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<meta name="keywords" content="C1837160, codeine response, codeine, ultrarapid metabolism of, cyp2d6, finding, autosomal dominant, autosomal recessive, birth defects, chromosomal disease, chromosome, clinical features, clinical findings, clinical genetics, clinical recommendations, clinvar, congenital chromosomal disease, consumer genetic resources, cytogenetic location, disease characteristics, disease definitions, disease descriptions, disease ontology, disease synonyms, disease vocabulary, dysmorphology, entrez, familial disease, gene, gene-disease relationship, genereviews, genetic disease, genetic disorder, genetic terminology, genetic testing registry, genetics home reference, genomic disease, gtr, hereditary disease, heritable disease, hpo, human phenotype ontology, inherited disease, management guidelines, maternal inheritance, medgen, medical genetics, medical subject headings, mesh, mitochondrial inheritance, mode of inheritance, national center for biotechnology information, national institutes of health, national library of medicine, ncbi, nih, nlm, omim, ordo, orphanet, paternal inheritance, phenome, position statements, professional practice guidelines, rare disease, reference sequence, refseq, snomed ct, syndrome, undiagnosed diseases, x-linked recessive" /><meta name="description" content="Codeine, an opioid analgesic, is used for the treatment of pain. It is metabolized by cytochrome P450-2D6 (CYP2D6) to morphine, an active metabolite with pain-relief action. The CYP2D6 gene has many polymorphisms that result in different enzyme activities. An individual can be an ultrarapid, normal, intermediate, or poor metabolizer of codeine, based on their CYP2D6 genotype. The CYP2D6 ultrarapid phenotype is associated with a higher risk of severe toxicity when treated with codeine, due to increased metabolism of codeine and thus enhanced morphine formation. Conversely, the CYP2D6 poor metabolizer phenotype is associated with ineffective pain relief from codeine treatment due to reduced formation of morphine. Accordingly, therapeutic recommendations for codeine based on an individual’s CYP2D6 genotype have been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in Clinical Pharmacology and Therapeutics and are available on the PharmGKB website." /><meta name="robots" content="index,nofollow,noarchive" />
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<!--
|
||
UID=324697
|
||
ConceptID=C1837160
|
||
-->
|
||
<!--imgCountBooks = 0--><h1 class="medgenTitle"><div class="MedGenTitleText">Codeine response</div></h1><div class="aux"><div class="resc"><dl class="rprtid"><dt>MedGen UID: </dt><dd>324697</dd><dt><span class="dotprefix"> •</span>Concept ID: </dt><dd><a href="/medgen/docs/help/#sources" target="_blank" title="Concept Unique Identifier from NLM's Unified Medical Language system (UMLS) Click for more information."><span class="highlight" style="background-color:">C1837160</span></a></dd><dt><span class="dotprefix"> •</span></dt><dd>Finding</dd></dl></div></div><table class="medgenTable"><tbody><tr><td>Synonym:</td>
|
||
<td>Codeine, ultrarapid metabolism of</td></tr>
|
||
<tr><td>Drug:</td>
|
||
<td>
|
||
<div class="divPopper rprt" id="drug_3517"><div><strong>Codeine</strong><div class="aux"><div class="resc"><dl class="rprtid"><dt>MedGen UID: </dt><dd>3517</dd><dt><span class="dotprefix"> •</span>Concept ID: </dt><dd><a href="/medgen/docs/help/#sources" target="_blank" title="Concept Unique Identifier from NLM's Unified Medical Language system (UMLS) Click for more information.">C0009214</a></dd><dt><span class="dotprefix"> •</span></dt><dd>Pharmacologic Substance</dd></dl></div></div></div>
|
||
<div class="spaceAbove">A naturally occurring phenanthrene alkaloid and opioid agonist with analgesic, antidiarrheal and antitussive activities. Codeine mimics the actions of endogenous opioids by binding to the opioid receptors at many sites within the central nervous system (CNS). Stimulation of mu-subtype opioid receptors results in a decrease in the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline; in addition, the codeine metabolite morphine induces opening of G-protein-coupled inwardly rectifying potassium (GIRK) channels and blocks the opening of N-type voltage-gated calcium channels, resulting in hyperpolarization and reduced neuronal excitability. Stimulation of gut mu-subtype opioid receptors results in a reduction in intestinal motility and delayed intestinal transit times. Antitussive activity is mediated through codeine''s action on the cough center in the medulla. [from NCI]</div></div>
|
||
<div class="hangingIndent"><a title="click for more information" class="jig-ncbipopper" href="#drug_3517" data-jigconfig="hasArrow: true, openEvent: 'click', closeEvent: 'mouseout', openAnimation: 'fadeIn', closeAnimation: 'fadeOut', triggerPosition: 'center right', destPosition: 'center left', arrowDirection: 'left'">Codeine</a></div></td></tr>
|
||
<tr><td colspan="2" class="small"> </td></tr><tr><td><a class="help jig-ncbi-popper" data-jig="ncbipopper" href="#target-gene-loc">Gene (location):<img class="pulldown" src="//static.pubmed.gov/portal/portal3rc.fcgi/4223267/img/4204968" /></a><div class="display-none" id="target-gene-loc">
|
||
Gene(s) directly associated with<br />
|
||
this condition or phenotype.</div></td>
|
||
<td><a target="_blank" title="CYP2D6 - ID: 1565 - NCBI Gene" href="/gene/1565" class="medgenPMinfo">CYP2D6</a> (22q13.2)</td></tr>
|
||
<tr><td colspan="2" class="small"> </td></tr><tr><td>OMIM<span class="superscript">®</span>:</td>
|
||
<td><a href="https://omim.org/entry/124030" target="_blank">124030</a>; <a href="https://omim.org/entry/608902" target="_blank">608902</a></td></tr>
|
||
