Scandinavian Journal of Pain
Volume 1, Issue 1 , Pages 24-33, January 2010

Does co-administration of paroxetine change oxycodone analgesia: An interaction study in chronic pain patients

  • K.K. Lemberg

      Affiliations

    • Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland
    • Corresponding Author InformationCorresponding author at: Institute of Biomedicine/Pharmacology, P.O. Box 63, FIN-00014 University of Helsiki, Finland. Tel.: +358 50 5950009; fax: +358 9 19125364.
    • ,
  • T.E. Heiskanen

      Affiliations

    • Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland
    • ,
  • M. Neuvonen

      Affiliations

    • Department of Clinical Pharmacology, Helsinki University Central Hospital, Helsinki, Finland
    • ,
  • V.K. Kontinen

      Affiliations

    • Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland
    • Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland
    • ,
  • P.J. Neuvonen

      Affiliations

    • Department of Clinical Pharmacology, Helsinki University Central Hospital, Helsinki, Finland
    • ,
  • M.-L. Dahl

      Affiliations

    • Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden
    • ,
  • E.A. Kalso

      Affiliations

    • Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland

Article Outline

Abstract 

Oxycodone is a strong opioid and it is increasingly used in the management of acute and chronic pain. The pharmacodynamic effects of oxycodone are mainly mediated by the μ-opioid receptor. However, its affinity for the μ-opioid receptor is significantly lower compared with that of morphine and it has been suggested that active metabolites may play a role in oxycodone analgesia. Oxycodone is mainly metabolized by hepatic cytochrome (CYP) enzymes 2D6 and 3A4. Oxycodone is metabolized to oxymorphone, a potent μ-opioid receptor agonist by CYP2D6. However, CYP3A4 is quantitatively a more important metabolic pathway. Chronic pain patients often use multiple medications. Therefore it is important to understand how blocking or inducing these metabolic pathways may affect oxycodone induced analgesia. The aim of this study was to find out whether blocking CYP2D6 would decrease oxycodone induced analgesia in chronic pain patients.

The effects of the antidepressant paroxetine, a potent inhibitor of CYP2D6, on the analgesic effects and pharmacokinetics of oral oxycodone were studied in 20 chronic pain patients using a randomized, double-blind, placebo-controlled cross-over study design. Pain intensity and rescue analgesics were recorded daily, and the pharmacokinetics and pharmacodynamics of oxycodone were studied on the 7th day of concomitant paroxetine (20mg/day) or placebo administration. The patients were genotyped for CYP2D6, 3A4, 3A5 and ABCB1.

Paroxetine had significant effects on the metabolism of oxycodone but it had no statistically significant effect on oxycodone analgesia or use of morphine for rescue analgesia. Paroxetine increased the dose-adjusted mean AUC0–12h of oxycodone by 19% (−23 to 113%; P=0.003), and that of noroxycodone by 100% (5–280%; P<0.0001) but decreased the AUC0–12h of oxymorphone by 67% (−100 to −22%; P<0.0001) and that of noroxymorphone by 68% (−100 to −16%; P<0.0001).

Adverse effects were also recorded in a pain diary for both 7-day periods (placebo/paroxetine). The most common adverse effects were drowsiness and nausea/vomiting. One patient out of four reported dizziness and headache during paroxetine co-administration, whereas no patient reported these during placebo administration (P=0.0471) indicating that these adverse effects were due to paroxetine.

No statistically significant associations of the CYP2D6 or CYP3A4/5 genotype of the patients and the pharmacokinetics of oxycodone or its metabolites, extent of paroxetine–oxycodone interaction, or analgesic effects were observed probably due to the limited number of patients studied.

The results of this study strongly suggest that CYP2D6 inhibition does not significantly change oxycodone analgesia in chronic pain patients and that the analgesic activity of oxycodone is mainly due to the parent compound and that metabolites, e.g. oxymorphone, play an insignificant role. The clinical implication of these results is that induction of the metabolism of oxycodone may lead to inadequate analgesia while increased drug effects can be expected after addition of potent CYP3A4/5 inhibitors particularly if combined with CYP2D6 inhibitors or when administered to poor metabolizers of CYP2D6.

Keywords: Oxycodone, Paroxetine, Noroxycodone, Oxymorphone, Noroxymorphone, Chronic pain, Analgesia

 

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1. Introduction 

Oral oxycodone is increasingly used to manage chronic pain. Patients needing oxycodone often use several concomitant drugs. Thus, safe and effective use of oxycodone requires knowledge about possible drug interactions.

Oxycodone is a derivate of the opium alkaloid thebaine and it shares many similarities in its molecular structure with codeine and morphine. In humans oxycodone has greater oral bioavailability (60–87%) (Leow et al., 1992, Pöyhiä et al., 1992) than morphine (19–30%) (Osborne et al., 1990) and it undergoes extensive metabolism by CYP enzymes, mainly in the liver. The recovery of oxycodone in urine as unmetabolized oxycodone or its direct conjugates is only 8–14% (Pöyhiä et al., 1992).

Oxycodone is a μ-opioid receptor agonist but it has a lower binding affinity for the μ-opioid receptor than morphine (Chen et al., 1991, Monory et al., 1999, Peckham and Traynor, 2006). Yet, oxycodone has good clinical effectiveness after systemic administration (Silvasti et al., 1998, Nieminen et al., 2009, Kalso et al., 1991, Curtis et al., 1999). Interestingly, its analgesic potency is significantly reduced after spinal administration (Backlund et al., 1997, Yanagidate and Dohi, 2004). Therefore, active metabolites of oxycodone have been suggested to be important for oxycodone analgesia (Kalso et al., 1990).

Oxycodone is N-demethylated by CYP3A4/5 to noroxycodone, which is the main metabolic route (Lalovic et al., 2004). The analgesic properties of noroxycodone have not been studied in humans, but in rodents it shows poor analgesic effect (Weinstein and Gaylord, 1979, Lemberg et al., 2006). Oxymorphone is formed via O-demethylation of oxycodone by CYP2D6, but with a significantly lower rate compared with the formation of noroxycodone (Lalovic et al., 2004). Compared with oxycodone, oxymorphone has about 45-fold higher affinity for the μ-opioid receptor and a higher potency to induce intracellular G-protein activation (Peckham and Traynor, 2006, Lemberg et al., 2006, Thompson et al., 2004, Lalovic et al., 2006). Oxymorphone is used as a potent opioid analgesic in humans and in veterinary medicine (Beaver et al., 1977, Dobbins et al., 2002, Aqua et al., 2007).

