Review Article - Anesthesiology and Clinical Science Research (2018) Volume 2, Issue 1
Towards personalized opioid dosing: A concise overview of CYP polymorphisms
- *Corresponding Author:
- Robert Taylor Jr
NEMA Research Inc, Naples
Florida 34108, USA
E-mail: [email protected]
Accepted date: March 29, 2018
Citation: Pergolizzi JV, Taylor R, LeQuang JA, et al. Towards personalized opioid dosing: A concise overview of CYP polymorphisms. Anaesthesiol Clin Sci Res. 2018;2(1):11-19
Concern about excess opioid prescribing and abuse makes it is more important than ever that the dose of opioid prescribed be sufficient to relieve pain, but not excessive. The wide variation among patients regarding opioid response poses clinical challenges to prescribers seeking to offer patients adequate but safe levels of analgesia. While many factors (pharmacodynamics and pharmacokinetic) can influence drug response, growing understanding of the genomic influences on the cytochrome (CYP) P450 enzymes may help better identify patients who will most benefit from opioid therapy and direct their dosing regimen. Since many opioids are primarily metabolized by Phase 1 CYP450 enzymes, CYP enzyme polymorphisms can result in variations in patient response. Many opioids and other drug classes are metabolized by the CYP families CYP2D6, CYP3A4, and to lesser extent CYP2B6 enzymes. Thus, patients who have genotype polymorphisms in these enzymes are phenotypically (clinically) poor, intermediate, extensive, or ultra-rapid metabolizers, affecting how rapidly or to what extent an individual patient metabolizes opioids. Moreover, these enzymes may be induced or inhibited by drugs or other substances. While phenotyping and genotyping individual patients is not yet a practical everyday solution, the advent of personalized medicine will likely allow for cost-effective, rapid testing that may better identify a patient’s metabolic type prior to prescribing opioid therapy. With better matching of the effective dose for each patient, it should be possible to avoid excess dosing, resulting in fewer prescribed pills and, presumably, fewer unused pills that are at risk for diversion.
Opioid, Metabolism, Cytochrome P450, Pharmacogenomics, Polymorphism.
Cytochrome P450 (CYP450) describes a family of isoenzymes located in the endoplasmic reticulum of liver cells, which catalyze metabolic conversion (biotransformation) of endogenous and exogenous compounds. Part of Phase I metabolism (oxidation, reduction, and hydrolysis), oxidation by way of CYP450 enzymes results in metabolic conversion of parent drugs to metabolites that are often (but not always) with reduced affinity and efficacy target receptors, and often (but not always) more water-soluble (more unlikely to be reabsorbed through kidney convoluted tubules and hence, more likely to be excreted in the urine) [1,2].
The human genome contains 70 CYP genes, which have been classified based on sequence homology, resulting in 18 families and 44 subfamilies [3,4]. Thus, CYP450 is the name of a superfamily of isoenzymes; drugs may be metabolized by one or more of its subfamilies, acting as enzymatic pathways . The main enzymes involved in the metabolism of current drugs belong to the CYP1, CYP2, and CYP3 families and include these isoforms: 1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5. In fact, about 90% of all current pharmaceutical products are metabolized by CYP1A2, 2C8/9, 2C19, 2D6, and 3A4  (Figure 1).
Figure 1. Graphical representation of the approximate fraction of common current drugs that are metabolized by specific P450 isozymes, and some factors that are known or suspected to alter the activity of each isozyme (↑,increase; ↓, decrease; ?, suspected). [source: From Zanger & Schwab (2013) Pharmacol Thera 138:103-141 with permission].
Nucleotides are the building blocks of DNA and a single nucleotide polymorphism (SNP) represents a difference in one of those nucleotides. SNPs are often seen in the DNA between genes, but SNPs can occur within a gene or within the regulatory region near a gene, in which case they may affect the gene’s function . Most variability in CYP450 activity can be traced to SNPs at the CYP450 gene locus .
A SNP can change the composition of the protein transcribed by the gene, which, in turn, leads to changes in gene expression and/or activity. New SNPs and their corresponding functional effects have recently been discovered and, indeed, continue to be discovered . Changes in transcribed proteins may cause changes to enzymes, drug transporters, and drug receptors which can make the functional effect greater, less, or nil . Because of the heritability of SNPs, the prevalence of certain polymorphisms can vary markedly between ethnic groups or races . These changes can be of great clinical relevance in that they can result in unexpected drug metabolism (more rapid metabolism, shorter half-lives, or, conversely, significantly elevated circulating plasma concentrations of the agent), which may lead to toxicity even within normally therapeutic dosing ranges .
Although the CYP2D6 enzyme accounts for only about 5% of the CYP content in the liver  it is responsible for the oxidative metabolism for about 25% of currently commercialized pharmaceutical agents, [4,11] —including opioids—along with antidepressants, antipsychotics, and antiarrhythmic agents . The CYP2D6 enzyme is encoded by the CYP2D6 gene, located on human chromosome 22. With more than 60 known alleles (defined as two or more alternative forms of a gene that occur by mutation and can be found at the same place on a chromosome) [5,12] CYP2D6 has numerous polymorphisms resulting in at least 130 possible genetic variations . The extensive effect of CYP2D6 on drug metabolism has made it the subject of considerable study .