</tbody></table></div><div class="rprt-body jig-ncbiinpagenav" data-jigconfig="smoothScroll: false, gotoTopLink: true, gotoTopLinkText: '', gotoTopLinkAttrs: {'title': 'Go to the top of the page'},allHeadingLevels: ['h1'], topOfPageTOC: true, tocId: 'my-toc'"><div id="rprt-tabs-1" class="rprt-tab"><div id="tb-termsProp-1"><div class="leftCol mgCol"><div>
|
||
<div class="portlet mgSection" id="ID_100">
|
||
<div class="portlet_head mgSectionHead ui-widget-header"><h1 class="nl" id="Definition">Definition</h1><a sid="100" href="#" class="portlet_shutter" title="Show/hide content"></a></div>
|
||
<div class="portlet_content ln">Codeine, an opioid analgesic, is used for the treatment of pain. It is metabolized by cytochrome P450-2D6 (CYP2D6) to morphine, an active metabolite with pain-relief action. The CYP2D6 gene has many polymorphisms that result in different enzyme activities. An individual can be an ultrarapid, normal, intermediate, or poor metabolizer of codeine, based on their CYP2D6 genotype. The CYP2D6 ultrarapid phenotype is associated with a higher risk of severe toxicity when treated with codeine, due to increased metabolism of codeine and thus enhanced morphine formation. Conversely, the CYP2D6 poor metabolizer phenotype is associated with ineffective pain relief from codeine treatment due to reduced formation of morphine. Accordingly, therapeutic recommendations for codeine based on an individual’s CYP2D6 genotype have been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in Clinical Pharmacology and Therapeutics and are available on the PharmGKB website. [from <a title="The Pharmacogenomics Knowledge Base" href="http://www.pharmgkb.org" class="defSource" target="_blank">PharmGKB</a>]</div>
|
||
</div>
|
||
|
||
<div class="portlet mgSection" id="ID_117">
|
||
<div class="portlet_head mgSectionHead ui-widget-header"><h1 class="nl" id="Additional_description">Additional description</h1><a sid="117" href="#" class="portlet_shutter" title="Show/hide content"></a></div>
|
||
<div class="portlet_content ln"><div class="mgSection"><strong>From Medical Genetics Summaries</strong><br />Codeine is used to relieve mild to moderately severe pain, and it belongs to the drug class of opioid analgesics. Codeine has also been prescribed to prevent coughing, though the antitussive administration is most often in liquid formulations and in conjunction with other medications.
|
||
The hepatic CYP2D6 enzyme metabolizes a quarter of all prescribed drugs, including codeine. The CYP2D6 enzyme converts codeine into its active metabolite, morphine, which provides its analgesic effect. Consequently, pain relief may be inadequate in individuals who have 2 inactive copies of CYP2D6 (“poor metabolizers”, PMs), because of reduced morphine levels.
|
||
In contrast, individuals who have more than 2 normal-function copies of the CYP2D6 gene (“ultrarapid metabolizers”, UMs) are able to metabolize codeine to morphine more rapidly and more completely. As a result, even with therapeutic doses of codeine, these individuals may experience the symptoms of morphine overdose, which include extreme sleepiness, confusion, and shallow breathing, which in some instances can be fatal. Nursing mothers with ultrarapid CYP2D6 metabolism may also produce breast milk containing higher than expected levels of morphine that can lead to severe adverse events in their infants.
|
||
The FDA-drug label for codeine states that even at labeled dosage regimens, individuals who are UMs may have life-threatening or fatal respiratory depression or experience signs of overdose. The label also contains a boxed warning, which states that respiratory depression and death have occurred in children who received codeine following tonsillectomy, adenoidectomy, or both, and had evidence of being CYP2D6 UMs.
|
||
The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that for an individual identified as a CYP2D6 UM, another analgesic should be used to avoid the risk of severe toxicity with a “normal” dose of codeine. CPIC also recommends avoiding codeine in individuals identified as CYP2D6 PMs due to the possibility of lack of effect. The Dutch Pharmacogenetics Working Group (DPWG) have published codeine dosing recommendations based on CYP2D6 genotype, and condition being treated (cough or pain), typical dosing, and additional risk factors, such as reduced kidney function or co-medication with CYP3A4 inhibitors. For UMs, the DPWG recommends an alternative to codeine for the treatment of pain (for example, oxycodone). <a target="_blank" href="https://www.ncbi.nlm.nih.gov/books/NBK100662">https://www.ncbi.nlm.nih.gov/books/NBK100662</a></div></div>
|
||
</div>
|
||
|
||
<div class="portlet mgSection" id="ID_105">
|
||
<div class="portlet_head mgSectionHead ui-widget-header"><h1 class="nl" id="Professional_guidelines">Professional guidelines</h1><a sid="105" href="#" class="portlet_shutter" title="Show/hide content"></a></div>
|
||
<div class="portlet_content ln"><h3 class="subhead">PubMed<a class="help jig-ncbi-popper" data-jig="ncbipopper" href="#guidelinesHelpPM"><img class="pulldown" src="//static.pubmed.gov/portal/portal3rc.fcgi/4223267/img/4204968" /></a></h3>
|
||
<div class="nl"><a target="_blank" href="/pubmed/30921525">Clinical Practice Guideline: Tonsillectomy in Children (Update)-Executive Summary.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Mitchell RB,
|
||
Archer SM,
|
||
Ishman SL,
|
||
Rosenfeld RM,
|
||
Coles S,
|
||
Finestone SA,
|
||
Friedman NR,
|
||
Giordano T,
|
||
Hildrew DM,
|
||
Kim TW,
|
||
Lloyd RM,
|
||
Parikh SR,
|
||
Shulman ST,
|
||
Walner DL,
|
||
Walsh SA,
|
||
Nnacheta LC</span><br />
|
||
<span class="medgenPMjournal">Otolaryngol Head Neck Surg</span>
|
||
2019 Feb;160(2):187-205.
|
||
doi: 10.1177/0194599818807917.