Codeine must undergo CYP2D6-mediated O-demethylation to morphine to have an analgesic effect. Therefore, CYP2D6 poor metabolizers have no analgesia from codeine (Dayer et al., 1988, Caraco et al., 1996, Poulsen et al., 1996). The significance of CYP2D6-mediated metabolites in oxycodone analgesia has not been studied in pain patients but other psychomotor effects of oxycodone do not seem to depend on CYP2D6-mediated metabolism (Lalovic et al., 2006, Heiskanen et al., 1998).

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) used in the management of depression and other psychiatric disorders. Paroxetine is mainly metabolized by CYP2D6 and it also acts as a potent inhibitor of CYP2D6, interfering with the metabolism of many clinically used drugs (Brøsen et al., 1991, Bloomer et al., 1992, Sindrup et al., 1992, Laugesen et al., 2005).

We used a placebo-controlled, randomized cross-over design to study the effect of paroxetine (20mg/day for 7 days) on the pharmacodynamics and pharmacokinetics of oral oxycodone in chronic pain patients. In order to control for the CYP2D6 status the patients were genotyped for CYP2D6. In addition, the patients were genotyped for CYP3A4/5 and ABCB1.

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2. Materials and methods 

2.1. Study design 

The study design is illustrated in Fig. 1. Twenty-eight patients (age range 29–76 years) with stable chronic malignant or non-malignant pain were recruited. Both opioid naïve patients and patients who had been on oxycodone or another opioid were included. Twenty patients (8 males and 12 females, median age of 57.5, range 29–76) completed the study. The demographic data of the patients are given in Table 1. Exclusion criteria were concomitant use of drugs that are potent inhibitors of CYP2D6 activity, clinically relevant renal, hepatic, respiratory or cardiac disease, pregnancy, lactation, alcohol or drug misuse and severe depression or other psychiatric disease. Before entering the study, the following laboratory tests were performed: serum creatinine, serum gamma-glutamyl transpeptidase, aspartate aminotransferase, and alanine aminotransferase. These had to be within ±15% of the normal limits in order for the patient to be included.

Table 1. Patient characteristics.
PatientGenderAge (years)Type of painDaily dose of oxycodone (mg)Non-opioid co-analgesics (daily dose)Other medications (daily dose)As needed-medications (dose)
1f56Neuropathic40Paracetamol 1.5gAlendronate 70mg/week, amlodipine 5mg, furosemide 40mg, warfarinLidocain-gel
3m76Ca. pancreas20Paracetamol 1.5g––
4m68Ca. pancreas320–Metoclopramide 30mg, osmotic laxative, sodium picosulphate 22.5mg–
5m65Ca. rectum40–haloperidol 1.5mg, lactulose 20ml–
6f49CRPS50Etoricoxib 90mg, gabapentin 2400mg, phenoxybenzamine 20mg, venlafaxine 75mgMontelucast 10μg, estradiolvalerate 1mg, simvastatin 10mg, esomeprazol 40mg, calsiumcarbonate 1g, colecalciferol 800IU, alendronate 70mg (week), amiloride 5mg, hydrochlorothiazide 50mg, candesartan 16mg, fluticasone 300μg, ebastine 20mg, formoterole 48μg, prednisolone 5mg, theophylline 900mg, tiotropium bromide 18μgAcrivastatine 8mg+pseudoephedrine 60mg, phenylpropanolamine–HCl, budesonide 100μg, ipratropium bromide+fenoterole hydrobromide 40/100μg
7f36Neuropathic30Etoricoxib 90mg, gabapentin 300mg–Ondansetron 4mg
9m58Neuropathic80–Allopurinol 100mg, amlodipine 5mg, bisoprolol 20mg, digoxin 0.25mg, enalapril 20mg, fluticasone 300μg, glyburide 3.5mg, hydrochlortiazide 12.5mg, metformin 1g, momethasone 200μg, rosiglitazone 4mg, salmeterole 150μg, simvastatin 20mg, tiotropium bromide 18μg, warfarinSalbutamol 200μg
10f29Neuropathic80Pregabalin 600mgAmiloride 2.5mg, budesonide 160μg, formoterole 4.5μg, hydrochlortiazide 25mg, tizanidine 4mgOsmotic laxative
12m65Neuropathic100Gabapentin 2000mgAlendronate 70mg/week, bisoprolol 2.5mg, budesonide 400μg, diazepam 5mg, ferrosulphate 100mg, leflunomide 20mg, prednisolone 7.5mg, tamsulosine 0.4mg, verapamil 160mgGlyceryl nitrate 0.5mg, omeprazol 20mg
14m59Neuropathic120Gabapentin 3600mg, mirtazapin 15mgAcetosalicylic acid 100mg, atorvastatin 20mg, bisoprolol 2.5mg, budesonide 320μg, formoterole 4.5μg, metformin 750mg, pantoprazole 40mg, sodium picosulphate 3.75mg, tamsulosine 0.4mgSalbutamol 200μg
15m58Low back pain40Amitriptyline 70mg, gabapentin 3600mgEnalapril 20mg, folic acid 5mg/week, lactulose 20ml, leflunomide 20mg, methotrexate 10mg/week, metoprolol 95mg, prednisolone 5mg, rosuvastatin 10mg, zolpidem 10mg–
16f58Neuropathic40Amitriptyline 37.5mg, chlordiazepoxide 15mg, ibuprofen 2400mg, pregabalin 600mgBisoprolol 10mg, levothyroxin 0.1mg, sulphasalazine 3g, temazepam 20mg, tizanidine 12mgLactulose 20ml, zyclizine 10mg
19m57Ischemic pain80Paracetamol 3g, pregabalin 300mgBisoprolol 5mg, diazepam 20mg, kefalexine 1.5g, Rosuvastatin 10mg, zopiclone 15mg–
20m38Neuropathic80Amitriptyline 120mg, gabapentin 3600mgLactulose 20ml–
21f45Neuropathic40–Plantago seed laxative 12g–
23m63Ca. pancreas40–Hydroxizine 25mg, pancreatine 900mg, tamsulosine 0.4mgmgLactulose 20ml, zyclizine 10mg
24m51Neuropathic60Paracetamol 2g, pregabalin 150mgAcetosalicylic acid 100mg, bisoprolol 5mg, furosemide 40mg, montelucaste 10mg, potassium chloride 1g, ramipril 7.5mg–
25f49Neuropathic20–––
27m57Low back pain40Amitriptyline 50mg, gabapentin 3600mgBisoprolol 5mg, glyburide 1.75mg, hydrochlortiazide 12.5mg, lisinopril 20mg, metformin 1.5gMetoclopramide 10mg, lactulose 20ml
28f61Ca. rectum40Mirtazapin 30mg, paracetamol 4gSodium picosulphate 3.75mgOndansetron 5mg

