Codeine and Human Genetics

Analgesic properties of codeine are hinged on its conversion to morphine. Gene CYP2D6 is the one responsible for the conversion of codeine to morphine [1]. Therefore, Codeine metabolizes is the determining factor regarding the effectiveness of the drug. Gene variations of CYP2D6 affect codeine's metabolizes rate [2]. Some variations of the gene result to fast codeine metabolisms while others result to slow metabolism. The percentage of codeine metabolized to morphine is higher in persons with three or more copies of normal function alleles [3]. Conversely, individuals lacking active copies of gene CYPED6 have a low percentage of morphine conversion.

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Molecular Mechanism of Codeine

Codeine is an example of an opiate and a naturally occurring phenanthrene that has antitussive, analgesic, and antidiarrheal activities. Codeine copies the working of endogenous opioids where it binds itself to opioid receptors at sites of the central nervous system [4]. Resulting simulation of the mu subtype receptors results in a decrease of the nociceptive neurotransmitters released. Subsequently, morphine triggers opening of G-protein inwards rectifying potassium channels and shutting the N-type calcium channels that are voltage-gated [5]. Reduced neuronal excitability and hyperpolarization happen after the potassium channels are rectified and the Calcium channels blocked. Gut mu subtype opioid receptor simulation causes reduced intestinal mobility and delayed intestinal transit periods. Actions of codeine in the medulla's cough center mediate antitussive activity.

Clinical Relevance of Codeine

Codeine has two main clinical applications: reliving mild to moderate-severe pain [6] and suppressing cough [7]. Genetic testing of the gene CYP2D6 variants is available for public use and can be employed in predicting the reaction of the patient to codeine medications [8]. Where the phenotype of CYP2D6 is not routinely assessed, clinicians can adopt the traditional trial and error method in prescribing codeine. In this method, doses of analgesic prodrugs are increased while pain adjuvants are added where the analgesic response is below optimum level [9].

References

[1] Agarwal, D., Udoji, A.M., Trescot, A. Genetic Testing for Opioid Pain Management: A Primer. 2017 Feb, [Cited 2018 Nov 24] 6:93105, Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447546/pdf/40122_2017_Article_69.pdf

[2] Bernard, S., Neville, K.A, Nguyen, A.T., Flockhart, D.A. Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications. 2005 Dec [Cited 2018 Nov 24] 11(2): 126-135, Available from: http://theoncologist.alphamedpress.org/content/11/2/126.full

[3] Dean, Laura. Codeine Therapy and CYP2D6 Genotype. Medical Genetics Summaries. 2012 Sep [Cited 2018 Nov 24] Available from: https://www.ncbi.nlm.nih.gov/books/NBK100662/

[4] Cotton, S. CODEINE AND OXYCODONE: Painkillers that can become addictive. Molecule of the Month. 2015 Dec, [Cited 2018 Nov 24] Available from: http://www.chm.bris.ac.uk/motm/codeine/codeineh.htm

[5] National Center for Biotechnology Information. PubChem Compound Database; CID=5284371, https://pubchem.ncbi.nlm.nih.gov/compound/5284371 (accessed Nov. 24, 2018).

[6] WynnJones, W., Casely, E., Laycock, H., Bantel, C. Codeine: the 'safe' analgesic? British Journal of Anaesthesia. 2013 May [Cited 2018 Nov 24] 110(5): 843-844, Available from: https://academic.oup.com/bja/article/110/5/843/331212

[7] Bolster, D.C., Davenport, P.W. Codeine and Cough: An Ineffective Gold Standard. Current Opinion in Allergy and Clinical Immunology. 2007 Feb [Cited 2018 Nov 24] 7(1):3236 Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921574/#

[8] Pinto, N., Dolan, M.E., Clinically Relevant Genetic Variations in Drug Metabolizing Enzymes. 2011 Jun [Cited 2018 Nov 24] 12(5):487-497. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110519/

[9] Johnson MI, Radford H (2016) CYP2D6 Polymorphisms and Response to Codeine and Tramadol. Analg Resusc: Curr Res 5:1. doi:10.4172/2324-903X.1000e106