|
||
<span class="bold">PMID: </span><a href="/pubmed/30921525" target="_blank">30921525</a></div>
|
||
|
||
<div class="nl"><a target="_blank" href="/pubmed/30798778">Clinical Practice Guideline: Tonsillectomy in Children (Update).</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Mitchell RB,
|
||
Archer SM,
|
||
Ishman SL,
|
||
Rosenfeld RM,
|
||
Coles S,
|
||
Finestone SA,
|
||
Friedman NR,
|
||
Giordano T,
|
||
Hildrew DM,
|
||
Kim TW,
|
||
Lloyd RM,
|
||
Parikh SR,
|
||
Shulman ST,
|
||
Walner DL,
|
||
Walsh SA,
|
||
Nnacheta LC</span><br />
|
||
<span class="medgenPMjournal">Otolaryngol Head Neck Surg</span>
|
||
2019 Feb;160(1_suppl):S1-S42.
|
||
doi: 10.1177/0194599818801757.
|
||
<span class="bold">PMID: </span><a href="/pubmed/30798778" target="_blank">30798778</a></div>
|
||
|
||
<div class="nl"><a target="_blank" href="/pubmed/28699646">Review of Opioid Pharmacogenetics and Considerations for Pain Management.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Owusu Obeng A,
|
||
Hamadeh I,
|
||
Smith M</span><br />
|
||
<span class="medgenPMjournal">Pharmacotherapy</span>
|
||
2017 Sep;37(9):1105-1121.
|
||
Epub 2017 Sep 6
|
||
doi: 10.1002/phar.1986.
|
||
<span class="bold">PMID: </span><a href="/pubmed/28699646" target="_blank">28699646</a></div>
|
||
<div><a target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/?term=(%22codeine%22%5Btiab%3A~0%5D)%20AND%20(%22english%20and%20humans%22%5BFilter%5D)%20AND%20(%20(%22practice%20guideline%22%5BFilter%5D)%20OR%20(practice*%5Btitl%5D%20AND%20(guideline%5Btitl%5D%20OR%20parameter%5Btitl%5D%20OR%20resource%5Btitl%5D%20OR%20bulletin%5Btitl%5D%20OR%20best%5Btitl%5D))%20OR%20(genetic*%5Btitl%5D%20AND%20(evaluation%5Btitl%5D%20OR%20counseling%5Btitl%5D%20OR%20screening%5Btitl%5D%20OR%20test*%5Btitl%5D))%20OR%20(clinical%5Btitl%5D%20AND%20((expert%5Btitl%5D%20AND%20consensus%5Btitl%5D)%20OR%20utility%5Btitl%5D%20OR%20guideline*%5Btitl%5D))%20OR%20(management%5Btitl%5D%20AND%20(clinical%5Btitl%5D%20OR%20diagnos*%5Btitl%5D%20OR%20recommendation%5Btitl%5D%20OR%20pain%5Btitl%5D%20OR%20surveillance%5Btitl%5D%20OR%20emergency%5Btitl%5D%20OR%20guideline*%5Btitl%5D%20OR%20therap*))%20OR%20(treatment%5Btitl%5D%20AND%20((evaluation%5Btitl%5D%20AND%20diagnosis%5Btitl%5D)%20OR%20(assessment%5Btitl%5D%20AND%20prevention%5Btitl%5D)%20OR%20therap*))%20OR%20(Diagnos*%5Btitl%5D%20AND%20(prenatal%5Btitl%5D%20OR%20treatment%5Btitl%5D%20OR%20follow-up%5Btitl%5D%20OR%20statement%5Btitl%5D%20OR%20criteria%5Btitl%5D%20OR%20newborn%5Btitl%5D%20OR%20differential%5Btitl%5D%20OR%20neonatal%5Btitl%5D%20OR%20neonate%5Btitl%5D))%20OR%20(guideline*%5Btitl%5D%20AND%20(pharmacogenetic*%5Btitl%5D%20OR%20recommendation%5Btitl%5D%20OR%20therap*%5Btitl%5D%20OR%20evidence-based%5Btitl%5D%20OR%20consensus%5Btitl%5D%20OR%20(technical%5Btitl%5D%20AND%20standard*%5Btitl%5D)%20OR%20(molecular%5Btitl%5D%20AND%20testing%5Btitl%5D)))%20OR%20(risk%5Btitl%5D%20AND%20assessment%5Btitl%5D)%20OR%20(recommendation*%5Btitl%5D%20AND%20(statement%5Btitl%5D%20OR%20Evidence-based%5Btitl%5D%20OR%20Consensus%5Btitl%5D))%20OR%20(care%20AND%20((Patient%5Btitl%5D%20AND%20standard*%5Btitl%5D)%20OR%20primary%5Btitl%5D%20OR%20psychosocial%5Btitl%5D))%20OR%20(Health%5Btitl%5D%20AND%20supervision%5Btitl%5D)%20OR%20(statement%5Btitl%5D%20AND%20(policy%5Btitl%5D%20OR%20position%5Btitl%5D%20OR%20Consensus%5Btitl%5D))%20OR%20(pharmacogenetics%5Btitl%5D%20AND%20(Dosing%5Btitl%5D%20OR%20therap*%5Btitl%5D%20OR%20genotype*%5Btitl%5D%20OR%20drug*%5Btitl%5D))%20OR%20(Chemotherapy%5Btitl%5D%20AND%20decision*%5Btitl%5D)%20OR%20(screening%5Btitl%5D%20AND%20(newborn%5Btitl%5D%20OR%20neonat*%5Btitl%5D%20OR%20detection%5Btitl%5D%20OR%20diagnos*%5Btitl%5D))%20OR%20(criteria%5Btitl%5D%20OR%20genotype*%5Btitl%5D)%20)%20NOT%20(%22Case%20reports%22%5BPublication%20type%5D%20OR%20%22clinical%20study%22%5BPublication%20Type%5D%20OR%20%22randomized%20controlled%20trial%22%5BPublication%20Type%5D)" title="PubMed