CRPS (Complex Regional Pain Syndrome), neuropathic (pain due to nerve injury) and Ca. (carcinoma). The doses of warfarin are not given in the table because of the variance depending on the INR-values.

During a run-in period, the patients were titrated to an acceptable level of pain relief (the average pain intensity ≤30 on a 100mm Visual Analogue Scale (VAS)) with controlled-release oxycodone (Oxycontin®, Mundipharma, Finland) tablets taken twice daily with a 12-h interval. For breakthrough pain the patients were instructed to take oral morphine (morphine hydrochloride 4mg/ml, Helsinki University Central Hospital Pharmacy, Helsinki, Finland) solution in a dose, which was approximately equivalent to 1/6 of their total daily dose of oxycodone. The equianalgesic dose ratio for oral oxycodone and morphine was assumed to be 2:3 (Heiskanen and Kalso, 1997). Once the patient was on a stable dose of oxycodone and needed not more than two doses of rescue analgesia per day for at least 3 days, the patient was randomized to take either placebo or paroxetine 20mg (Seroxat® 20mg, GlaxoSmithKline, Mayenne, France) orally once daily in the morning. Pain intensity (average during the period; VAS 100mm) was recorded in a pain diary at 8 AM (before the morning dose), at 2 PM and at 8 PM before the evening dose of oxycodone. The doses of rescue medication and adverse effects were recorded daily in the diary. The patient was on the first drug (placebo or paroxetine) for 7 days, after which a 1-week wash out period took place before crossing over to the second treatment-phase. Other medications remained unchanged during the treatment-phases.

On the 7th day of both treatment-phases, the patient arrived at the Pain Clinic. The patient did not take either oxycodone or paroxetine/placebo in the morning before coming to the Pain Clinic. A normal light breakfast was allowed at home. Timed blood samples (10ml each) were drawn from the cannulated forearm vein for the measurement of oxycodone, noroxycodone, oxymorphone, noroxymorphone and paroxetine before taking the tablets (oxycodone+paroxetine/placebo) and at 0.5, 1, 2, 4, 6, 8, 10 and 12h later. Lunch was served at noon (4h after drug intake). Pain intensity and relief were assessed on a 100mm visual analogue scale (VAS) and an 8-point verbal rating scale for pain intensity (VRSpi) and a 5-point verbal rating scale for pain relief (VRSpr) every hour. Also, drug effects were assessed using a 100mm Modified Drug Effect Scale (Pöyhiä et al., 1991). Adverse effects were reported using a questionnaire. Use of rescue medication was recorded throughout the study. The blood samples were collected to tubes containing ethylenediaminetetra-acetic acid (EDTA). Plasma was separated within 30min, and stored at −20°C until analysis. In total, the patients visited the Pain Clinic 5 times during the study (inclusion, start of titration, start of first double-blind-phase and end of each double-blind-phase). During the oxycodone dose titration-phase the patients were contacted by the study nurse or the investigator by telephone every 3rd day until a stable opioid dose was reached.

2.2. Determination of plasma oxycodone, three of its metabolites and paroxetine 

Plasma concentrations of oxycodone, oxymorphone, noroxycodone, noroxymorphone, and paroxetine were measured by use of PE SCIEX API 3000 liquid chromatography–tandem mass spectrometry system (Sciex Division of MDS Inc., Toronto, Ontario, Canada). The reversed phase gradient chromatography was performed on an XBridge C18 (2.1mm×100mm, 3.5μm I.D.) analytical column protected by an XBridge C18 (2.1mm×10mm, 3.5μm I.D.) guard column (Waters Corp., Milford, MASS). The mobile phase consisted of (channel A) 5mM ammonium formate (pH 9.4, adjusted with 25% ammonium hydroxide solution) and (channel B) methanol, and the mobile phase flow rate was kept at 180μL/min. d3-Oxycodone, d3-oxymorphone, d3-noroxycodone and venlafaxine served as internal standard. d3-Noroxycodone was also used as internal standard for noroxymorphone. The mass spectrometer was operated in positive TurboIonSpray® mode and the samples were analyzed via multiple reactant monitoring (MRM) employing the transition of the [M+H]+ precursor ion to a product ion for each analyte and internal standard. The selected ion transitions were as follows: m/z 288 to m/z 213 for noroxymorphone, m/z 302 to m/z 227 for noroxycodone and oxymorphone, m/z 305 to m/z 230 For d3-noroxycodone and d3-oxymorphone, m/z 316 to m/z 241 for oxycodone, 319 to m/z 244 for d3-oxycodone, m/z 330 to m/z 192 for paroxetine, and m/z 278 t/m/z 58 for venlafaxine. The limit of quantification was 0.1ng/ml for oxycodone and oxymorphone, 0.25ng/ml for noroxycodone, noroxymorphone, and 1.0ng/ml for paroxetine. The interday coefficient of variation (CV) at the concentrations of 0.1, 5.0 and 100ng/ml (n=6) was for oxycodone 13, 3.9, 3.3% and for oxymorphone 9.6, 3.6, 8.3%, respectively. The interday CV at the concentrations of 0.25, 5.0 and 100ng/ml (n=6) was for noroxycodone 11, 3.5, 4.2%, and for noroxymorphone 8.4, 7.8, 2.8%. The interday CV for paroxetine at 5.0 and 100ng/ml (n=6) was 4.2 and 8.0%, respectively.

