Adverse Drug Reactions Due to Opioid Use in Oldest-Old Patients Visiting the Emergency Unit of the Geneva Geriatric Hospital.

Opioid use has much increased in several countries during the last two decades, accompanied by a rise in associated morbidity and mortality, especially in the United States. Data on a possible opioid crisis are scarcer in Europe. We performed a study aiming to assess the frequency of adverse drug reactions (ADR) related to opioids in patients presenting to the emergency unit (EU) of a geriatric tertiary Swiss University Hospital. This particular setting is intended for patients aged 75 and older. Our retrospective, monocentric survey of opioid use and related ADR was conducted over two months in 2018. The main and secondary outcomes were the frequency of EU visits considered due to an opioid ADR and insufficient pain relief, respectively. Current opioid use was identified in 20.3% (n=99) of the 487 included EU visits (mean age 86). An ADR was the suspected cause of the EU visit in 22 opioid users, mainly fall-related injury and gastrointestinal disorders. All these patients had at least one comorbid condition. In 19/22 cases (86%) of ADR, a drug-drug interaction might have been involved. In 12 opioid users (12%), insufficient pain relief was suspected as the cause of the EU visit. In conclusion, one-third of opioid users visiting a geriatric EU consulted for a problem related to its use mainly adverse drug-related reaction (22%) followed by insufficient pain relief (12%).

Drug metabolic enzyme genotype-phenotype discrepancy: High phenoconversion rate in patients treated with antidepressants.

Cytochromes from the P450 family (CYP) play a central role in the primary metabolism of frequently prescribed antidepressants, potentially affecting their efficacy and tolerance. There are however important differences in the drug metabolic capacities of each individual resulting from a combination of intrinsic and environmental factors. This variability can present an important risk for patients and increases the difficulty of drug prescription in clinical practice. Pharmacogenetic studies have uncovered a number of alleles defining the intrinsic metabolizer status, however, additional factors affecting cytochrome activity can modify this activity and result in a phenoconversion. The present study investigates the discrepancy between the genetically predicted and actually measured activities for the six most important liver cytochromes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) in a cohort of patients under antidepressant treatment, previously shown to have a high proportion of patients with low metabolizing activities. We now performed the genetic characterization of this cohort to determine the extent of the genetic versus environmental contribution in these decreased activities. For all enzyme tested, we observed an important rate of phenoconversion, affecting between 33 % and 65 % of the patients, as well as a significant (p < 1E-06) global reduction in the effective but not predicted activities of CYP2D6, CYP2C9 and CYP2C19 compared to the general population. Our results highlight the advantages of phenotyping versus genotyping as well as the increased risk of treatment failure or adverse effect occurrence in a polymedicated population.

Simultaneous determination of melatonin and 6-hydroxymelatonin in human overnight urine by LC-MS/MS.

For the quantification of the pineal hormone melatonin and its metabolite, 6-hydroxymelatonin, in human overnight urine, a single accurate method by liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed. Urine samples were deconjugated using ß-glucuronidase/arylsulfatase from Helix pomatia before solid phase extraction (SPE) purification. Chromatographic separation was performed using a reverse phase C18 column with a 7-minute gradient elution. Water was used as matrix to prepare the calibration standards, and deuterated analogues of melatonin and 6-hydroxymelatonin were used as internal standards. This newly developed method was validated in terms of linearity, accuracy, repeatability, intermediate precision, recovery, matrix effect, and stability according to the guidelines of the European Medicines Agency. The method was successfully applied to the analysis of overnight urine samples from 12 healthy volunteers, showing significant correlations of urinary melatonin and 6-hydroxymelatonin excretion rates with age. The urinary 6-hydroxymelatonin to melatonin ratio was also established and will be assessed in further studies as a potential endogenous metric of CYP1A2 activity.

Coadministration of ticagrelor and ritonavir: Toward prospective dose adjustment to maintain an optimal platelet inhibition using the PBPK approach.

Ticagrelor is a potent antiplatelet drug metabolized by cytochrome (CYP)3A. It is contraindicated in patients with human immunodeficiency virus (HIV) because of the expected CYP3A inhibition by most protease inhibitors, such as ritonavir and an increased bleeding risk. In this study, a physiologically based pharmacokinetic (PBPK) model was created for ticagrelor and its active metabolite (AM). Based on the simulated interaction between ticagrelor 180 mg and ritonavir 100 mg, a lower dose of ticagrelor was calculated to obtain, when coadministered with ritonavir, the same pharmacokinetic (PK) and platelet inhibition as ticagrelor administered alone. A clinical study was thereafter conducted in healthy volunteers. Observed PK profiles of ticagrelor and its AM were successfully predicted with the model. Platelet inhibition was nearly complete in both sessions despite administration of a fourfold lower dose of ticagrelor in the second session. This PBPK model could be prospectively used to broaden the usage of ticagrelor in patients with ritonavir-treated HIV regardless of the CYP3A inhibition.