search">See all (243)</a></div><h3 class="subhead">Curated<a class="help jig-ncbi-popper" data-jig="ncbipopper" href="#guidelinesHelpCurated"><img class="pulldown" src="//static.pubmed.gov/portal/portal3rc.fcgi/4223267/img/4204968" /></a></h3><h3 class="nl vspace"><a href="https://www.g-standaard.nl/risicoanalyse/M0002415.pdf" target="_blank">Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Guidelines [Internet]. Netherlands. Codeine - CYP2D6</a></h3>
|
||
</div>
|
||
</div>
|
||
<div class="display-none help-popup" id="guidelinesHelpPM">These guidelines are articles in PubMed that match specific search criteria developed by MedGen to capture the most relevant practice guidelines. This list may not be comprehensive and may include broader topics as well. See the <a href="/medgen/docs/faq/" title="Frequently asked questions" target="_blank">FAQ</a> for details.</div><div class="display-none help-popup" id="guidelinesHelpCurated">These guidelines are manually curated by the MedGen team
|
||
to supplement articles available in PubMed. See the <a href="/medgen/docs/faq/" title="Frequently asked questions" target="_blank">FAQ</a> for details.</div>
|
||
<div class="portlet mgSection" id="ID_103">
|
||
<div class="portlet_head mgSectionHead ui-widget-header"><h1 class="nl" id="Recent_clinical_studies">Recent clinical studies</h1><a sid="103" href="#" class="portlet_shutter" title="Show/hide content"></a></div>
|
||
<div class="portlet_content ln"><h3 class="subhead">Etiology</h3>
|
||
<div class="nl"><a target="_blank" href="/pubmed/31141989">A Single Site Population Study to Investigate CYP2D6 Phenotype of Patients with Persistent Non-Malignant Pain.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Radford H,
|
||
Simpson KH,
|
||
Rogerson S,
|
||
Johnson MI</span><br />
|
||
<span class="medgenPMjournal">Medicina (Kaunas)</span>
|
||
2019 May 28;55(6)
|
||
doi: 10.3390/medicina55060220.
|
||
<span class="bold">PMID: </span><a href="/pubmed/31141989" target="_blank">31141989</a><a href="/pmc/articles/PMC6631257" target="_blank" class="PubMedFree">Free PMC Article</a></div>
|
||
|
||
<div class="nl"><a target="_blank" href="/pubmed/23922910">A clinical tool for reducing central nervous system depression among neonates exposed to codeine through breast milk.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Kelly LE,
|
||
Chaudhry SA,
|
||
Rieder MJ,
|
||
't Jong G,
|
||
Moretti ME,
|
||
Lausman A,
|
||
Ross C,
|
||
Berger H,
|
||
Carleton B,
|
||
Hayden MR,
|
||
Madadi P,
|
||
Koren G</span><br />
|
||
<span class="medgenPMjournal">PLoS One</span>
|
||
2013;8(7):e70073.
|
||
Epub 2013 Jul 29
|
||
doi: 10.1371/journal.pone.0070073.
|
||
<span class="bold">PMID: </span><a href="/pubmed/23922910" target="_blank">23922910</a><a href="/pmc/articles/PMC3726489" target="_blank" class="PubMedFree">Free PMC Article</a></div>
|
||
<div><a target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Codeine%20response%22%20AND%20Etiology%2Fbroad%5Bfilter%5D%20%20AND%20%22english%20and%20humans%22%5Bfilter%5D%20NOT%20comment%5BPTYP%5D%20NOT%20letter%5BPTYP%5D" title="PubMed search">See all (2)</a></div><h3 class="subhead">Diagnosis</h3>
|
||
<div class="nl"><a target="_blank" href="/pubmed/31141989">A Single Site Population Study to Investigate CYP2D6 Phenotype of Patients with Persistent Non-Malignant Pain.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Radford H,
|
||
Simpson KH,
|
||
Rogerson S,
|
||
Johnson MI</span><br />
|
||
<span class="medgenPMjournal">Medicina (Kaunas)</span>
|
||
2019 May 28;55(6)
|
||
doi: 10.3390/medicina55060220.