An individual’s drug-metabolizing phenotype is based on the combination of CYP2D6 alleles, which are expressed as normal, reduced, or enhanced catalytic activity . Individuals with two normal function alleles are called “extensive metabolizers” and have normal enzymatic activity.
Individuals with two nonfunctional or null alleles have little to no enzymatic activity and are called “poor metabolizers”; the majority of CYP2D6 polymorphisms result in decreased enzymatic activity i.e., poor metabolism [10,15-17]. Individuals with one null allele or two deficient alleles are called “intermediate metabolizers” and have compromised (but not absent) enzymatic activity. This particular polymorphism is common among Asian patients, affecting as many as 50% of certain Asian populations [6,18]. Gene duplication, that is, having more than two copies of the CYP2D6 gene in one chromosome, may occur; individuals with more than two functional CYP2D6 alleles are known as “ultra-rapid metabolizers” . This polymorphism is particularly high among Saudi Arabians (20%) and Ethiopians (29%) [6,18]. Within these four broad metabolic types there can still be considerable variability in metabolic rates.
An alternative method for describing metabolic type is to assign a number to the alleles. Normal function alleles count as 1, reduced-function alleles as 0.5, and non-functional alleles as 0. Tallying the individual’s alleles will result in any of six possible scores: 0, 0.5, 1, 1.5, 2, and >2.
Those who score 0 are poor metabolizers, intermediate metabolizers score 0.5 to 1, extensive metabolizers’ rate 1 to 2, and those with a score over 2 are ultra-rapid metabolizers . In this connection, it should be noted that patients who score 1 on this test may be grouped into the intermediate metabolizer or the extensive metabolizer category. They are considered intermediate if their score is obtained by two alleles of 0.5 points each (0.5 + 0.5 = 1), but if they achieve their score by having one functional allele (1 point), they are categorized as extensive metabolizers (1 + 0 = 1) .
CYP2D6 polymorphisms may explain at least in part the interpatient differences in opioid response and the variations in circulating plasma levels of opioid agents . CYP2D6 polymorphisms may affect analgesic benefit, side effects, and tolerability of opioids in individual patients.
CYP3A4 and 3A5
CYP3A4 is the most abundant of all of the CYP450 isoforms and accounts for about half of all of the CYP450 enzymes in the liver, but there is little polymorphism and thus little variation in CYP3A4 expression in humans . On the other hand, CYP3A5 is far less abundant (making up about 2% of the CYP450 enzymes in the liver in Caucasians), but is highly polymorphic and its contributory role to CYP3A4 activity accounts for the overall variability observed in the CYP3A4/5 enzyme .
Owing to linkage disequilibrium and other factors, CYP3A4 and CYP3A5 overlap to the extent that it is difficult to draw clear conclusions about one genotype or the other . These two isoforms have similar sequence homology and nearly identical substrate specificity, but differ in functional activity. When appropriate, we will describe them as they are often described in the literature, that is, as CYP3A4/5.
The CYP2B6 gene on chromosome 19 is responsible for coding metabolic enzymes of the CYP450 family [22-24] and exhibits marked variations among individuals in terms of mRNA expression which has been attributed to genetic polymorphisms . CYP2B6*6 has been reported to be implicated in opioid addiction as well as response to methadone maintenance therapy [24,26]. The CYP2B6 enzyme is not a major metabolic pathway for the most commonly prescribed opioids.
An enzyme molecule typically has an “active site” that binds to a substrate (e.g., drug) and orients it for catalysis. The substrate is changed by the action of the enzyme, which then releases the product. Two theoretic models explain how this might work. The “lock-and-key” hypothesis supposes that the substrate and the active site of the enzyme are a close match and allow for a tight fit with no further modification . By contrast, the “induced fit” hypothesis proposes that the active site and substrate are not a close match but the active site has sufficient flexibility to morph into the appropriate shape to form a close match with the substrate. The induced fit hypothesis holds that the interaction between enzyme and substrate is weak, but cumulative weak interactions cause conformational changes to the enzyme that jointly contribute to its binding strength.
The following section presents a summary of some opioids that undergo metabolism involving CYP450 enzymes. Some opioids, notably but not exclusively morphine, are mainly metabolized via non-CYP450 pathways (e.g. phase 2 glucuronidation).
Buprenorphine is available for parenteral, oral, sublingual, and transdermal administration. Buprenorphine is metabolized via the CYP3A4 isoform as its primary metabolic pathway with a contribution from UDP-glucuronosyltransferase (UGT) 2B enzymes . The UGT enzymes are not part of the cytochrome superfamily of enzymes. The major metabolite of buprenorphine is norbuprenorphine, a pharmacologically active compound that is then metabolized to its glucuronide conjugates .