Prediction of Metabolic Interactions With Oxycodone via CYP2D6 and CYP3A Inhibition Using a Physiologically Based Pharmacokinetic Model.

Evaluation of a potential risk of metabolic drug-drug interactions (DDI) is of high importance in the clinical setting. In this study, a physiologically based pharmacokinetic (PBPK) model was developed for oxycodone and its two primary metabolites, oxymorphone and noroxycodone, in order to assess different DDI scenarios using published in vitro and in vivo data. Once developed and refined, the model was able to simulate pharmacokinetics of the three compounds and the DDI extent in case of coadministration with an inhibitor, as well as the oxymorphone concentration variation between CYP2D6 extensive metabolizers (EM) and poor metabolizers (PM). The reliability of the model was tested against published clinical studies monitoring different inhibitors and dose regimens, and all predicted area under the concentration-time curve (AUC) ratios were within the twofold acceptance range. This approach represents a strategy to evaluate the impact of coadministration of different CYP inhibitors using mechanistic incorporation of drug-dependent and system-dependent available in vitro and in vivo data.

Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots.

The suitability of the capillary dried blood spot (DBS) sampling method was assessed for simultaneous phenotyping of cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) using a cocktail approach. Ten volunteers received an oral cocktail capsule containing low doses of the probes bupropion (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and fexofenadine (P-gp) with coffee/Coke (CYP1A2) on four occasions. They received the cocktail alone (session 1), and with the CYP inhibitors fluvoxamine and voriconazole (session 2) and quinidine (session 3). In session 4, subjects received the cocktail after a 7-day pretreatment with the inducer rifampicin. The concentrations of probes/metabolites were determined in DBS and plasma using a single liquid chromatography-tandem mass spectrometry method. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. Important modulation of CYP and P-gp activities was observed in the presence of inhibitors and the inducer. Minimally invasive one- and three-point (at 2, 3, and 6 h) DBS-sampling methods were found to reliably reflect CYP and P-gp activities at each session.

Applications of CYP450 testing in the clinical setting.

Interindividual variability in drug response is a major clinical problem. Polymedication and genetic polymorphisms modulating drug-metabolising enzyme activities (cytochromes P450, CYP) are identified sources of variability in drug responses. We present here the relevant data on the clinical impact of the major CYP polymorphisms (CYP2D6, CYP2C19 and CYP2C9) on drug therapy where genotyping and phenotyping may be considered, and the guidelines developed when available. CYP2D6 is responsible for the oxidative metabolism of up to 25% of commonly prescribed drugs such as antidepressants, antipsychotics, opioids, antiarrythmics and tamoxifen. The ultrarapid metaboliser (UM) phenotype is recognised as a cause of therapeutic inefficacy of antidepressant, whereas an increased risk of toxicity has been reported in poor metabolisers (PMs) with several psychotropics (desipramine, venlafaxine, amitriptyline, haloperidol). CYP2D6 polymorphism influences the analgesic response to prodrug opioids (codeine, tramadol and oxycodone). In PMs for CYP2D6, reduced analgesic effects have been observed, whereas in UMs cases of life-threatening toxicity have been reported with tramadol and codeine. CYP2D6 PM phenotype has been associated with an increased risk of toxicity of metoprolol, timolol, carvedilol and propafenone. Although conflicting results have been reported regarding the association between CYP2D6 genotype and tamoxifen effects, CYP2D6 genotyping may be useful in selecting adjuvant hormonal therapy in postmenopausal women. CYP2C19 is responsible for metabolising clopidogrel, proton pump inhibitors (PPIs) and some antidepressants. Carriers of CYP2C19 variant alleles exhibit a reduced capacity to produce the active metabolite of clopidogrel, and are at increased risk of adverse cardiovascular events. For PPIs, it has been shown that the mean intragastric pH values and the Helicobacter pylori eradication rates were higher in carriers of CYP2C19 variant alleles. CYP2C19 is involved in the metabolism of several antidepressants. As a result of an increased risk of adverse effects in CYP2C19 PMs, dose reductions are recommended for some agents (imipramine, sertraline). CYP2C9 is responsible for metabolising vitamin K antagonists (VKAs), non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas, angiotensin II receptor antagonists and phenytoin. For VKAs, CYP2C9 polymorphism has been associated with lower doses, longer time to reach treatment stability and higher frequencies of supratherapeutic international normalised ratios (INRs). Prescribing algorithms are available in order to adapt dosing to genotype. Although the existing data are controversial, some studies have suggested an increased risk of NSAID-associated gastrointestinal bleeding in carriers of CYP2C9 variant alleles. A relationship between CYP2C9 polymorphisms and the pharmacokinetics of sulfonylureas and angiotensin II receptor antagonists has also been observed. The clinical impact in terms of hypoglycaemia and blood pressure was, however, modest. Finally, homozygous and heterozygous carriers of CYP2C9 variant alleles require lower doses of phenytoin to reach therapeutic plasma concentrations, and are at increased risk of toxicity. New diagnostic techniques made safer and easier should allow quicker diagnosis of metabolic variations. Genotyping and phenotyping may therefore be considered where dosing guidelines according to CYP genotype have been published, and help identify the right molecule for the right patient.