|
||
<span class="bold">PMID: </span><a href="/pubmed/31141989" target="_blank">31141989</a><a href="/pmc/articles/PMC6631257" target="_blank" class="PubMedFree">Free PMC Article</a></div>
|
||
|
||
<div class="nl"><a target="_blank" href="/pubmed/23922910">A clinical tool for reducing central nervous system depression among neonates exposed to codeine through breast milk.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Kelly LE,
|
||
Chaudhry SA,
|
||
Rieder MJ,
|
||
't Jong G,
|
||
Moretti ME,
|
||
Lausman A,
|
||
Ross C,
|
||
Berger H,
|
||
Carleton B,
|
||
Hayden MR,
|
||
Madadi P,
|
||
Koren G</span><br />
|
||
<span class="medgenPMjournal">PLoS One</span>
|
||
2013;8(7):e70073.
|
||
Epub 2013 Jul 29
|
||
doi: 10.1371/journal.pone.0070073.
|
||
<span class="bold">PMID: </span><a href="/pubmed/23922910" target="_blank">23922910</a><a href="/pmc/articles/PMC3726489" target="_blank" class="PubMedFree">Free PMC Article</a></div>
|
||
<div><a target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Codeine%20response%22%20AND%20Diagnosis%2Fbroad%5Bfilter%5D%20%20AND%20%22english%20and%20humans%22%5Bfilter%5D%20NOT%20comment%5BPTYP%5D%20NOT%20letter%5BPTYP%5D" title="PubMed search">See all (2)</a></div><h3 class="subhead">Therapy</h3>
|
||
<div class="nl"><a target="_blank" href="/pubmed/31141989">A Single Site Population Study to Investigate CYP2D6 Phenotype of Patients with Persistent Non-Malignant Pain.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Radford H,
|
||
Simpson KH,
|
||
Rogerson S,
|
||
Johnson MI</span><br />
|
||
<span class="medgenPMjournal">Medicina (Kaunas)</span>
|
||
2019 May 28;55(6)
|
||
doi: 10.3390/medicina55060220.
|
||
<span class="bold">PMID: </span><a href="/pubmed/31141989" target="_blank">31141989</a><a href="/pmc/articles/PMC6631257" target="_blank" class="PubMedFree">Free PMC Article</a></div>
|
||
|
||
<div class="nl"><a target="_blank" href="/pubmed/23922910">A clinical tool for reducing central nervous system depression among neonates exposed to codeine through breast milk.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Kelly LE,
|
||
Chaudhry SA,
|
||
Rieder MJ,
|
||
't Jong G,
|
||
Moretti ME,
|
||
Lausman A,
|
||
Ross C,
|
||
Berger H,
|
||
Carleton B,
|
||
Hayden MR,
|
||
Madadi P,
|
||
Koren G</span><br />
|
||
<span class="medgenPMjournal">PLoS One</span>
|
||
2013;8(7):e70073.
|
||
Epub 2013 Jul 29
|
||
doi: 10.1371/journal.pone.0070073.
|
||
<span class="bold">PMID: </span><a href="/pubmed/23922910" target="_blank">23922910</a><a href="/pmc/articles/PMC3726489" target="_blank" class="PubMedFree">Free PMC Article</a></div>
|
||
<div><a target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Codeine%20response%22%20AND%20Therapy%2Fbroad%5Bfilter%5D%20%20AND%20%22english%20and%20humans%22%5Bfilter%5D%20NOT%20comment%5BPTYP%5D%20NOT%20letter%5BPTYP%5D" title="PubMed search">See all (2)</a></div><h3 class="subhead">Prognosis</h3>
|
||
<div class="nl"><a target="_blank" href="/pubmed/31141989">A Single Site Population Study to Investigate CYP2D6 Phenotype of Patients with Persistent Non-Malignant Pain.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Radford H,
|
||
Simpson KH,
|
||
Rogerson S,
|
||
Johnson MI</span><br />
|
||
<span class="medgenPMjournal">Medicina (Kaunas)</span>
|
||
2019 May 28;55(6)
|
||
doi: 10.3390/medicina55060220.
|
||
<span class="bold">PMID: </span><a href="/pubmed/31141989" target="_blank">31141989</a><a href="/pmc/articles/PMC6631257" target="_blank" class="PubMedFree">Free PMC Article</a></div>
|
||
|
||
<div class="nl"><a target="_blank" href="/pubmed/23922910">A clinical tool for reducing central nervous system depression among neonates exposed to codeine through breast milk.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Kelly LE,
|
||
Chaudhry SA,
|
||
Rieder MJ,
|
||
't Jong G,
|
||
Moretti ME,
|
||
Lausman A,
|
||
Ross C,
|
||
Berger H,
|
||
Carleton B,
|
||
Hayden MR,
|
||
Madadi P,
|
||
Koren G</span><br />
|
||
<span class="medgenPMjournal">PLoS One</span>
|
||
2013;8(7):e70073.
|
||
Epub 2013 Jul 29
|
||
doi: 10.1371/journal.pone.0070073.
|
||
<span class="bold">PMID: </span><a href="/pubmed/23922910" target="_blank">23922910</a><a href="/pmc/articles/PMC3726489" target="_blank" class="PubMedFree">Free PMC Article</a></div>
|
||
<div><a target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Codeine%20response%22%20AND%20Prognosis%2Fbroad%5Bfilter%5D%20%20AND%20%22english%20and%20humans%22%5Bfilter%5D%20NOT%20comment%5BPTYP%5D%20NOT%20letter%5BPTYP%5D" title="PubMed search">See all (2)</a></div><h3 class="subhead">Clinical prediction guides</h3>
|
||
<div class="nl"><a target="_blank" href="/pubmed/31141989">A Single Site Population Study to Investigate CYP2D6 Phenotype of Patients with Persistent Non-Malignant Pain.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Radford H,
|
||
Simpson KH,
|
||
Rogerson S,
|
||
Johnson MI</span><br />
|
||
<span class="medgenPMjournal">Medicina (Kaunas)</span>
|
||
2019 May 28;55(6)
|
||
doi: 10.3390/medicina55060220.