Codeine is primarily considered a prodrug that is converted by CYP2D6 first to morphine and then to morphine-6-glucuronide (M6G) . Codeine O-demethylation conversion to morphine occurs mainly in the liver microsomes, but some metabolism takes place in the intestine and the brain. Codeine is also N-demethylated to the metabolite norcodeine via its minor metabolic pathway CYP3A4 . Codeine is eliminated mainly by glucuronidation with O-demethylation to morphine and N-demethylation to norcodeine . Since the analgesic benefit of codeine derives mainly from its morphine metabolite, the O-demethylation pathway via the CYP2D6 enzyme is of particular interest, in that it produces the active metabolite . While the analgesic effect of codeine is largely attributable to the metabolism of codeine to morphine . other pathways and metabolites come into play. Conversion of codeine to codeine- 6-glucuronide occurs via UGT2B7, which also catalyzes morphine glucuronidation to morphine-3-glucuronide (M3G) and M6G.
Codeine is considered a “weak opioid” agonist by the World Health Organization (WHO)  and is widely prescribed around the world for relief of moderate pain. It has low affinity for the μ-opioid receptor (200 times less than morphine) and low intrinsic activity there (50 times less than morphine) . Because it has been categorized as a “weak opioid,” it has been considered a safer alternative for pain control than many other strong opioids, which may account for its widespread use in treating pain, including pediatric patients . Patients with gene duplication (ultrarapid metabolizers) may be predisposed to opioid toxicity even at therapeutic or very low doses of codeine, since they can produce large amounts of morphine and M6G from relatively small amounts of codeine . A case report in 2006 identified a neonate who died of opioid toxicity after his mother was prescribed codeine plus acetaminophen to control episiotomy-related pain. The mother had a CYP2D6 polymorphism and was an ultra-rapid metabolizer and the baby ingested quantities of morphine via her breast milk [35,36].
Since CYP2D6 ultrarapid metabolism is not rare and consequences are potentially lethal, codeine currently is one of two opioids in the United States which is required by the Food and Drug Administration (FDA) to include pharmacogenetic information about CYP2D6 metabolism on its labeling . (The other is tramadol.)
Fentanyl is a highly lipophilic opioid distributed extensively throughout the body and metabolized via CYP3A4/5 primarily to the inactive metabolite norfentanyl . The pharmacokinetic activity of norfentanyl depends on the patient’s ability to metabolize and excrete fentanyl.
Variations in the alleles CYP3A4*1B and CYP3A5*3 have been associated with variations in fentanyl metabolism. A study of 25 fentanyl-related deaths found evidence that CYP3A5*3 is associated with impaired fentanyl metabolism . In a study of cancer patients administered transdermal fentanyl for pain control, patients with homozygous CYP3A5*3 alleles had a two-fold increase in fentanyl plasma concentration compared to other patients . In a study of postoperative pain patients, the CYP3A5*3 allele affected plasma exposure of fentanyl but did not impact urinary excretion of fentanyl in the early postoperative period .
Hydrocodone may be considered a type of prodrug, in that it is metabolized via CYP2D6 into hydromorphone, which is five times more potent than the parent drug hydrocodone . Hydrocodone metabolism is similar to that of codeine, in that CYP2D6 catalyzes O-demethylation to dihydromorphine (an active metabolite similar to morphine) and N-demethylation to norhydrocodone [5,41]. The analgesic effect of hydrocodone derives mainly from its metabolites . About 40% of hydrocodone is cleared via non-CYP pathways .
A case report describes a fatal case of hydrocodone toxicity in a five-year-old developmentally delayed girl who had been administered hydrocodone for a respiratory tract infection. The patient had a CYP2D6 polymorphism, resulting in the hydrocodone metabolizing to large amounts of hydromorphone, exacerbated by polypharmacy .
The metabolism of hydromorphone has not yet been entirely elucidated but takes place largely via the UGT2B7 pathway. It is thought that hydromorphone metabolism might involve some CYP3A and CYP2C9 activity, but CYP2D6 is not involved in the agent’s therapeutic activity [44,45].
Levorphanol (levo-3-hydroxy-N-methylmorphinan) is anopioid that was originally marketed as an alternative to morphine [46,47]. It undergoes glucuronidation in the liver via the UGT2B7 enzyme, similar to morphine.
G. Meperidine (CYP2B6)
Meperidine is an opioid analgesic agent that is metabolized via multiple enzymes. Most of the metabolism occurs via CYP2B6 (57%) with contributions from CYP3A4 (28%) and CYP2C19 (15%) and very minor contributions (<1%) from isoforms CYP3A5 and CYP2D6 .
Methadone (CYP3A4 and CYP2B6)
Methadone is a racemic compound (R- and S- enantiomers). Methadone is metabolized via isoenzymes CYP3A4 and CYP2B6. CYP2B6 preferentially metabolizes the S- enantiomer and can affect clearance and plasma concentrations of methadone . The clinical disposition of methadone has historically been attributed largely to CYP3A4, although CYP2B6 plays an important role . While methadone is not a substrate for CYP2D6  methadone can inhibit CYP2D6 in vitro and in vivo [51,52]. Methadone reduces the clearance of tramadol in patients and for that reason; tramadol may not be optimal for use as an analgesic agent in patients receiving methadone maintenance treatment .
