CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial

Smith, D. Max; Weitzel, Kristin; Elsey, Amanda R.; Langaee, Taimour; Gong, Yan; Wake, Dyson T; Duong, Benjamin Q.; Hagen, Melanie; Harle, Christopher A.; Mercado, Elvira; Nagoshi, Ying; Newsom, Kimberly; Wright, Ashleigh; Rosenberg, Eric I.; Starostik, Petr; Clare‐Salzler, Michael; Schmidt, Siegfried; Fillingim, Roger B.; Johnson, Julie A.; Cavallari, Larisa H.

doi:10.1038/s41436-018-0431-8

Cited by 109 publications

(125 citation statements)

References 36 publications

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“…Oxymorphone, which is the second most abundant metabolite, exhibits 8 times the potency and 40 times the affinity on μ‐opioid receptor as compared to oxycodone. Despite this, the majority of studies suggest that the contribution of oxymorphone to the pharmacodynamic effects of oxycodone administrations is minimal, presumably attributed to the very low plasma concentrations, rapid glucuronidation to an inactive metabolite and/or the low rate of crossing the blood‐brain barrier . Nevertheless, opposing results have been demonstrated by Samer et al, although the impact on pupil size was not as substantial as other pharmacodynamic parameters, thus questioning the central effects of oxymorphone .…”

Section: Discussionmentioning

confidence: 97%

Population pharmacokinetic‐pharmacodynamic modelling of liquid and controlled‐release formulations of oxycodone in healthy volunteers

Ladebo

Foster

Abuhelwa

et al. 2019

Basic Clin Pharma Tox

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Oral controlled‐release formulations are playing an ever‐increasing role in opioid therapy; however, little is known about their influence on the relationship between pharmacokinetics and pharmacodynamics. The study aim was to characterize the pharmacokinetic‐pharmacodynamics of two controlled‐release tablet formulations and a liquid formulation of oxycodone in healthy, opioid‐naïve volunteers, which can serve as a reference for future patient studies. A semi‐double‐blinded, three‐way crossover study was conducted, with fifteen healthy volunteers receiving two differently designed 20 mg monophasic controlled‐release oxycodone tablets and 10 mg oral solution oxycodone in a randomized order. Venous plasma concentrations and pupil diameter were determined pre‐dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.33, 2.66, 3, 3.33, 3.66, 4, 5, 6, 8, 12 and 24 hour post‐dose. Oxycodone pharmacokinetics was best described by a two‐compartment model with first‐order absorption. The controlled‐release formulations had an absorption lag of 0.23 hour and a slower absorption rate constant (kaCR = 0.19 hour‐1) compared to the oral solution (kaSOL = 0.94 hour‐1). Effects on pupil diameter were delayed relative to plasma (14 minutes half‐life) for all formulations and were best described by a proportional Emax model. The plasma concentration of oxycodone at half‐maximum effect was lower in males (31.1 μg/L) compared to females (52.8 μg/L; P < .001). The absorption profile of controlled‐release oxycodone formulations provided a prolonged onset and offset of action compared to oral solution oxycodone. The controlled‐release formulations showed no differences in pharmacokinetic and pharmacodynamic parameters suggesting that both may be used interchangeably in human beings with normal gastrointestinal function.

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Section: Discussionmentioning

confidence: 97%

Population pharmacokinetic‐pharmacodynamic modelling of liquid and controlled‐release formulations of oxycodone in healthy volunteers

Ladebo

Foster

Abuhelwa

et al. 2019

Basic Clin Pharma Tox

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“…Despite calls for comparative effectiveness research in genomic medicine, the use of PCTs to develop this evidence base remains sparse . At present, the majority of genomic and precision medicine research has occurred within the early phases of the translational continuum (T0/T1), focusing primarily on gene discovery, support for analytic and clinical validity, and the development of health applications .…”

Section: Discussionmentioning

confidence: 99%

“…Despite calls for comparative effectiveness research in genomic medicine, 7,8 the use of PCTs to develop this evidence base remains sparse. 34,35 At present, the majority of genomic and precision medicine research has occurred within the early phases of the translational continuum (T0/T1), focusing primarily on gene discovery, support for analytic and clinical validity, and the development of health applications. 2,9 Although growing, very few research initiatives have been 22 Regular CVD risk score calculations refer to the daily generation of 10-year CVD risk scores using the birthday parity method as described by Vassy et al 21 CVD, cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Pragmatic Trials in Genomic Medicine: The Integrating Pharmacogenetics In Clinical Care (I‐PICC) Study