|
||
<span class="bold">PMID: </span><a href="/pubmed/31141989" target="_blank">31141989</a><a href="/pmc/articles/PMC6631257" target="_blank" class="PubMedFree">Free PMC Article</a></div>
|
||
|
||
<div class="nl"><a target="_blank" href="/pubmed/23922910">A clinical tool for reducing central nervous system depression among neonates exposed to codeine through breast milk.</a></div>
|
||
<div class="portlet_content ln"><span class="medgenPMauthor">Kelly LE,
|
||
Chaudhry SA,
|
||
Rieder MJ,
|
||
't Jong G,
|
||
Moretti ME,
|
||
Lausman A,
|
||
Ross C,
|
||
Berger H,
|
||
Carleton B,
|
||
Hayden MR,
|
||
Madadi P,
|
||
Koren G</span><br />
|
||
<span class="medgenPMjournal">PLoS One</span>
|
||
2013;8(7):e70073.
|
||
Epub 2013 Jul 29
|
||
doi: 10.1371/journal.pone.0070073.
|
||
<span class="bold">PMID: </span><a href="/pubmed/23922910" target="_blank">23922910</a><a href="/pmc/articles/PMC3726489" target="_blank" class="PubMedFree">Free PMC Article</a></div>
|
||
<div><a target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Codeine%20response%22%20AND%20Clinical%20prediction%20guides%2Fbroad%5Bfilter%5D%20%20AND%20%22english%20and%20humans%22%5Bfilter%5D%20NOT%20comment%5BPTYP%5D%20NOT%20letter%5BPTYP%5D" title="PubMed search">See all (2)</a></div></div>
|
||
</div>
|
||
|
||
<div class="portlet mgSection" id="ID_120">
|
||
<div class="portlet_head mgSectionHead ui-widget-header"><h1 class="nl" id="Therapeutic_recommendations">Therapeutic recommendations</h1><a sid="120" href="#" class="portlet_shutter" title="Show/hide content"></a></div>
|
||
<div class="portlet_content ln" id="therapeutic"><strong>From <a href="https://www.ncbi.nlm.nih.gov/books/NBK100662" target="_blank">Medical Genetics Summaries</a></strong><br /><div id="TheraputicContent"><div class="divPopper rprt" id="codeine_REF_3" style="display: none;">3. Codeine sulfate tablets for oral use [package insert]. Philadelphia, PA: Lannett Company, I.; 2019. Available from: <a href="https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5819bdf7-300e-45b8-8f3a-447b53656293" target="_blank">https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5819bdf7-300e-45b8-8f3a-447b53656293</a></div><div class="divPopper rprt" id="codeine_REF_19" style="display: none;">19. Zipursky, J. and D.N.
|
||
Juurlink, The Implausibility of Neonatal Opioid Toxicity from Breastfeeding.
|
||
Clin Pharmacol Ther, 2020. 108(5): p. 964-970.
|
||
</div><div class="divPopper rprt" id="codeine_REF_4" style="display: none;">4. Crews, K.R., A.A.
|
||
Monte, R.
|
||
Huddart, K.E.
|
||
Caudle, et al., Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy.
|
||
Clin Pharmacol Ther, 2021.
|
||
</div><div class="divPopper rprt" id="codeine_REF_5" style="display: none;">5. Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Guidelines [Internet]. Netherlands. Codeine - CYP2D6 [Cited June 2020]. Available from <a href="https://www.knmp.nl/" target="_blank">https://www.knmp.nl/</a> (Search for Pharmacogenetic Recommendations).</div><div class="divPopper rprt" id="codeine_REF_65" style="display: none;">65. Madadi, P., U.
|
||
Amstutz, M.
|
||
Rieder, S.
|
||
Ito, et al., Clinical practice guideline: CYP2D6 genotyping for safe and efficacious codeine therapy.
|
||
J Popul Ther Clin Pharmacol, 2013. 20(3): p. e369-96.