Since methadone is widely used in treatment programs for opioid addiction, genetic variability must be considered to better gauge therapeutic response. In a meta-analysis (n=7 articles), trough (R-) methadone plasma concentrations were higher in homozygous carriers of CYP2B6*6 compared to non-carriers (p=0.03) and trough (S-) methadone plasma concentrations were also higher in homozygous carriers of the CYP2B6*6 haplotype compared to non-carriers (p=0.02) . However, among the carriers of the CYP2B6*6 haplotype, there can still be considerable heterogeneity. This suggests that patients who are homozygous for the CYP2B6*6 genotype metabolize methadone more slowly and therefore have higher trough concentrations of R- and S-methadone in plasma. The ATP-binding cassette, subfamily B, member 1 (ABCB1) gene is probably the most consistently mentioned gene with respect to response to methadone therapy . However, there is no significant association found with the ABCB1 polymorphism and trough plasma concentrations of R-, S-, methadone dose, and response .
Methadone has complicated pharmacokinetics, may be used as an alternative opioid agent in patients who do not respond well to other opioids, and is sometimes considered as a second-line treatment for cancer pain. Clinicians may prescribe racemic methadone (R- and S-methadone) and levomethadone (R-methadone) . Both enantiomers are known to bind to NMDA-receptor sites, making them effective in treating neuropathic pain. Most studies of methadone have been conducted in cohorts of opioid addicts receiving methadone maintenance therapy, which may impact the overall generalizability of their findings .
The main metabolic pathway for morphine in mammals is glucuronidation catalyzed by UGT enzymes . Variations in morphine response have been attributed to differing individual abilities to glucuronidate morphine or to UGT2B7 polymorphisms or both . Morphine’s main metabolite is morphine-3-glucuronide (M3G) which has central nervous system stimulatory effects but is thought to be inactive in analgesia . Morphine-6-glucuronide (M6G) is a minor metabolite, but is thought to play a role in pain relief.
Oxycodone (CYP2D6 and CYP3A4/5)
Oxycodone undergoes N-demethylation as its main metabolic pathway, mediated by CYP3A, and also undergoes O-demethylation mediated by the CYP2D6 enzyme, which accounts for only about 10% of metabolites excreted in the urine [57,58]. The CYP2D6 oxycodone metabolite of oxymorphone has a 40-fold higher mu-opioid-receptor binding affinity than the parent drug oxycodone  and is a more potent mu-opioidreceptor agonist than oxycodone, yet it is thought to play only a minor role in analgesia. Quantitatively, the CYP2D6 pathway is the more important one . In contrast to certain other opioids, the main effects of oxycodone in humans appear to be governed by the parent drug rather than its oxidative and reductive metabolites .
While women have greater CYP3A4/5 activity in relation to CYP2D6 activity, there is no evidence in the literature that supports sex-based differences in oxycodone metabolism or use patterns . When concern was raised about the use of codeine in pediatric patients, there was a tendency to regard oxycodone as a “safer” alternative. However, maternal use of oxycodone during breastfeeding has been associated with a 20.1% rate of infant central nervous system (CNS) depression compared to 16.7% for mothers taking codeine and 0.5% for mothers taking acetaminophen .
One hundred twenty-one surgical patients who received oxycodone 0.05 mg/kg before emergence from anesthesia and then had oxycodone via patient-controlled analgesia (PCA) for the first 48 postsurgical hours were evaluated in a clinical trial . Blood samples were taken at 30, 90, and 180 minutes after the initial dose of oxycodone. The primary endpoint of the study was the plasma concentration ratios of oxymorphone (metabolite) to oxycodone and the second was postoperative analgesic consumption. The ratios of oxymorphone to oxycodone were 0.10 (poor metabolizers), 0.13 (intermediate metabolizers), 0.18 (extensive metabolizers), and 0.28 (ultrarapid metabolizers), p=0.005. At 12 hours, oxycodone consumption was significantly highest in the poor metabolizer group compared to the other groups (p=0.005). Pain intensity scores were similar across groups . This study underscores how metabolic type can affect opioid dose, serum concentrations, and opioid consumption.
Tramadol is a racemic mixture and its analgesic effect results from a synergistic interaction of its two enantiomers and their metabolites. Of the 11 demethylated compounds resulting from tramadol metabolism, analgesic properties are thought to reside primarily in O-desmethyltramadol which is metabolized via CYP2D6. O-desmethyltramadol possesses a 200-times greater affinity for mu-opioid-receptors than the parent compound [41,62,63].
Like codeine, tramadol carries pharmacogenetic information about CYP2D6 polymorphisms on its labeling . Individuals with more than two functional CYP2D6 genes (ultrarapid metabolizers) may be at elevated risk for opioid-associated side effects [14,31] and they have higher peak plasma concentration, greater miosis, and experience a greater degree of analgesic effect than CYP2D6 extensive metabolizers .
