CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial.
ABSTRACT: PURPOSE:CYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of CYP2D6-guided opioid prescribing on pain control. METHODS:Participants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided (n?=?235) or usual care (n?=?135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS® measures. RESULTS:On stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine (n?=?45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01?±?1.59 vs. -0.40?±?1.20; adj P?=?0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ?30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61?±?1.39) and usual care (-0.54?±?1.69) groups (adj P?=?0.540). CONCLUSION:These data support the potential benefits of CYP2D6-guided pain management.
Project description:Background: Tramadol and codeine are metabolized by CYP2D6 and are subject to drug-gene and drug-drug interactions. Methods: This interim analysis examined prescribing behavior and efficacy in 102 individuals prescribed tramadol or codeine while receiving pharmaco-genotyping as part of the INGENIOUS trial (NCT02297126). Results: Within 60 days of receiving tramadol or codeine, clinicians more frequently prescribed an alternative opioid in ultrarapid and poor metabolizers (odds ratio: 19.0; 95% CI: 2.8-160.4) as compared with normal or indeterminate metabolizers (p = 0.01). After adjusting the CYP2D6 activity score for drug-drug interactions, uncontrolled pain was reported more frequently in individuals with reduced CYP2D6 activity (odds ratio: 0.50; 95% CI: 0.25-0.94). Conclusion: Phenoconversion for drug-drug and drug-gene interactions is an important consideration in pharmacogenomic implementation; drug-drug interactions may obscure the potential benefits of genotyping.
Project description:Variation in the CYP2D6 gene may affect response to opioids in both poor and ultrarapid metabolizers, but data demonstrating such associations have been mixed, and the impact of variants on toxicity-related symptoms (e.g., nausea) is unclear. Therefore, we examined the association between CYP2D6 phenotype and poor pain control or other adverse symptoms related to the use of opioids in a sample of primary care patients.We identified all patients in the Mayo Clinic RIGHT Protocol who were prescribed an opioid medication between July 01, 2013 and June 30, 2015, and categorized patients into three phenotypes: poor, intermediate to extensive, or ultrarapid CYP2D6 metabolizers. We reviewed the electronic health record of these patients for indications of poor pain control or adverse symptoms related to medication use. Associations between phenotype and outcomes were assessed using Chi-square tests and logistic regression.Overall, 257 (25% of RIGHT Protocol participants) patients received at least one opioid prescription; of these, 40 (15%) were poor metabolizers, 146 (57%) were intermediate to extensive metabolizers, and 71 (28%) were ultrarapid metabolizers. We removed patients that were prescribed a CYP2D6 inhibitor medication (n=38). After adjusting for age and sex, patients with a poor or ultrarapid phenotype were 2.7 times more likely to experience either poor pain control or an adverse symptom related to the prescription compared to patients with an intermediate to extensive phenotype (odds ratio: 2.68; 95% CI: 1.39, 5.17; p=0.003).Our results suggest that >30% of patients with a poor or ultrarapid CYP2D6 phenotype may experience an adverse outcome after being prescribed codeine, tramadol, oxycodone, or hydrocodone. These medications are frequently prescribed for pain relief, and ~39% of the US population is expected to carry one of these phenotypes, suggesting that the population-level impact of these gene-drug interactions could be substantial.
Project description:<h4>Background</h4>Several opioids have pharmacogenomic associations impacting analgesic efficacy. However, germline pharmacogenomic testing is not routinely incorporated into supportive oncology. We hypothesized that CYP2D6 profiling would correlate with opioid prescribing and hospitalizations.<h4>Materials and methods</h4>We analyzed 61,572 adult oncology patients from 2012 to 2018 for opioid exposures. CYP2D6 metabolizer phenotype (ultra-rapid [UM], normal metabolizer [NM], intermediate [IM], or poor [PM]), the latter two of which may cause inefficacy of codeine, tramadol, and standard-dose hydrocodone, was determined for patients genotyped for reasons unrelated to pain. The primary endpoint was number of opioid medications received during longitudinal care (IM/PMs vs. NMs). Secondary endpoint was likelihood of pain-related hospital encounters.<h4>Results</h4>Most patients with cancer (n = 34,675, 56%) received multiple opioids (average 2.8 ± 1.6/patient). Hydrocodone was most commonly prescribed (62%), followed by tramadol, oxycodone, and codeine. In the CYP2D6 genotyped cohort (n = 105), IM/PMs received a similar number of opioids (3.4 ± 1.4) as NMs (3.3 ± 1.9). However, IM/PMs were significantly more likely to experience pain-related hospital encounters compared with NMs, independent of other variables (odds ratio [OR] = 5.4; 95% confidence interval [CI], 1.2-23.6; p = .03). IM/PMs were also more likely to be treated with later-line opioids that do not require CYP2D6 metabolism, such as morphine and hydromorphone (OR = 3.3; 95% CI, 1.1-9.8; p = .03).<h4>Conclusion</h4>CYP2D6 genotype may identify patients with cancer at increased risk for inadequate analgesia when treated with typical first-line opioids like codeine, tramadol, or standard-dose hydrocodone. Palliative care considerations are an integral part of optimal oncology care, and these findings justify prospective evaluation of preemptive genotyping as a strategy to improve oncology pain management.<h4>Implications for practice</h4>Genomic variation in metabolic enzymes can predispose individuals to inefficacy when receiving opioid pain medications. Patients with intermediate and/or poor CYP2D6 metabolizer status do not adequately convert codeine, tramadol, and hydrocodone into active compounds, with resulting increased risk of inadequate analgesia. This study showed that patients with cancer frequently receive CYP2D6-dependent opioids. However, patients with CYP2D6 intermediate and poor metabolizer status had increased numbers of pain-related hospitalizations and more frequently required the potent non-CYP2D6 opioids morphine and hydromorphone. This may reflect inadequate initial analgesia with the common "first-line" CYP2D6-metabolized opioids. Preemptive genotyping to guide opioid prescribing during cancer care may improve pain-related patient outcomes.