2.3. Pharmacokinetics 

The pharmacokinetics of oxycodone and its metabolites were evaluated, using plasma drug concentrations adjusted by the daily oxycodone dose (in mg), by peak concentration in plasma (Cmax) and area under the plasma concentration–time curve from 0 to 12h (AUC0–12). The pharmacokinetic calculations were performed with the program Prism 4.0 (GraphPad Software Inc., San Diego, CA, USA).

2.4. Genotyping methods 

Blood samples (10ml) for genotyping were collected into EDTA vacutainer tubes and kept frozen at −20°C until analysis. Genomic DNA was isolated from whole blood using the QIAamp® DNA Blood Mini Kit (QIAGEN Ltd.). The CYP2D6 alleles *3, *4, *6, *7, *8 as well as *41 were analyzed using TaqMan® Pre-Developed Assay Reagents for allelic discrimination and the ABI PRISM 7000 Sequence Detection System (Applied Biosystems, Foster City, CA, USA). The CYP2D6*5 allele (total deletion of the gene) was detected by long PCR followed by 1% agarose gel electrophoresis (Hersberger et al., 2000). The CYP2D6 gene duplication, which usually confers ultrarapid metabolism, was detected using long PCR (Steijns and Van Der Weide, 1998). When neither the CYP2D6 variants *3, *4, *5, *6, *7, *8, *41 nor the duplication was detected, the allele was classified as functional CYP2D6*1. Subjects carrying one defective allele together with the functional *1 were classified as heterozygous extensive metabolizers and those with two *1 alleles as homozygous extensive metabolizers. Subjects carrying a gene duplication together with CYP2D6*1 were classified as ultrarapid metabolizers. CYP3A4 detrimental alleles were identified by allele-specific PCR followed by digestion with restriction enzymes, CYP3A4*1B (−290A>G; rs 2740574) and CYP3A4*3 (1437T>C, Met445ThR; rs 4986910) (van Schaik et al., 2000, van Schaik et al., 2001) and CYP3A4*4 allele (352A>G, Ile118Val) (Wang et al., 2005). The CYP3A5*2 (27289C>A, T398N; rs 28365083) and CYP3A5*6 (14690G>A, splicing defect; rs 10264272) alleles were also analyzed by allele-specific PCR followed by digestion with restriction enzymes, as previously described by van Schaik et al. (van Schaik et al., 2000, van Schaik et al., 2001, van Schaik et al., 2002). The presence of the CYP3A5*3 (6986A>G, splicing defect; rs 776746) allele was investigated by TaqMan™ allelic discrimination in the ABI PRISM 7000 Sequence Detection System (Mirghani et al., 2006). ABCB1 polymorphisms were analyzed with real-time PCR by TaqMan kits purchased from Applied Biosystems (for 1236C>T, rs1128503, Assay ID: C___7586662_10, for 3435C>T, rs1045642, Assay ID: C___7586657_1_, and for 2577G>A/T, rs2032582, Forward Primer GTA AGC AGT AGG GAG TAA CAA AAT AAC ACT, Reverse Primer GAC AAG CAC TGA AAG ATA AGA AAG AAC T, 2677G probe VIC-CCT TCC CAG CAC CT, 2677A probe FAM-CTT CCC AGT ACC TTC, 2677T probe FAM-CTT CCC AGA ACC TT), according to the guidelines of the manufacturer.

2.5. Ethical considerations 

The study was approved by the ethics committee of the Department of Surgery of the Helsinki University Central Hospital and the National Agency for Medicines, Finland. All patients gave a written informed consent.

2.6. Statistical analysis 

The paired t-test was used for the statistical analysis of the AUCs of study groups and Fisher's exact test for the statistical analysis for the association between the observed adverse effects and treatments (placebo or paroxetine) (Prism 4.0, GraphPad Software Inc., San Diego, CA, USA). Analysis of variance (ANOVA) for repeated measures (StatView 5.0.1, SAS Institute, Inc., Cary, NC, USA) was used for comparing the VAS-pain values over time (Fig. 3). P<0.05 was considered to represent a statistically significant difference.

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3. Results 

Twenty-eight patients were recruited to the study. Twenty patients completed the whole trial. Their demographic data are given in Table 1.

3.1. Analgesia 

During a run-in period before randomization, the patients were titrated to stable pain intensity with twice daily oral controlled-release oxycodone. Oxycodone induced good analgesia in all but four patients who were withdrawn from the study due to inadequate analgesia.

During the double-blind-phase, the patients were instructed to take rescue oral morphine mixture to maintain pain relief. The number of additional morphine administrations per day needed for rescue analgesia did not differ significantly between the placebo (0.84±1.0; mean±SD) and paroxetine (0.63±0.68) phases of the study. Furthermore, paroxetine did not change the visual analogue scale (VAS) values of pain intensity or pain relief compared with placebo, studied on the 7th day of daily co-administration with oxycodone (Fig. 2a and b). The VAS-pain intensity values indicated more pain in the evenings compared with mornings and noon (P<0.001) (Fig. 3). CYP2D6, 3A4/5 and ABCB1 genotypes had no significant effect on the VAS-pain intensity values (data not shown).

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  • Fig. 2. 

    Pain intensities (a) and pain relief (b) rated on a VAS-scale (mean±SEM, n=20) during co-administration of placebo or paroxetine (20mg/day) with oral oxycodone. No statistically significant differences between the phases were found.

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  • Fig. 3. 

    The VAS-pain intensity values in the pain diary, recorded at 8 AM (before the morning dose), 2 PM and 8 PM (before the evening dose) during oxycodone twice daily co-administered with either paroxetine (●) or placebo (○) (mean±SEM). The values show a statistically significant increase in pain intensity in the evenings compared with mornings and noon (P<0.001) in repeated measures ANOVA when time of the day, the drug (paroxetine vs placebo, n.s.) and study days (1–6, n.s.) are included in the analysis as independent factors.