Identification and weighting of the most critical "real-life" drug-drug interactions with acenocoumarol in a tertiary care hospital.

PURPOSE: The objective of this study was to identify the most clinically relevant drug-drug interactions (DDIs) at risk of affecting acenocoumarol safety in our tertiary care university hospital, a 2,000 bed institution. METHODS: We identified DDIs occurring with acenocoumarol by combining two different sources of information: a 1-year retrospective analysis of acenocoumarol prescriptions and comedications from our Computerized Physician Order Entry (CPOE) system (n = 2,439 hospitalizations) and a retrospective study of clinical pharmacology consultations involving acenocoumarol over the past 14 years (1994-2007) (n = 407). We classified these DDIs using an original risk-analysis method. A criticality index was calculated for each associated drug by multiplying three scores based on mechanism of interaction, involvement in a supratherapeutic international normalized ratio (INR) (≥ 6) and involvement in a severe bleeding. RESULTS: One hundred and twenty-six DDIs were identified and weighted. Twenty-eight drugs had a criticality index ≥ 20 and were therefore considered at high risk for interacting with acenocoumarol by increasing its effect: 75% of these drugs involved a pharmacokinetic mechanism and 14 % a pharmacodynamic mechanism. An unknown mechanism of interaction was involved in 11 % of drugs. CONCLUSION: Twenty-eight specific drugs were identified as being at high risk for interacting with acenocoumarol in our hospital using an original risk-analysis method. Most analyzed drugs interact with acenocoumarol via a pharmacokinetic mechanism. Actions such as the implementation of alerts in our CPOE system should be specifically developed for these drugs.

[Comparison of four drug interaction screening programs]. / Quel programme informatique de détection des interactions médicamenteuses néfastes?

Adverse drug events (ADE) are a major public health issue, with drug-drug interactions (DDI) being one of well-recognized causes of ADE that could be preventable by the use of DDI screening software. We compared the ability of four programs to detect clinically important DDI. We tested 62 drug pairs with and 12 drug pairs without clinically important DDI. Lexi-Interact and Epocrates were the most sensitive (95%) compared to the Compendium and Theriaque (80 and 73%, respectively). The Compendium and Theriaque also showed the lowest negative predictive value. All programs showed high specificity and positive predictive value. The qualitative assessment showed the best performances for Compendium and Lexi-Interact. The last one seems to be the best screening program, but the Compendium is in French and is freely available.

Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection.

Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.

The paraoxonase-1 pathway is not a major bioactivation pathway of clopidogrel in vitro.

BACKGROUND AND PURPOSE: Clopidogrel is a prodrug bioactivated by cytochrome P450s (CYPs). More recently, paraoxonase-1 (PON1) has been proposed as a major contributor to clopidogrel metabolism. The purpose of this study was to assess the relative contribution of CYPs and PON1 to clopidogrel metabolism in vitro. EXPERIMENTAL APPROACH: Clopidogrel metabolism was studied in human serum, recombinant PON1 enzyme (rePON1), pooled human liver microsomes (HLMs), HLMs with the CYP2C19*1/*1 genotype and HLMs with the CYP2C19*2/*2 genotype. Inhibition studies were also performed using specific CYP inhibitors and antibodies. Clopidogrel and its metabolites were measured using LC/MS/MS method. KEY RESULTS: PON1 activity was highest in the human serum and there was no difference in PON1 activity between any of the HLM groups. The production of clopidogrel's active metabolite (clopidogrel-AM) from 2-oxo-clopidogrel in pooled HLMs was approximately 500 times that in serum. When 2-oxo-clopidogrel was incubated with rePON1, clopidogrel-AM was not detected. Clopidogrel-AM production from 2-oxo-clopidogrel was lower in CYP2C19*2/*2 HLMs compared with CYP2C19*1/*1 HLMs, while PON1 activity in HLMs with both genotypes was similar. Moreover, incubation with inhibitors of CYP3A, CYP2B6 and CYP2C19 significantly reduced clopidogrel bioactivation while a PON1 inhibitor, EDTA, had only a weak inhibitory effect. CONCLUSION AND IMPLICATIONS: This in vitro study shows that the contribution of PON1 to clopidogrel metabolism is limited at clinically relevant concentrations. Moreover, CYP2C19, CYP2B6 and CYP3A play important roles in the bioactivation of clopidogrel.