Brunette

Miller

Majahalme

et al. 2019

Clinical Translational Sci

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Pragmatic clinical trials (PCTs) have an established presence in clinical research and yet have only recently garnered attention within the landscape of genomic medicine. Using the PRagmatic‐Explanatory Continuum Indicator Summary 2 (PRECIS‐2) as a framework, this paper illustrates the application of PCT principles to The Integrating Pharmacogenetics In Clinical Care (I‐PICC) Study, a trial of pharmacogenetic testing prior to statin initiation for cardiovascular disease prevention in primary care. The trial achieved high engagement with providers (85% enrolled of those approached) and enrolled a representative sample of participants for which statin therapy would be recommended. The I‐PICC Study has a high level of pragmatism, which should enhance the generalizability of its findings. The PRECIS‐2 may be useful in the design and evaluation of PCTs of genomic medicine interventions, contributing to the generation of evidence that can bridge the gap between genomics innovation and clinical adoption.

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“…8 A clinical trial investigating the effects of CYP2D6-guided opioid prescribing on pain control found that intermediate and poor metabolizers prescribed genotype-appropriate doses of tramadol and/or codeine (n = 45) had greater improvement of pain intensity in the CYP2D6-guided versus usual care arm. 9 Our own investigations of patient response related to codeine, tramadol, hydrocodone, and oxycodone in a cohort of 257 patients found that more than 30% of those with a CYP2D6 poor or ultra-rapid phenotype experienced either adverse reactions or lack of pain relief related to opioid use. 10 In short, these results suggest poor pain control in individuals with CYP2D6 poor metabolizer status and more adverse reactions in individuals with CYP2D6 ultra-rapid metabolizer status.…”

Section: Introductionmentioning

confidence: 99%

<p>Sex Differences in Associations Between CYP2D6 Phenotypes and Response to Opioid Analgesics</p>

Lopes

Bielinski

Moyer³

et al. 2020

PGPM

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Background: Several small studies have previously investigated associations between the cytochrome P450 2D6 (CYP2D6) metabolism and response to opioids. We used a large sample of patients to study associations between CYP2D6 phenotypes and estimated CYP2D6 enzymatic activity scores with pain control and adverse reactions related to codeine and tramadol use. We conducted additional analyses to determine whether our results were consistent among men and women. Methods: We used data from 2,877 participants in the RIGHT Protocol who were prescribed codeine and/or tramadol between 01/01/2005 and 12/31/2017 and who were not prescribed CYP2D6 inhibitors within 1 year prior to the opioid prescription. CYP2D6 phenotype categories were condensed into four groups: (1) Ultra-rapid and Rapid (n = 61), (2) Normal and Intermediate to Normal (n = 1,448), (3) Intermediate and Intermediate to Poor (n = 1,175), and (4) Poor metabolizer status (n = 193). Opioid-related outcomes included indications of poor pain control or adverse reactions related to medication use. We modeled the risk of each outcome using logistic regression, adjusting for age, sex, race, and ethnicity. Results: The results revealed a trend from poor to ultra-rapid and rapid CYP2D6 phenotypes in which the risk of adverse reactions incrementally increased and the risk of poor pain control incrementally decreased. This trend reached statistical significance among female (but not male) participants. Among normal and intermediate to normal metabolizers, a larger proportion of women experienced adverse reactions relative to men. Discussion: We replicated and extended the findings of previous research indicating associations between CYP2D6 phenotypes and response to opioids. In addition, the observed associations were stronger in women than in men. We recommend sex differences to be factored in future research investigating associations between pharmacogenomics and response to medications.

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CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial

Cited by 109 publications

References 36 publications

Population pharmacokinetic‐pharmacodynamic modelling of liquid and controlled‐release formulations of oxycodone in healthy volunteers

Population pharmacokinetic‐pharmacodynamic modelling of liquid and controlled‐release formulations of oxycodone in healthy volunteers

Pragmatic Trials in Genomic Medicine: The Integrating Pharmacogenetics In Clinical Care (I‐PICC) Study

<p>Sex Differences in Associations Between CYP2D6 Phenotypes and Response to Opioid Analgesics</p>

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