3.2. Pharmacokinetics 

The plasma concentrations of oxycodone and its three metabolites varied greatly from patient to patient according to the individually titrated oxycodone dose. However, the dose-corrected plasma concentrations were quite similar (Fig. 4). The plasma concentrations of oxycodone and noroxycodone were at a similar level (Fig. 4a and b), being clearly higher than those of noroxymorphone (Fig. 4d) and, in particular, those of oxymorphone (Fig. 4c).

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  • Fig. 4. 

    The dose-adjusted plasma concentrations (ng/ml/mg; mean±SEM, n=20) of oxycodone, noroxycodone, oxymorphone and noroxymorphone after administration of the same dose of oral oxycodone with either placebo or paroxetine (20mg/day) for 7 days (a–d). The opioid concentrations are divided by the daily oxycodone dose. The plasma concentrations of paroxetine (ng/ml; mean±SEM, n=20) on day 7 (e). Time zero refers to the time of drug administration.

Compared with placebo, paroxetine increased the mean peak (dose-adjusted) plasma concentration (Cmax) of oxycodone by 26% (range −12 to 130%; P=0.001) and the mean area under plasma (dose-adjusted) concentration–time curve (AUC0–12h) of oxycodone by 19% (range −23 to 113%; P=0.003) (Fig. 4a, Table 2).

Table 2. Pharmacokinetic parameters.
Placebo-phaseParoxetine-phaseChange from placebo-phase (%), mean (range)P value
Oxycodone
Cmax (ng/ml/mg)0.70 (±0.22)0.88 (±0.29)26 (−12 to 130)0.001
AUC0–12h (ng/ml/mgh)6.49 (±2.62)7.73 (±3.23)19 (−23 to 113)0.003

Noroxycodone
Cmax (ng/ml/mg)0.45 (±0.19)0.91 (±0.44)102 (2.0–267)<0.0001
AUC0–12h (ng/ml/mgh)4.38 (±1.97)8.77 (±3.34)100 (5.2–280)<0.0001

Oxymorphone
Cmax (ng/ml/mg)0.019 (±0.01)0.008 (±0.006)−57 (−100 to 4.0)<0.0001
AUC0–12h (ng/ml/mgh)0.15 (±0.08)0.049 (±0.049)−67 (−100 to −22)<0.0001

Noroxymorphone
Cmax (ng/ml/mg)0.10 (±0.005)0.038 (±0.04)−62 (−90 to −7.4)<0.0001
AUC0–12h (ng/ml/mgh)0.97 (±0.49)0.31 (±0.37)−68 (−100 to −16)<0.0001

Cmax: dose-adjusted maximum concentration (ng/ml/mg); AUC0–12h: dose-adjusted area under plasma drug concentration–time curve (ng/ml/mgh); (±SD).

Paroxetine increased the mean (dose-adjusted) Cmax of noroxycodone by 102% (2–267%; P<0.0001) and its mean AUC0–12h by 100% (5–280%; P<0.0001), compared with the corresponding values during the placebo-phase (Fig. 4b, Table 2).

Paroxetine decreased the mean (dose-adjusted) Cmax and AUC0–12h of oxymorphone by 57% (P<0.0001) and 67% (P<0.0001), respectively (Fig. 4c, Table 2). Also the mean (dose-adjusted) Cmax and AUC0–12h of noroxymorphone were greatly reduced by paroxetine, i.e. by 62% (P<0.0001) and 68% (P<0.0001), respectively (Fig. 4d, Table 2).

The mean plasma concentration of paroxetine was quite stable during the (7th) study day in the paroxetine-phase (Fig. 4e). All patients had expected paroxetine concentrations during the paroxetine-phase but none had paroxetine in the plasma samples during the placebo-phase, indicating good compliance in the use of paroxetine.

3.3. Patient genotypes 

The CYP2D6, CYP3A4, CYP3A5 and ABCB1 genotypes of the 20 patients who completed the study are given in Table 3. Fourteen patients had two functional CYP2D6 alleles (homozygous extensive metabolizers), four had one functional allele (heterozygous extensive metabolizers) and two had three or more functional alleles, being classified as ultrarapid metabolizers. None of the studied patients were poor metabolizers for CYP2D6.

Table 3. The genotypes of the 20 patients who completed the study.
Patient no.CYP2D6CYP3A4CYP3A5ABCB1236C>TABCB3435C>TABCB2577G>T or A
12*1/*1*3/*3T/TT/TT/T
31*1/*1*3/*3C/TT/TG/T
42*1/*1*3/*3C/TT/TG/T
51*1/*3*3/*3T/TC/TT/T
63 or more*1/*1*3/*3C/TC/TG/T
72*1/*1*1/*3C/CC/CG/A
92*1/*1*3/*3C/TC/TG/T
102*1/*1*3/*3C/CC/TG/T
122*1/*1*3/*3C/CC/CG/G
142*1/*1*3/*3C/TC/CG/T
152*1/*1*3/*3T/TT/TT/T
162*1/*1*3/*3T/TT/TT/T
192*1/*1B*3/*3C/CC/CG/G
203 or more*1/*3*3/*3T/TT/TT/T
211*1*1*3/*3C/CT/TG/G
232*1/*3*3/*3C/CC/CG/G
242*3/*3*3/*3T/TC/TT/A
251*3/*3*3/*3C/TC/TG/G
272*1/*3*3/*3T/TT/TT/T
282*1/*1*3/*3C/TC/TG/T

CYP2D6 genotype is expressed as number of functional CYP2D6 genes. Patients with two functional CYP2D6 alleles were classified as homozygous extensive metabolizers, with one functional allele as heterozygous extensive metabolizers and with three or more functional alleles as ultrarapid metabolizers.

No statistically significant associations of the CYP2D6 or CYP3A4/5 genotype of the patients and the pharmacokinetics of oxycodone or its metabolites, extent of paroxetine–oxycodone interaction, or analgesic effects were observed (data not shown). This may also be related to the limited number of patients studied.