|
||
</div><p><b>This section contains excerpted</b>
|
||
<sup>1 </sup>
|
||
<b>information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.</b>
|
||
</p><h2>2019 Statement from the US Food and Drug Administration (FDA)</h2><p>Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultrarapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect.</p><p>Some individuals may be ultrarapid metabolizers because of a specific <i>CYP2D6</i> genotype (e.g., gene duplications denoted as <i>*1/*1xN</i> or <i>*1/*2xN</i>). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultrarapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). Therefore, individuals who are ultrarapid metabolizers should not use codeine sulfate tablets.</p><p><b>Please review the complete therapeutic recommendations that are located here:</b>
|
||
(<a title="click for more information" class="jig-ncbipopper s_TOP" href="#codeine_REF_3" data-jigconfig="hasArrow: true, openEvent: 'click', closeEvent: 'mouseout', openAnimation: 'fadeIn', closeAnimation: 'fadeOut', triggerPosition: 'center right', destPosition: 'center left', arrowDirection: 'left'">3</a>)</p><h2>2020 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC)</h2><p>For CYP2D6 normal metabolizers (i.e. CYP2D6 activity score 1.25 to 2.25), a label recommended age- or weight-specific starting dose of codeine or tramadol, as recommended in the product label, is warranted. A label recommended starting dosing is also recommended for intermediate metabolizers (i.e. activity score of 0.25 to 1); these patients should be monitored closely for less than optimal response and should be offered an alternative analgesic if warranted. For CYP2D6 poor metabolizers (i.e. activity score of 0), current evidence supports the avoidance of codeine and tramadol and the use of an alternative analgesics due to the likelihood of suboptimal or lack of effect. There is insufficient evidence in the literature to recommend a higher dose of codeine or tramadol in poor metabolizers, especially considering the evidence that some adverse events do not differ between poor and normal metabolizers (<a title="click for more information" class="jig-ncbipopper s_TOP" href="#codeine_REF_19" data-jigconfig="hasArrow: true, openEvent: 'click', closeEvent: 'mouseout', openAnimation: 'fadeIn', closeAnimation: 'fadeOut', triggerPosition: 'center right', destPosition: 'center left', arrowDirection: 'left'">19</a>). For CYP2D6 ultrarapid metabolizers (i.e. activity score of >2.25), codeine or tramadol should not be used, in order to avoid the risk of severe toxicity with label-recommended dosing. Non-opioid analgesics and if needed, other opioids that are not affected by CYP2D6 phenotype, are potential alternatives for use in CYP2D6 poor and ultrarapid metabolizers based on the type, severity and chronicity of the pain being treated.</p><p><b>Please review the complete therapeutic recommendations that are located here:</b>
|
||
(<a title="click for more information" class="jig-ncbipopper s_TOP" href="#codeine_REF_4" data-jigconfig="hasArrow: true, openEvent: 'click', closeEvent: 'mouseout', openAnimation: 'fadeIn', closeAnimation: 'fadeOut', triggerPosition: 'center right', destPosition: 'center left', arrowDirection: 'left'">4</a>).</p><h2>2017 Summary of Recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)</h2><p><b>CYP2D6 Intermediate Metabolizers</b>
|
||
</p><p>For COUGH:</p><p>1. no action required</p><p>For PAIN:</p><p>It is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.</p><p>1. be alert to a reduced effectiveness</p><p>2. in the case of inadequate effectiveness:</p><p>1. try a dose increase</p><p>2. if this does not work: choose an alternative</p><ul><li>Do not select tramadol, as this is also metabolised by CYP2D6</li><li>Morphine is not metabolised by CYP2D6.</li><li>Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.</li></ul><p>3. if no alternative is selected: advise the patient to report inadequate analgesia</p><p><b>Poor Metabolizers</b>
|
||
</p><p>For COUGH:</p><p>1. no action required</p><p>For PAIN:</p><p>It is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.</p><p>1. choose an alternative</p><p>Do not select tramadol, as this is also metabolised by CYP2D6</p><ul><li>Morphine is not metabolised by CYP2D6.</li><li>Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.</li></ul><p>2. if an alternative is not an option: advise the patient to report inadequate analgesia.</p><p><b>Ultrarapid Metabolizers</b>
|
||
</p><p>DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:</p><p>Codeine is contra-indicated</p><ul><li>if possible, select an alternative<ul><li>For PAIN: do not select tramadol, as this is also metabolised by CYP2D6.</li></ul></li></ul><p>Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.</p><ul><li>For COUGH: noscapine is not metabolised by CYP2D6.</li></ul><p>DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:</p><ul><li>no action required</li></ul><p><b>Please review the complete therapeutic recommendations that are located here:</b>
|
||
(<a title="click for more information" class="jig-ncbipopper s_TOP" href="#codeine_REF_5" data-jigconfig="hasArrow: true, openEvent: 'click', closeEvent: 'mouseout', openAnimation: 'fadeIn', closeAnimation: 'fadeOut', triggerPosition: 'center right', destPosition: 'center left', arrowDirection: 'left'">5</a>)</p><p><b>2013 Clinical practice Guideline from the “Canadian Pharmacogenomics Network for Drug Safety (CPNDS) Clinical Recommendations Group: CYP2D6 genotyping for safe and efficacious codeine therapy”</b>
|
||
