU market.[25] This decision was ratified by the European Commission in March 2023.[26] The UK government recalled all products containing pholcodine in March 2023.[27]
^Maurer HH, Fritz CF (December 1990). "Toxicological detection of pholcodine and its metabolites in urine and hair using radio immunoassay, fluorescence polarisation immunoassay, enzyme immunoassay, and gas chromatography-mass spectrometry".International Journal of Legal Medicine.104 (1):43–6.doi:10.1007/BF01816483.PMID11453092.S2CID5935454.
^Baselt R (2008).Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1258–1260.
^Florvaag E, Johansson SG (August 2009). "The pholcodine story".Immunology and Allergy Clinics of North America.29 (3):419–27.doi:10.1016/j.iac.2009.04.002.PMID19563989.
^Florvaag E, Johansson SG, Irgens Å, de Pater GH (July 2011). "IgE-sensitization to the cough suppressant pholcodine and the effects of its withdrawal from the Norwegian market".Allergy.66 (7):955–60.doi:10.1111/j.1398-9995.2010.02518.x.PMID21241314.S2CID21048759.