3.4. Adverse effects 

During the run-in period, nausea and/or vomiting were reported by 11 of the 20 patients (55%) during both phases of the study. Drowsiness occurred in 13 of the 20 patients (65%) during the paroxetine-phase and in 10 patients (50%) during the placebo-phase. One-fourth of the patients reported dizziness and headache during the paroxetine-phase (P=0.0471), whereas these adverse effects were not reported during the placebo-phase. Several subjective effects were recorded on the 7th day of both treatment-phases in the Pain Clinic with no statistically significant differences between the phases (Fig. 5).

  • View full-size image.
  • Fig. 5. 

    The graded psychodynamic effects on a 0–10 VAS-scale (mean±SEM) during placebo (○) and paroxetine (●) 20mg/day co-administration. No statistically significant differences were found between the two phases.

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4. Discussion 

This study was performed in chronic pain patients providing clinically relevant information about the pharmacology of oxycodone in “real life”. The chronic pain patients requiring opioid medication were a heterogenous group with multiple medications and various diseases (Table 1). Paroxetine is a potent inhibitor of CYP2D6 and it can potentially be co-administered with oxycodone to treat depression. It was chosen instead of quinidine, another potent blocker of CYP2D6 (Otton et al., 1984), which was considered too risky in out patients. The dose of 20mg/day paroxetine used in this study was considered not to have any significant analgesic effect. The dose of paroxetine in this study was half of what (40mg/day) was previously reported to have minor analgesic effect in diabetic neuropathy (Sindrup et al., 1990). SSRIs are not considered effective in chronic pain unless they reduce co-morbid depression or anxiety the treatment of which requires higher doses and a longer duration of treatment than in this study. Inhibition of the CYP2D6-mediated metabolism of oxycodone by paroxetine resulted in a clear pharmacokinetic effect with greatly reduced concentrations of oxymorphone and noroxymorphone. This was not reflected in the pharmacodynamics as the oxycodone induced analgesic effect was only slightly affected by paroxetine. The results are in agreement with the pharmacokinetic studies performed in healthy volunteers (Lalovic et al., 2006, Heiskanen et al., 1998). Thus, the results suggest that oxycodone can be administered with paroxetine or other drugs inhibiting CYP2D6 without interfering with oxycodone analgesia.

All 20 patients completing the study were extensive (18) or ultrarapid (2) metabolizers via CYP2D6, and therefore a suitable population to study CYP2D6-mediated metabolism by blocking its function with paroxetine (Table 3). Analgesia induced by orally administered oxycodone on study day 7 was not significantly influenced by paroxetine (Fig. 2), which caused a moderate increase in plasma oxycodone concentrations and somewhat greater changes in the plasma concentrations of three of its metabolites (Fig. 4). Similarly, neither the pain intensity levels nor the consumption of additional morphine used for rescue analgesia during the study were significantly changed by paroxetine compared with placebo, further suggesting that similar analgesia was obtained. The slight though not significant decrease in the use of additional morphine in the paroxetine-phase (0.63 administrations/day) compared with the placebo-phase (0.84) may be due to the increase of the plasma concentrations of oxycodone in the paroxetine-phase compared with placebo.

Interestingly, the patients reported more pain towards the evenings compared with the mornings and noon (Fig. 3). This is in agreement with a recent study performed in chronic pain patients with painful diabetic neuropathy and postherpetic neuralgia, showing that pain increased throughout the day, without being affected by gabapentin and/or morphine administration (Odrcich et al., 2006). This difference may be explained by more pain related to activity during the day, but also by diurnal variation in the endogenous pain modulating systems (Petraglia et al., 1983). The clinical implication of this finding is that the evening dose of oxycodone should be higher and/or administered earlier.

Paroxetine caused an about 2-fold increase in the plasma concentrations of noroxycodone, the major metabolite of oxycodone in humans, produced by CYP3A4/5 and further metabolized by CYP2D6 (Table 2, Fig. 4b) (Pöyhiä et al., 1992, Lalovic et al., 2004, Heiskanen et al., 1998, Pöyhiä et al., 1991). A similar increase was previously seen after blocking CYP2D6 with quinidine (Heiskanen et al., 1998). Noroxycodone has a poor antinociceptive potency in vivo (Weinstein and Gaylord, 1979, Lemberg et al., 2006), because of its low affinity for the μ-opioid receptor compared with oxycodone (Lalovic et al., 2006). Thus, oxycodone induced analgesia seems not to be dependent on noroxycodone.

Oxymorphone is the most potent μ-opioid receptor agonist of the studied metabolites of oxycodone (Lalovic et al., 2006). However, the plasma concentrations of oxymorphone were very low (Fig. 4c), as has been observed also in other studies in humans (Lalovic et al., 2006, Heiskanen et al., 1998). Furthermore, paroxetine decreased the AUC0–12h of oxymorphone, to about one-third of the control value (Fig. 4c) without any decrease in analgesia. This suggests a limited role of oxymorphone in the analgesic effect of oral oxycodone in the treatment of chronic pain. However, a more sensitive human experimental pain model where analgesia was studied after oral oxycodone in poor and extensive metabolizers for CYP2D6 indicated some role for oxymorphone (Zwisler et al., 2009).

The AUC0–12h of plasma noroxymorphone concentrations was also decreased to about one-third by co-administration of paroxetine with oxycodone. Noroxymorphone is mainly formed by the CYP2D6-dependent O-demethylation of noroxycodone (Lalovic et al., 2004). Noroxymorphone is a relatively potent μ-opioid receptor agonist with a 2–3-fold higher affinity for the μ-opioid receptor compared with oxycodone (Chen et al., 1991, Lalovic et al., 2006). Its potency to activate intracellular G-proteins is 2-fold higher than that of oxycodone in the GTPγ[35S] binding assay (Thompson et al., 2004, Lalovic et al., 2006). The central nervous system concentrations of noroxymorphone have been low after intragastric administration of oxycodone to rats, the brain/plasma concentration ratio for noroxymorphone being as low as 0.008 (Lalovic et al., 2006). This is due to the high hydrophilicity (low logD value) of noroxymorphone and hence poor permeability across the lipid-rich blood–brain-barrier.