Project description:Background:Opioids are widely used for chronic low back pain (CLBP); however, it is still unclear how to predict their effectiveness and safety. Codeine, tramadol and oxycodone are metabolized by CYP/CYP450 2D6 (CYP2D6), a highly polymorphic enzyme linked to allele-specific related differences in metabolic activity. Purpose:CYP2D6 genetic polymorphisms could potentially help to predict the effectiveness and safety of opioid-based drugs in clinical practice, especially in the treatment of CLBP. Patients and methods:A cohort of 224 Italian patients with CLBP treated with codeine or oxycodone was retrospectively evaluated to determine whether adverse reactions and effectiveness were related to CYP2D6 single-nucleotide polymorphisms. CYP2D6 genotyping was performed using the xTAG® CYP2D6 Kit v3 (Luminex) to determine CYP2D6 metabolizer phenotype (poor, intermediate, rapid and ultrarapid). Subjects from the cohort were categorized into two groups according to the occurrence of side effects (Case) or benefit (Control) after chronic analgesic treatment. The impact of CYP2D6 polymorphism on treatment outcome was tested at the metabolizer phenotype, diplotype and haplotype levels. Results:CYP2D6 polymorphism was significantly associated with opioid treatment outcome (Omnibus P=0.018, for both global haplotype and diplotype distribution test). CYP2D6*6 and *9 carriers, alleles characterized by a reduced (*9) or absent (*6) enzymatic activity, were significantly (P<0.05) associated with therapeutic failure. CYP2D6 ultrarapid metabolizers (CYP2D6*2N patients) showed an increased risk of side effects, as would be predicted. Despite their low frequency, CYP2D6 *1/*11, *4/*6 and *41/* 2N diplotypes showed significant (P<0.05) associations of efficacy and side effects with chronic opioid treatment. Conclusion:Our results showed that reduced CYP2D6 activity is correlated with lack of therapeutic effect. We found that the pharmacogenetic analysis of CYP2D6 could be helpful in foreseeing the safety and effectiveness of codeine or oxycodone treatment in CLBP.
Project description:Cytochrome P450 2D6 (CYP2D6) O-demethylates codeine to the active drug, morphine. However, the utility of testing for CYP2D6 metabolizer status in patients receiving codeine in real-world clinical practice is poorly defined. Using data from a DNA bank linked to de-identified electronic health records, we studied 157 patients with a baseline pain score higher than 4 (0-10 scale) who received codeine. Based on CYP2D6 genotyping, 69 were classified as poor/intermediate and 88 as normal/ultrarapid CYP2D6 metabolizers. Pain response was defined as a score of 4 or lower while receiving codeine. In a propensity-score adjusted model, poor/intermediate metabolizers had lower odds (OR = 0.35, p = 0.02) of achieving a pain response than normal/ultrarapid metabolizers. To discriminate between codeine responders and nonresponders, a score including CYP2D6 phenotype and clinical variables was built. The response rate was 38.5% among patients in the high, 17.3% in the intermediate, and 9.4% in the low-score groups, respectively (p = 0.001).
Project description:Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.
Project description:Cytochrome P450 2D6 (CYP2D6) activity is highly variable due to several factors, including genetic polymorphisms and drug-drug-gene interactions. Hydrocodone, oxycodone, codeine, and tramadol the most commonly prescribed CYP2D6-activated opioids for pain. However, the co-administration of CYP2D6 interacting drugs can modulate CYP2D6-medicated activation of these opioids, affecting drug analgesia, effectiveness, and safety, and can impact healthcare costs. A retrospective, observational cohort analysis was performed in a large (<i>n</i> = 50,843) adult population. This study used drug claims data to derive medication risk scores and matching propensity scores to estimate the effects of opioid use and drug-drug interactions (DDIs) on medical expenditures. 4088 individuals were identified as opioid users; 95% of those were prescribed CYP2D6-activated opioids. Among those, 15% were identified as being at risk for DDIs. Opioid users had a significant increase in yearly medical expenditure compared to non-opioid users ($2457 vs. $1210). In matched individuals, average healthcare expenditures were higher for opioid users with DDIs compared to those without DDIs ($7841 vs. $5625). The derived medication risk score was higher in CYP2D6 opioid users with interacting drug(s) compared to no DDI (15 vs. 12). Higher costs associated with CYP2D6 opioid use under DDI conditions suggest inadequate CYP2D6 opioid prescribing practices. Efforts to improve chronic opioid use in adults should reduce interacting drug combinations, especially among patients using CYP2D6 activated opioids.