By contrast, poor CYP2D6 metabolizsers may require higher doses of tramadol in order to achieve the same analgesic effect. An analysis of serum concentrations of the (+)Odesmethyltramadol in different CYP2D6 genotypes found that poor metabolizers had smaller quantities of the active metabolite compared to others.
Other factors that affect opioid metabolism
Drug response involves a complex interplay of factors. These include environment, age, sex, ethnic group, comorbid conditions, concurrent medication use, and organ dysfunction . Drug response may be further affected by diet, lifestyle, and smoking [65-68]. Inflammation has been associated with a reduced expression of CYP3A4 via proinflammatory cytokines (such as interleukin [IL] 6), which might potentially affect opioid metabolism .
Polypharmacy refers to taking multiple agents concurrently; it is prevalent among chronic pain patients, cancer patients, and the elderly . Drug metabolism is clearly impacted by polypharmacy, that is, taking agents known to inhibit certain CYP pathways can disrupt metabolism or, in other cases, block alternative biotransformative pathways . Renal dysfunction can decrease elimination, allowing for a potentially toxic buildup of metabolites . Powerful CYP2D6 inhibitors can cause poor metabolism of a drug even in a patient who might otherwise be considered an ultrarapid metabolizer. This effect is known as “phenoconversion” . It is important to be aware of potential drug-drug interactions with opioids and agents that may inhibit or induce the catalysis of opioid analgesics.
Inhibitors refer to prescription drugs, over-the-counter medications, supplements, and even foods that can disrupt CYP activity and affect how a concurrently taken drug is metabolized. Powerful CYP2D6 inhibitors which can cause a > 5-fold increase in the plasma area-under-the-curve concentration (AUC) or more than an 80% decrease in clearance include bupropion, cinacalcet, fluoxetine, paroxetine, and quinidine. Other but less potent CYP2D6 inhibitors are amiodarone, chlorpromazine, cimetidine, duloxetine, flecainide, haloperidol, metoclopramide, propafenone, risperidone, ritonavir, sertraline, and terbinafine [2,14].
CYP3A4/5 inhibitors include amiodarone, carbamazepine, cyclosporine, dexamethasone, dihydralazine, diltiazem, doxycycline, erythromycin, imatinib, meprobamate, metamizole, methylprednisolone, nefazodone, nelfinavir, phenobarbital, phenytoin, ritonavir, topiramate, verapamil, and others. St. John’s Wort, a popular herbal supplement,  grapefruit, and licorice2 are also CYP3A4/5 inhibitors.
Inducers are molecules that promote gene expression by enhancing activators or disabling repressors. CYP2D6 inducers include dexamethasone, glutethimide, and rifampicin. CYP3A4/5 inducers include carbamazepine, clotrimazole, dexamethasone, phenobarbital, phenytoin, rifampin, and sulfinpyrazone .
Ethnicity and opioid metabolism
Since CYP polymorphisms are inheritable, ethnic, racial, and geographic variations in opioid response have been known for decades. Many polymorphisms and the resulting metabolic types are far from rare. For CYP2D6, for example, about 7% of the Caucasian population could be classified as poor metabolizers, while about 3.5% of this same population are ultrarapid metabolizers  CYP2D6 gene duplication, resulting in ultrarapid metabolism, is highly prevalent in Saudi Arabia and Ethiopia (over 20%) but less common elsewhere. Reduced CYP2D6 enzymatic activity is more common in Japanese (39% to 41%) and Chinese (50% to 70%) than the U.S. Caucasian population (2% to 8%) or African-American population (15% to 26%) .
Polymorphisms affecting the CYP3A4/5 enzymes also vary by race, ethnicity, and geography. Splice variants in the CYP3A4*1B affect about 2% to 10% of Caucasians, 9% to 11% of Hispanics, and 35% to 67% of African-Americans in the United States; this polymorphism is very rare in China [21,73].
While ethnic and racial distribution patterns of CYP polymorphisms can be interesting, they do not provide guidance on how to treat individual patients. In some cases, the history of an opioid-experienced patient may provide some insight into that patient’s ability to metabolize opioids.
For others, it may be useful to phenotype or genotype the patient. Phenotyping is a relatively elaborate test in which the patient takes a probe drug and blood is drawn at various time points in order to analyze real-time in vivo CYP enzymatic activity. Phenotyping provides a good analysis of the interplay of genetic, environmental, and endogenous factors involved in drug response . However, because phenotyping is a costly and time-consuming procedure, it is not a practical solution for all opioid patients . Genotyping, on the other hand, relies on polymerase chain reactions (PCRs) to amplify the patient’s DNA and applies other detection methods, such as restriction fragment length polymorphism after hydrolysis with restriction enzymes, among others, for each allele . Alleles are assessed individually and thus only a subset of alleles can be analyzed. A number of commercial systems are available for this type of testing. New test methods are being developed with the goal of finding a fast, inexpensive, reliable test method that can help guide opioid prescribing choices.