are located here: https://www.ncbi.nlm.nih.gov/pubmed/24214521 (<a title="click for more information" class="jig-ncbipopper s_TOP" href="#codeine_REF_65" data-jigconfig="hasArrow: true, openEvent: 'click', closeEvent: 'mouseout', openAnimation: 'fadeIn', closeAnimation: 'fadeOut', triggerPosition: 'center right', destPosition: 'center left', arrowDirection: 'left'">65</a>).</p><p><sup>1</sup>
|
||
|
||
The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labelled all formulations containing the generic drug.</p></div></div>
|
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<h2 class="offscreen_noflow">Supplemental Content</h2>
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<div class="portlet_head mgSectionHead ui-widget-header"><h1 class="nl" id="Table_of_contents">Table of contents</h1><a sid="113" href="#" class="portlet_shutter" title="Show/hide content"></a></div>
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<div class="portlet_content ln"><ul><li><a href="/gtr/tests?term=C1837160%5bDISCUI%5d&filter=method%3A2%5F8" target="_blank">Deletion/duplication analysis (7)</a></li>
|
||
<li><a href="/gtr/tests?term=C1837160%5bDISCUI%5d&filter=method%3A2%5F7" target="_blank">Sequence analysis of the entire coding region (1)</a></li>
|
||
<li><a href="/gtr/tests?term=C1837160%5bDISCUI%5d&filter=method%3A2%5F19" target="_blank">Targeted variant analysis (16)</a></li>
|
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<li class="portletSeeAll portletSeeAllPad"><total><a href="/gtr/tests?term=C1837160%5bDISCUI%5d" target="_blank">See all (16)</a></total></li>
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<div class="portlet_content ln"><ul><li><a href="https://www.pharmgkb.org/chemical/PA449088" target="_blank">PharmGKB</a></li><li><a href="https://clinicaltrials.gov/search?cond=Codeine%20response" target="_blank">ClinicalTrials.gov</a></li></ul></div>
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<div class="portlet_content ln"><ul class="a_poppers"><li><a target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/?term=(%22codeine%22%5Btiab%3A~0%5D)%20AND%20(%22english%20and%20humans%22%5BFilter%5D)%20AND%20(%20(%22practice%20guideline%22%5BFilter%5D)%20OR%20(practice*%5Btitl%5D%20AND%20(guideline%5Btitl%5D%20OR%20parameter%5Btitl%5D%20OR%20resource%5Btitl%5D%20OR%20bulletin%5Btitl%5D%20OR%20best%5Btitl%5D))%20OR%20(genetic*%5Btitl%5D%20AND%20(evaluation%5Btitl%5D%20OR%20counseling%5Btitl%5D%20OR%20screening%5Btitl%5D%20OR%20test*%5Btitl%5D))%20OR%20(clinical%5Btitl%5D%20AND%20((expert%5Btitl%5D%20AND%20consensus%5Btitl%5D)%20OR%20utility%5Btitl%5D%20OR%20guideline*%5Btitl%5D))%20OR%20(management%5Btitl%5D%20AND%20(clinical%5Btitl%5D%20OR%20diagnos*%5Btitl%5D%20OR%20recommendation%5Btitl%5D%20OR%20pain%5Btitl%5D%20OR%20surveillance%5Btitl%5D%20OR%20emergency%5Btitl%5D%20OR%20guideline*%5Btitl%5D%20OR%20therap*))%20OR%20(treatment%5Btitl%5D%20AND%20((evaluation%5Btitl%5D%20AND%20diagnosis%5Btitl%5D)%20OR%20(assessment%5Btitl%5D%20AND%20prevention%5Btitl%5D)%20OR%20therap*))%20OR%20(Diagnos*%5Btitl%5D%20AND%20(prenatal%5Btitl%5D%20OR%20treatment%5Btitl%5D%20OR%20follow-up%5Btitl%5D%20OR%20statement%5Btitl%5D%20OR%20criteria%5Btitl%5D%20OR%20newborn%5Btitl%5D%20OR%20differential%5Btitl%5D%20OR%20neonatal%5Btitl%5D%20OR%20neonate%5Btitl%5D))%20OR%20(guideline*%5Btitl%5D%20AND%20(pharmacogenetic*%5Btitl%5D%20OR%20recommendation%5Btitl%5D%20OR%20therap*%5Btitl%5D%20OR%20evidence-based%5Btitl%5D%20OR%20consensus%5Btitl%5D%20OR%20(technical%5Btitl%5D%20AND%20standard*%5Btitl%5D)%20OR%20(molecular%5Btitl%5D%20AND%20testing%5Btitl%5D)))%20OR%20(risk%5Btitl%5D%20AND%20assessment%5Btitl%5D)%20OR%20(recommendation*%5Btitl%5D%20AND%20(statement%5Btitl%5D%20OR%20Evidence-based%5Btitl%5D%20OR%20Consensus%5Btitl%5D))%20OR%20(care%20AND%20((Patient%5Btitl%5D%20AND%20standard*%5Btitl%5D)%20OR%20primary%5Btitl%5D%20OR%20psychosocial%5Btitl%5D))%20OR%20(Health%5Btitl%5D%20AND%20supervision%5Btitl%5D)%20OR%20(statement%5Btitl%5D%20AND%20(policy%5Btitl%5D%20OR%20position%5Btitl%5D%20OR%20Consensus%5Btitl%5D))%20OR%20(pharmacogenetics%5Btitl%5D%20AND%20(Dosing%5Btitl%5D%20OR%20therap*%5Btitl%5D%20OR%20genotype*%5Btitl%5D%20OR%20drug*%5Btitl%5D))%20OR%20(Chemotherapy%5Btitl%5D%20AND%20decision*%5Btitl%5D)%20OR%20(screening%5Btitl%5D%20AND%20(newborn%5Btitl%5D%20OR%20neonat*%5Btitl%5D%20OR%20detection%5Btitl%5D%20OR%20diagnos*%5Btitl%5D))%20OR%20(criteria%5Btitl%5D%20OR%20genotype*%5Btitl%5D)%20)%20NOT%20(%22Case%20reports%22%5BPublication%20type%5D%20OR%20%22clinical%20study%22%5BPublication%20Type%5D%20OR%20%22randomized%20controlled%20trial%22%5BPublication%20Type%5D)" title="PubMed search">PubMed</a><div class="help-popup">See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the <a href="/medgen/docs/faq/" title="Frequently asked questions" target="_blank">FAQ</a> for details.</div></li></ul><h3 class="subhead">Curated</h3><ul class="a_poppers"><li><a target="_blank" href="https://www.g-standaard.nl/risicoanalyse/M0002415.pdf">DPWG, 2020</a><div>Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Guidelines [Internet]. Netherlands. Codeine - CYP2D6</div></li></ul></div>
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<div class="portlet_content ln"><ul><li><a href="http://www.omim.org/search?index=entry&start=1&limit=10&sort=score%20desc&field=number&search=124030" target="_blank">OMIM</a></li><li><a href="/clinvar/?term=1565[geneid]" target="_blank">View CYP2D6 variations in ClinVar</a></li><li><a href="/nuccore/197100374" target="_blank">RefSeqGene</a></li></ul></div>
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<a href="/books/NBK100662" ref="ncbi_uid=&discoId=gtr_reviews&linkpos=1&linkpostotal=3" target="_blank">Medical Genetics Summaries</a>
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