No significant differences were found between various CYP2D6 or CYP3A4/5 genotypes in the pharmacokinetics or pharmacodynamics of oxycodone. This is not surprising considering the limited number of subjects in most genotype groups. All subjects were extensive or ultrarapid metabolizers via CYP2D6, i.e. during the control-phase oxymorphone and noroxymorphone were formed in these patients at a higher rate than if the patients had been poor CYP2D6 metabolizers. This is important considering the study design and interpretation of the data, because an unchanged analgesic effect of oxycodone by paroxetine in poor CYP2D6 metabolizers would have been expected to be caused by the absence of CYP2D6-mediated metabolites already during the placebo-phase.

If the metabolites of oxycodone do not significantly contribute to analgesia after oral oxycodone in chronic pain patients, how can we explain the discrepancy between the relatively low μ-opioid receptor affinity and efficacy of oxycodone but effective clinical analgesia compared with morphine? Studies in rats have indicated that oxycodone has a significantly better permeability across the blood–brain-barrier compared with morphine (Lalovic et al., 2006, Boström et al., 2006, Boström et al., 2008). The concentrations of oxycodone are 2–6 times higher in the brain compared with plasma whereas the concentrations of oxymorphone are similar in plasma and the CNS. The penetration of noroxymorphone to the CNS is very low (Lalovic et al., 2006, Boström et al., 2006).

P-glycoprotein is an ATP-dependent efflux transport protein that influences the absorption, distribution and excretion of many clinically relevant drugs (Schinkel, 1999). Many opioids, e.g. morphine and methadone are ligands for P-glycoprotein, which actively decreases their CNS concentrations (Letrent et al., 1999, Thompson et al., 2000). A recent study showed a significant reduction in morphine induced pain relief in cancer patients who carried a genotype associated with a poorly functioning μ-opioid receptor (OPRM1, A118G, homozygous G/G) and a well functioning P-glycoprotein (ABCB1, C3435T, homozygous C/C) (Campa et al., 2008). In vitro and in vivo studies have provided conflicting results regarding the interaction of oxycodone with P-glycoprotein (Boström et al., 2005, Hassan et al., 2007).

In the literature, only a few case reports describing interactions between oxycodone and other drugs have been published. Our study suggests that antidepressants that inhibit CYP2D6 do not significantly affect oxycodone analgesia. However, a pharmacodynamic interaction such as serotonin syndrome can result from co-administration of serotonin reuptake inhibitors and opioids (Rosebraucgh et al., 2001, Karunatilake and Buckley, 2006, Rang and Irving, 2008). Lee et al. reported of a patient who had inadequate pain relief after rifampicin, a potent CYP3A4 enzyme inducer, was added to oxycodone medication (Lee et al., 2006). It was suggested that the reduced analgesic efficacy was related to lower oxycodone concentrations due to increased metabolism of oxycodone by rifampicin. Rifampicin has been shown to significantly decrease the plasma concentrations of oxycodone after both oral and intravenous administration with attenuated pharmacological effects (Nieminen et al., 2009). Also, the CYP3A inhibitor voriconazole significantly increased the plasma concentrations of oxycodone with a modest change of some pharmacodynamic effects not including analgesia (Hagelberg et al., 2009).

Our study supports the view that oxycodone induced analgesia and adverse effects are mainly due to the parent drug rather than its metabolites. Thus, induction of the metabolism of oxycodone may lead to inadequate analgesia while increased drug effects can be expected after addition of potent CYP3A4/5 inhibitors as suggested by recent studies by other groups. This could be the case particularly if CYP3A4/5 inhibitors are combined with CYP2D6 inhibitors, leading to increased plasma oxycodone concentrations.

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Acknowledgements 

This study received financial support from the Helsinki University Central Hospital Research Funds (T102010066), the Swedish Research Council (521-2005-4771) and an unrestricted grant from Mundipharma, Finland. Eija Kalso has received honoraria for lectures from Egalet, Janssen-Cilag, Mundipharma, Nycomed, Orion Pharma, Pfizer, Prostrakan, and Wyeth. Tarja Heiskanen has received honoraria for lectures from Janssen-Cilag, Mundipharma, and Wyeth. Vesa K. Kontinen has received honoraria for lectures from Janssen-Cilag, MSD, and Pfizer. We wish to thank all patients who participated in the study and Soile Haakana, RN and Leena Murto, RN, Gunilla Frenne, engineer, and Maria Gabriella Scordo, MD, PhD, for excellent assistance in the study.