It will be interesting to see how our understanding of CYP polymorphisms will affect future prescribing practices . As techniques become more practical, inexpensive, and easier to implement they will find more widespread use with the goal that opioid dosing can be safer, more rational, more effective, and more predictable.
Of great concern is the potential for drug-drug interactions when a patient takes an opioid analgesic agent along with other drugs, both prescription and over-the-counter medications. Pharmacokinetic drug-drug interactions with opioids are not uncommon [77-80]. And may have an adverse economic impact on the healthcare system which is not fully appreciated [81,82]. Since polypharmacy is common, particularly in the chronic pain population,  such drug-drug interactions must be considered carefully by clinicians. In a prospective observational study in academic U.S. emergency rooms (n=502) 250 patients had taken either one CYP2D6 inhibitor or inducer (either pharmaceutical agent, supplement, or illicit drug) in the 48 hours before presenting to the emergency department. Patients who took a CYP2D6 agent were one-third as likely to respond to hydrocodone (odds ratio 0.33, 95% confidence interval, 0.1 to 0.8) than non-users .
Drug-drug interactions appear to be more likely when a drug relies on one sole metabolic pathway of limited capacity, because substrates can saturate enzymatic action and inhibit catalysis. CYP2D6 is such a pathway; on the other hand, CYP3A4 has a higher capacity . Thus, when assessing drug response, even if a polymorphism is known to prescribers in advance, there are several additional considerations that may influence prescribing choices. First, the affected pathway must be considered in that major pathway “collisions” are of greater concern than competition on minor pathways. When drugs compete for a single metabolic pathway it must also be considered what the therapeutic window of that other drug is. Other pathways of elimination may affect competition as well. When a pathway leads to an active metabolite, it is of greater concern than a pathway that does not. Thus, phenotyping or genotyping a patient at risk of drug-drug interactions must be balanced against other considerations .
Many commonly prescribed opioids are metabolized via the CYPenzyme family, and our evolving understanding of CYP polymorphisms is increasing the knowledge of how these drugs may be metabolized differently by different patients. Understanding polymorphisms allows clinicians to stratify patients into metabolic types which help guide – and ideally, optimize – prescribing and dosage choices. New tools to help classify patients and quantify doses may make opioid therapy safer, more effective, and more predictable in the future.
- Samer CF, Lorenzini KI, Rollason V, et al. Applications of CYP450 testing in the clinical setting. Mol Diagn Ther. 2013;17(3):165-184.
- Crews K, Gaedigk A, Dunnenberger H, et al. Clinical pharmacogenetics implementation consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther. 2012;91:321-326.
- Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet. 2009;48(11):689-723.
- Foster A, Mobley E, Wang Z. Complicated pain management in a CYP450 2D6 poor metabolizer. Pain Pract. 2007;7(4):352-356.
- McGraw J, Waller D. Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol. 2012;8(3):371-382.
- Dendukuri N, Khetani K, McIsaac M, et al. Testing for HER2-positive breast cancer: A systematic review and cost-effectiveness analysis. CMAJ. 2007;176(10):1429-1434.
- Ma JD, Lee KC, Kuo GM. Clinical application of pharmacogenomics. J Pharm Pract. 2012;25(4):417-427.
- Gardiner S, Begg E. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev. 2006;58:521-590.
- Monte AA, Heard KJ, Campbell J, et al. The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness. Acad Emerg Med. 2014;21(8):879-885.
- Ingelman-Sundberg M, Daly A, Oscarson M, et al. Human cytochrome P450 (CYP) genes: recommendations for the nomenclature of alleles. Pharmacogenetics. 2000;10:91-93.
- Teh L, Bertilsson L. Pharmacogenomics of CYP2D6: Molecular genetics, interethnic differences and clinical importance. Drug Metab Pharmacokinet. 2012;27:55-67.
- Haufroid V, Hantson P. CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants. Clin Toxicol. 2015;53(6):501-510.
- Brousseau DC, McCarver DG, Drendel AL, et al. The effect of CYP2D6 polymorphisms on the response to pain treatment for pediatric sickle cell pain crisis. J Pediatr. 2007;150(6):623-626.
- Stamer UM, Lehnen K, Hothker F, et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain. 2003;105(1-2):231-238.
- Zanger U, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: Overview and update on pharmacology, genetics and biochemistry. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:23-37.
- Xie HG, Kim RB, Wood AJ, et al. Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol. 2001;41:815-850.
- Zahari Z, Ismail R. Influence of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) polymorphisms on pain sensitivity and clinical response to weak opioid analgesics. Drug Metab Pharmacokinet. 2014;29(1):29-43.
- Zwisler ST, Enggaard TP, Mikkelsen S, et al. Impact of the CYP2D6 genotype on post-operative intravenous oxycodone analgesia. Acta Anaesthesiol Scand. 2010;54(2):232-240.