[Adverse effects of proton pump inhibitors: should we worry about long-term exposure?]. / Effets indésirables des inhibiteurs de la pompe à proton : faut-il craindre de les prescrire au long cours ?

Long-term treatment with proton pump inhibitors (PPI) is becoming more prevalent. Although they are well tolerated in the short term, serious concerns about long-term use have arisen. Recent data suggest that the latter is associated with an increased risk for osteoporotic fracture (especially vertebral), Clostridium difficile infection and rebound acid hypersecretion after treatment discontinuation. Acute interstitial nephritis is rare but may progress to chronic renal failure. An increased risk of community-acquired pneumonia has not been established in the general population and seems limited to the most vulnerable patients. Consistent data are still missing to correctly assess the risk of iron deficiency, vitamin B12 deficiency or hypomagnesaemia and the risk of digestive malignant diseases, despite the pathophysiological basis that exists concerning gastric malignancy. Many drug interactions can occur on long-term treatment, including some that imply the cytochrome P450 enzymes. Finally, the risk-benefit balance for a chronic PPI use in children seems unfavorable in most cases.

Oral flurbiprofen metabolic ratio assessment using a single-point dried blood spot.

We investigated whether a single blood measurement using the minimally invasive technique of a finger prick to draw a blood sample of 5 µl (to yield a dried blood spot (DBS)) is suitable for the assessment of flurbiprofen (FLB) metabolic ratio (MR). Ten healthy volunteers who had been genotyped for CYP2C9 were recruited as subjects. They received FLB alone in session 1 and FLB with fluconazole in session 2. In session 3, the subjects were pretreated for 4 days with rifampicin and received FLB with the last dose of rifampicin on day 5. Plasma and DBS samples were obtained between 0 and 8 h after FLB administration, and urine was collected during the 8 h after administration. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. FLB's apparent clearance values decreased by 35% in plasma and DBS during session 2 and increased by 75% in plasma and by 30% in DBS during session 3. Good correlations were observed between MRs calculated from urine, plasma, and DBS samples.

[Analgesic placebo effect: contribution of the neurosciences]. / Effet placebo analgésique: apport des neurosciences.

Over the past twenty years, neuroscience has changed our understanding of placebo analgesia. Often perceived by researchers as a response bias adding noise to the assessment of efficacy, in the patients' view, it is associated with charlatanism. The origin of the word, qualifying a patient's response to "please" the doctor, did not help its rightful appreciation. However, today the placebo analgesia is considered as a psychobiological phenomenon. Thanks to pharmacological manipulations and the development of functional brain imaging, the neural circuitry involved in this effect as well as the role of endorphins and dopamine have been identified. This article describes our current knowledge about this fascinating phenomenon: a psychological modulation can lead to a biological effect.

[Placebo, an underestimated ally]. / Le placebo, un allié mésestimé...

Patients' views and patient-oriented outcomes are increasingly acknowledged, including beliefs about pain and illness, and expectations of treatment. Indeed, how far patient expectations influence outcomes has developed into an important area of research, and all the more so as the impact of expectations on subjective outcome is related to the placebo effects; indeed, expectations can both mediate and modulate these effects. Surgery has been suggested as conveying a placebo effect related to the ceremony of surgical preparation, the use of sophisticated techniques and the need for hospitalization possibly leading to increased pain management, more active sympathy and disease recognition.

[Opioid rotation: from theory to practice. Interdisciplinary recommendations from the Geneva University Hospitals pain network]. / Rotation des opioïdes: de ta théorie à la pratique. Recommandations interdisciptinaires du réseau douleur des HUG.