Project description:<h4>Objective</h4>To assess the potential impact of Pharmacogenomic (PGx) variation in cytochrome P450 2D6 (CYP2D6) enzyme function, using loss in quality-adjusted life years (QALYs) associated with treatment problems, and the willingness to pay to avoid treatment problems from patients' and payers' perspectives.<h4>Patients and methods</h4>The study included patients prescribed tramadol or codeine, or both, between January 1, 2005, and December 31, 2017. Demographic information and adverse drug events, including adverse drug events and poor pain control, were collected from the electronic health records using natural language processing techniques and review by trained abstractors. Patients' willingness to pay and QALY estimates were based on comprehensive literature review. The CYP2D6 phenotypes were divided into 4 groups: ultra-rapid metabolizers, normal metabolizers, intermediate metabolizers, and poor metabolizers.<h4>Results</h4>Among the 2860 identified patients, 63 (2%) were ultrarapid metabolizers, 1449 (50%) were normal metabolizers, 1155 (40%) were intermediate metabolizers, and 193 (7%) were poor metabolizers. The patients' average estimated willingness-to-pay value to avoid treatment problems was $23 per month; poor metabolizers developed problems with the highest estimated willingness-to-pay value ($32 per month). The mean QALY loss among all patients was 0.024 QALYs (8.8 healthy days); poor metabolizers had the highest loss (0.027 QALYs, 9.9 healthy days).<h4>Conclusion</h4>Patients with various phenotypes developed different treatment problem profiles. Poor CYP2D6 metabolizers developed problems with highest willingness to pay, and they might potentially benefit most from PGx-guided treatment and problem prevention.
Project description:Children represent a vulnerable population in which management of nociceptive pain is complex. Drug responses in children differ from adults due to age-related differences. Moreover, therapeutic choices are limited by the lack of indication for a number of analgesic drugs due to the challenge of conducting clinical trials in children. Furthermore the assessment of efficacy as well as tolerance may be complicated by children's inability to communicate properly. According to the World Health Organization, weak opioids such as tramadol and codeine, may be used in addition to paracetamol and ibuprofen for moderate nociceptive pain in both children and adults. However, codeine prescription has been restricted for the last 5 years in children because of the risk of fatal overdoses linked to the variable activity of cytochrome P450 (CYP) 2D6 which bioactivates codeine. Even though tramadol has been considered a safe alternative to codeine, it is well established that tramadol pharmacodynamic opioid effects, efficacy and safety, are also largely influenced by CYP2D6 activity. For this reason, the US Food and Drug Administration recently released a boxed warning regarding the use of tramadol in children. To provide safe and effective tramadol prescription in children, a personalized approach, with dose adaptation according to CYP2D6 activity, would certainly be the safest method. We therefore recommend this approach in children requiring chronic or recurrent nociceptive pain treatment with tramadol. In case of acute inpatients nociceptive pain management, prescribing tramadol at the minimal effective dose, in a child appropriate dosage form and after clear instructions are given to the parents, remains reasonable based on current data. In all other situations, morphine should be preferred for moderate to severe nociceptive pain conditions.
Project description:Clinical pharmacogenetics, the use of genetic data to guide drug therapy decisions, is beginning to be used for medications commonly prescribed by family physicians. However, clinicians are largely unfamiliar with principles supporting clinical use of this type of data. For example, genetic variability in the cytochrome P450 2D6 drug metabolizing enzyme can alter the clinical effects of some opioid analgesics (e.g., codeine, tramadol), whereas variability in the CYP2C19 enzyme affects the antiplatelet agent clopidogrel. If testing is performed, patients who are ultrarapid or poor metabolizers of CYP2D6 should avoid codeine use (and possibly tramadol, hydrocodone, and oxycodone) because of the potential for increased toxicity or lack of effectiveness. Patients undergoing percutaneous coronary intervention for acute coronary syndromes who are known to be poor metabolizers of CYP2C19 should consider alternate antiplatelet therapy (e.g., ticagrelor, prasugrel). Some guidelines are available that address appropriate drug therapy changes, and others are in development. Additionally, a number of clinical resources are emerging to support family physicians in the use of pharmacogenetics. When used appropriately, pharmacogenetic testing can be a practical tool to optimize drug therapy and avoid medication adverse effects.