- Xie HG, Wood AJ, Kim RB, et al. Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics. 2004;5(3):243-272.
- Wang H, Tompkins LM. CYP2B6: New insights into a historically overlooked cytochrome P450 isozyme. Curr Drug Metab. 2008;9(7):598-610.
- Li Y, Kantelip JP, Gerritsen-van Schieveen P, et al. Interindividual variability of methadone response: impact of genetic polymorphism. Mol Diagn Ther. 2008;12(2):109-124.
- Fonseca F, De la Torre R, Diaz L, et al. Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response. PloS One. 2011;6(5):e19527.
- Crettol S, Deglon JJ, Besson J, et al. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther. 2005;78(6):593-604.
- Crettol S, Deglon JJ, Besson J, et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther. 2006;80(6):668-681.
- Billiet P. Enzymes: A protein with catalytic properties due to its power of specific activation. 2007.
- Blanco F, Muriel C, Labrador J, et al. Influence of UGT2B7, CYP3A4, and OPRM1 gene polymorphisms on transdermal buprenorphine pain control in patients with critical lower limb ischemia awaiting revascularization. Pain Pract. 2015.
- Marin SJ, McMillin GA. Quantitation of buprenorphine, norbuprenorphine, buprenorphine glucuronide, norbuprenorphine glucuronide, and naloxone in urine by LC-MS/MS. Methods Mol Biol. 2016;1383:69-78.
- Thorn C, Klein T, Altman R. Codeine and morphine pathway. Pharmacogenet Genomics. 2009;19(7):556-558.
- Stamer UM, Zhang L, Stuber F. Personalized therapy in pain management: where do we stand? Pharmacogenomics. 2010;11(6):843-864.
- Williams D, Hatch D, Howard R. Codeine phosphate in paediatric medicine. Br j anaesth. 2001;86(3):413-421.
- Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication assoicated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351:2827-2831.
- Koren G, Cairns J, Chitayat D, et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. The Lancet Oncology. 2006;368:704.
- Madadi P, Koren G, Cairns J, et al. Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can Fam Physician. 2007;53:33-35.
- Tanaka N, Naito T, Yagi T, et al. Impact of CYP3A5*3 on plasma exposure and urinary excretion of fentanyl and norfentanyl in the early postsurgical period. Ther Drug Monit. 2014;36(3):345-352.
- Jin M, Gock SB, Jannetto PJ, et al. Pharmacogenomics as molecular autopsy for forensic toxicology: genotyping cytochrome P450 3A4*1B and 3A5*3 for 25 fentanyl cases. J Anal Toxicol. 2005;29(7):590-598.
- Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature Genet. 2001;27(4):383-391.
- Volpe DA, McMahon Tobin GA, Mellon RD, et al. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol. 2011;59(3):385-390.
- Hutchinson MR, Menelaou A, Foster DJ, et al. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol. 2004;57(3):287-297.
- Madadi P, Hildebrandt D, Gong IY, et al. Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions. Pediatrics. 2010;126(4):e986-989.
- Benetton SA, Borges VM, Chang TK, et al. Role of individual human cytochrome P450 enzymes in the in vitro metabolism of hydromorphone. Xenobiotica. 2004;34(4):335-344.
- Guengerich F. Cytochrome P-450 3A4: Regulation and role in drug metabolism. Ann Rev Pharmacol Toxicol. 1999;39:1-17.
- Prommer E. Levorphanol: The forgotten opioid. Support Care Cancer. 2007;15(3):259-264.
- Prommer EE. Levorphanol revisited. J Palliat Med. 2007;10(6):1228-1230.
- Ramirez J, Innocenti F, Schuetz EG, et al. CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes. Drug Metab Dispos. 2004;32(9):930-936.
- Wang SC, Ho IK, Tsou HH, et al. CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer. J Clin Psychopharmacol. 2011;31(4):463-469.
- Kharasch ED, Stubbert K. Role of cytochrome P4502B6 in methadone metabolism and clearance. J Clin Pharmacol. 2013;53(3):305-313.
- Gelston EA, Coller JK, Lopatko OV, et al. Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: A study using codeine in methadone- and buprenorphine-maintained subjects. Br J Clin Pharmacol. 2012;73(5):786-794.
- Coller JK, Michalakas JR, James HM, et al. Inhibition of CYP2D6-mediated tramadol O-demethylation in methadone but not buprenorphine maintenance patients. Br J Clin Pharmacol. 2012;74(5):835-841.
- Dennis BB, Bawor M, Thabane L, et al. Impact of ABCB1 and CYP2B6 genetic polymorphisms on methadone metabolism, dose and treatment response in patients with opioid addiction: A systematic review and meta-analysis. PloS One. 2014;9(1):e86114.
- De Gregori S, De Gregori M, Ranzani GN, et al. Morphine metabolism, transport and brain disposition. Metab Brain Dis. 2012;27(1):1-5.
- Holthe M, Klepstad P, Zahlsen K, et al. Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy. Eur J Clin Pharmacol. 2002;58(5):353-356.