Opioids are widely used to treat moderate to severe pain of cancer or non cancer origin. Although opioids provide an adequate analgesia in many patients, their use can be limited by inefficacy and/or intolerable side effects. Opioid rotation is one of the strategies that have been proposed to overcome these therapeutic difficulties. This article revisits the concept of opioid rotation, from pharmacological rational to clinical application.

Impact of genetic polymorphisms and drug-drug interactions on clopidogrel and prasugrel response variability.

Thienopyridine antiaggregating platelet agents (clopidogrel and prasugrel) act as irreversible P2Y12 receptor inhibitors. They are used with aspirin to prevent thrombotic complications after an acute coronary syndrome or percutaneous coronary intervention. A large interindividual variability in response to clopidogrel and to a lesser extent to prasugrel is observed and may be related to their metabolism. Clopidogrel and prasugrel are indeed prodrugs converted into their respective active metabolites by several cytochromes P450 (CYPs). Besides clopidogrel inactivation (85%) by esterases to the carboxylic acid, clopidogrel is metabolized by CYPs to 2-oxo-clopidogrel (15%) and further metabolized to an unstable but potent platelet-aggregating inhibitor. Prasugrel is more potent than clopidogrel with a better bioavailability and lower pharmacodynamic variability. Prasugrel is completely converted by esterases to an intermediate oxo-metabolite (R-95913) further bioactivated by CYPs. Numerous clinical studies have shown the influence of CYP2C19 polymorphism on clopidogrel antiplatelet activity. Moreover, unwanted drug-drug pharmacokinetic interactions influencing CYP2C19 activity and clopidogrel bioactivation such as with proton pump inhibitors remain a matter of intense controversy. Several studies have also demonstrated that CYP3A4/5 and CYP1A2 are important in clopidogrel bioactivation and should also be considered as potential targets for unwanted drug-drug interactions. Prasugrel bioactivation is mainly related to CYP3A4 and 2B6 activity and therefore the question of the effect of drug-drug interaction on its activity is open. The purpose of this review is to critically examine the current literature evaluating the influence of genetic and environmental factors such as unwanted drug-drug interaction affecting clopidogrel and prasugrel antiplatelet activity.

The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone.

BACKGROUND AND PURPOSE: There is high interindividual variability in the activity of drug-metabolizing enzymes catalysing the oxidation of oxycodone [cytochrome P450 (CYP) 2D6 and 3A], due to genetic polymorphisms and/or drug-drug interactions. The effects of CYP2D6 and/or CYP3A activity modulation on the pharmacokinetics of oxycodone remains poorly explored. EXPERIMENTAL APPROACH: A randomized crossover double-blind placebo-controlled study was performed with 10 healthy volunteers genotyped for CYP2D6 [six extensive (EM), two deficient (PM/IM) and two ultrarapid metabolizers (UM)]. The volunteers randomly received on five different occasions: oxycodone 0.2 mg x kg(-1) and placebo; oxycodone and quinidine (CYP2D6 inhibitor); oxycodone and ketoconazole (CYP3A inhibitor); oxycodone and quinidine+ketoconazole; placebo. Blood samples for plasma concentrations of oxycodone and metabolites (oxymorphone, noroxycodone and noroxymorphone) were collected for 24 h after dosing. Phenotyping for CYP2D6 (with dextromethorphan) and CYP3A (with midazolam) were assessed at each session. KEY RESULTS: CYP2D6 activity was correlated with oxymorphone and noroxymorphone AUCs and C(max) (-0.71 < Spearman correlation coefficient rhos < -0.92). Oxymorphone C(max) was 62% and 75% lower in PM than EM and UM. Noroxymorphone C(max) reduction was even more pronounced (90%). In UM, oxymorphone and noroxymorphone concentrations increased whereas noroxycodone exposure was halved. Blocking CYP2D6 (with quinidine) reduced oxymorphone and noroxymorphone C(max) by 40% and 80%, and increased noroxycodone AUC(infinity) by 70%. Blocking CYP3A4 (with ketoconazole) tripled oxymorphone AUC(infinity) and reduced noroxycodone and noroxymorphone AUCs by 80%. Shunting to CYP2D6 pathway was observed after CYP3A4 inhibition. CONCLUSIONS AND IMPLICATIONS: Drug-drug interactions via CYP2D6 and CYP3A affected oxycodone pharmacokinetics and its magnitude depended on CYP2D6 genotype.

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety.

BACKGROUND AND PURPOSE: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. EXPERIMENTAL APPROACH: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg x kg(-1)) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. KEY RESULTS: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone C(max) was correlated with SPT assessment (rho(S)= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. CONCLUSIONS AND IMPLICATIONS: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.