- Smith KJ, Elidemir O, Dishop MK, et al. Intravenous injection of pharmaceutical tablets presenting as multiple pulmonary nodules and declining pulmonary function in an adolescent with cystic fibrosis. Pediatrics. 2006;118(3):e924-928.
- Lalovic B, Kharasch E, Hoffer C, et al. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: Role of circulating active metabolites. Clin Pharmacol Ther. 2006;79(5):461-479.
- Elder NM, Atayee RS, Best BM, et al. Observations of urinary oxycodone and metabolite distributions in pain patients. Journal of Analytical Toxicology. 2014;38(3):129-134.
- Graziani M, Nistico R. Gender difference in prescription opioid abuse: A focus on oxycodone and hydrocodone. Pharmacol Res. 2016;108:31-38.
- Lam J, Kelly L, Ciszkowski C, et al. Central nervous system depression of neonates breastfed by mothers receiving oxycodone for postpartum analgesia. J Pediatr. 2012;160(1):33-37 e32.
- Stamer UM, Zhang L, Book M, et al. CYP2D6 genotype dependent oxycodone metabolism in postoperative patients. PloS One. 2013;8(3):e60239.
- Scott L, Perry C. Tramadol: A review of its use in perioperative pain. Drugs. 2000;60(1):139-176.
- Lai J, Ma SW, Porreca F, et al. Tramadol, M1 metabolite and enantiomer affinities for cloned human opioid receptors expressed in transfected HN9.10 neuroblastoma cells. Eur J Pharmacol. 1996;316(2-3):369-372.
- Kirchheiner J, Keulen J, Bauer S, et al. Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. J Clin Psychopharmacol. 2008;28:78-83.
- Pedersen RS, Damkier P, Brosen K. Tramadol as a new probe for cytochrome P450 2D6 phenotyping: a population study. Clin Pharmacol Ther. 2005;77(6):458-467.
- Garcia-Quetglas E, Azanza JR, Sadaba B, et al. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res. 2007;55(2):122-130.
- Stamer UM, Musshoff F, Kobilay M, et al. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther. 2007;82(1):41-47.
- Franceschi M, Scarcelli C, Niro V, et al. Prevalence, clinical features and avoidability of adverse drug reactions as cause of admission to a geriatric unit: A prospective study of 1756 patients. Drug Saf. 2008;31(6):545-556.
- Rivory L, Slaviero K, Clarke S. Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response. Br J Can. 2002;87:277-280.
- Giummarra MJ, Gibson SJ, Allen AR, et al. Polypharmacy and Chronic Pain: Harm Exposure Is Not All about the Opioids. Pain Med. 2014.
- Liu YT, Hao HP, Liu CX, et al. Drugs as CYP3A probes, inducers, and inhibitors. Drug Metab Rev. 2007;39(4):699-721.
- Kaplan HL, Busto UE, Baylon GJ, et al. Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability. J Pharmacol Exp Ther. 1997;281(1):103-108.
- Lamba JK, Lin YS, Schuetz EG, et al. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 2002;54(10):1271-1294.
- Kivisto KT, Kroemer HK. Use of probe drugs as predictors of drug metabolism in humans. J Clin Pharmacol. 1997;37(1):40S-48S.
- De Leon J. AmpliChip CYP450 test: poersonalized medicine has arrived in psychiatry. Expert Rev Mol Diagn. 2006;6(3):277-286.
- Linares OA, Daly D, Linares AD, et al. Personalized oxycodone dosing: using pharmacogenetic testing and clinical pharmacokinetics to reduce toxicity risk and increase effectiveness. Pain Med. 2014;15(5):791-806.
- Pergolizzi JV Jr, Labhsetwar SA, Puenpatom RA, et al. Exposure to potential CYP450 pharmacokinetic drug-drug interactions among osteoarthritis patients: incremental risk of multiple prescriptions. Pain Pract. 2011;11(4):325-336.
- Pergolizzi JV. Quantifying the impact of drug-drug interactions associated with opioids. Am J Manag Care. 2011;17(11):S288-292.
- Pergolizzi JV Jr, Labhsetwar SA, Puenpatom RA, et al. Prevalence of exposure to potential CYP450 pharmacokinetic drug-drug interactions among patients with chronic low back pain taking opioids. Pain Pract. 2011;11(3):230-239.
- Pergolizzi JV Jr, Ma L, Foster DR, et al. The prevalence of opioid-related major potential drug-drug interactions and their impact on health care costs in chronic pain patients. J Manag Care Pharm. 2014;20(5):467-476.
- Pergolizzi JV Jr, Labhsetwar SA, Amy Puenpatom R, et al. Economic impact of potential CYP450 pharmacokinetic drug-drug interactions among chronic low back pain patients taking opioids. Pain Pract. 2012;12(1):45-56.
- Pergolizzi JV Jr, Labhsetwar SA, Puenpatom RA, et al. Economic impact of potential drug-drug interactions among osteoarthritis patients taking opioids. Pain Pract. 2012;12(1):33-44.