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References 

  1. Aqua K, Gimbel JS, Singla N, Ma T, Ahdieh H, Kerwin R. Efficacy and tolerability of oxymorphone immediate release for acute postoperative pain after abdominal surgery: a randomized, double-blind, active- and placebo-controlled, parallel-group trial. Clin Ther. 2007;29:1000–1012
  2. Backlund M, Lindgren L, Kajimoto Y, Rosenberg PH. Comparison of epidural morphine and oxycodone for pain after abdominal surgery. J Clin Anaesth. 1997;9:30–35
  3. Beaver WT, Wallenstein SL, Houde RW, Rogers A. Comparisons of the analgesic effects of oral and intramuscular oxymorphone and of intramuscular oxymorphone and morphine in patients with cancer. J Clin Pharmacol. 1977;17:186–198
  4. Bloomer JC, Woods FR, Haddock RE, Lennard MS, Tucker GT. The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes. Br J Clin Pharmacol. 1992;33:521–523
  5. Boström E, Simonsson US, Hammarlund-Udenaes M. Oxycodone pharmacokinetics and pharmacodynamics in the rat in the presence of the P-glycoprotein inhibitor PSC833. J Pharm Sci. 2005;94:1060–1066
  6. Boström E, Simonsson US, Hammarlund-Udenaes M. In vivo blood–brain barrier transport of oxycodone in the rat-indications for active influx and implications for PK/PD. Drug Metab Dispos. 2006;34:1624–1631
  7. Boström E, Hammarlund-Udenaes M, Simonsson US. Blood–brain barrier transport helps to explain discrepancies in in vivo potency between oxycodone and morphine. Anesthesiology. 2008;108:495–505
  8. Brøsen K, Gram LF, Kragh-Sørensen P. Extremely slow metabolism of amitriptyline but normal metabolism of imipramine and desipramine in an extensive metabolizer of sparteine, debrisoquine and mephenytoin. Ther Drug Monit. 1991;13:177–182
  9. Campa D, Gioia A, Tomei A, Poli P, Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008;83:559–566
  10. Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther. 1996;278:1165–1174
  11. Chen ZR, Irvine RJ, Somogyi AA, Bochner F. Mu receptor binding of some commonly used opioids and their metabolites. Life Sci. 1991;48:2165–2171
  12. Curtis GB, Johnson GH, Clark P, Taylor R, Brown J, O’Callaghan R, et al. Relative potency of controlled-release oxycodone and controlled-release morphine in a postoperative pain model. Eur J Clin Pharmacol. 1999;55:425–429
  13. Dayer P, Desmeules J, Leemann T, Striberni R. Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufl). Biochem Biophys Res Commun. 1988;152:411–416
  14. Dobbins S, Brown NO, Shofer FS. Comparison of the effects of buprenorphine, oxymorphone hydrochloride, and ketoprofen for postoperative analgesia after onychectomy or onychectomy and sterilization in cats. J Am Anim Hosp Assoc. 2002;38:507–514
  15. Hagelberg NM, Nieminen TH, Saari TI, Neuvonen M, Neuvonen PJ, Laine K, et al. Voriconazole drastically increases exposure to oral oxycodone. Eur J Clin Pharmacol. 2009;65:263–271
  16. Hassan HE, Myers AL, Lee IJ, Coop A, Eddington ND. Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats. J Pharm Sci. 2007;96:2494–2506
  17. Heiskanen T, Kalso E. Controlled-release oxycodone and morphine in cancer related pain. Pain. 1997;73:37–45
  18. Heiskanen T, Olkkola KT, Kalso E. Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther. 1998;64:603–611
  19. Hersberger M, Marti-Jaun J, Rentsch K, Hanseler E. Rapid detection of the CYP2D6*3, CYP2D6*4, and CYP2D6*6 alleles by tetra-primer PCR and of the CYP2D6*5 allele by multiplex long PCR. Clin Chem. 2000;46:1072–1077
  20. Kalso E, Vainio A, Mattila MJ, Rosenberg PH, Seppälä T. Morphine and oxycodone in the management of cancer pain: plasma levels determined by chemical and radioreceptor assays. Pharmacol Toxicol. 1990;67:322–328
  21. Kalso E, Pöyhiä R, Onnela P, Linko K, Tigerstedt I, Tammisto T. Intravenous morphine and oxycodone for pain after abdominal surgery. Acta Anaesthesiol Scand. 1991;35:642–646
  22. Karunatilake H, Buckley NA. Serotonin syndrome induced by fluvoxamine and oxycodone. Ann Pharmacother. 2006;40:155–157
  23. Lalovic B, Phillips B, Risler LL, Howald W, Shen DD. Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos. 2004;32:447–454
  24. Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther. 2006;79:461–479
  25. Laugesen S, Enggaard TP, Pedersen RS, Sindrup SH, Brøsen K. Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol. Clin Pharmacol Ther. 2005;77:312–323
  26. Lee HK, Lewis LD, Tsongalis GJ, McMullin M, Schur BC, Wong SH, et al. Negative urine opioid screening caused by rifampin-mediated induction of oxycodone hepatic metabolism. Clin Chim Acta. 2006;367:196–200
  27. Lemberg KK, Kontinen VK, Siiskonen AO, Viljakka KM, Yli-Kauhaluoma JT, Korpi ER, et al. Antinociception by spinal and systemic oxycodone: why does the route make a difference? In vitro and in vivo studies in rats. Anesthesiology. 2006;105:801–812
  28. Leow KP, Smith MT, Williams B, Cramond T. Single-dose and steady-state pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer. Clin Pharmacol Ther. 1992;52:487–495
  29. Letrent SP, Pollack GM, Brouwer KR, Brouwer KL. Effects of a potent and specific P-glycoprotein inhibitor on the blood–brain barrier distribution and antinociceptive effect of morphine in the rat. Drug Metab Dispos. 1999;27:827–834
  30. Mirghani RA, Sayi J, Aklillu E, Allqvist A, Jande M, Wennerholm A, et al. CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population. Pharmacogenet Genomics. 2006;16:637–645
  31. Monory K, Greiner E, Sartania N, Sallai L, Pouille Y, Schmidhammer H, et al. Opioid binding profiles of new hydrazone, oxime, carbazone and semicarbazone derivatives of 14-alkoxymorphinans. Life Sci. 1999;64:2011–2020
  32. Nieminen TH, Hagelberg NM, Saari TI, Pertovaara A, Neuvonen M, Laine K, et al. Rifampin greatlyreduces the plasma concentrations of intravenous and oral oxycodone. Anesthesiology. 2009;110:1371–1378
  33. Odrcich M, Bailey JM, Cahill CM, Gilron I. Chronobiological characteristics of painful diabetic neuropathy and postherpetic neuralgia: diurnal pain variation and effects of analgesic therapy. Pain. 2006;120:207–212
  34. Osborne R, Joel S, Trew D, Slevin M. Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther. 1990;47:12–19
  35. Otton SV, Inaba T, Kalow W. Competitive inhibition of sparteine oxidation in human liver by beta-adrenoceptor antagonists and other cardiovascular drugs. Life Sci. 1984;34:73–80
  36. Peckham EM, Traynor JR. Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague–Dawley rats. J Pharmacol Exp Ther. 2006;316:1195–1201
  37. Petraglia F, Facchinetti F, Parrini D, Micieli G, De Luca S, Genazzani AR. Simultaneous circadian variations of plasma ACTH, beta-lipotropin, beta-endorphin and cortisol. Horm Res. 1983;17:147–152
  38. Poulsen L, Brøsen K, Arendt-Nielsen L, Gram LF, Elbaek K, Sindrup SH. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol. 1996;51:289–295
  39. Pöyhiä R, Olkkola KT, Seppälä T, Kalso E. The pharmacokinetics of oxycodone after intravenous injection in adults. Br J Clin Pharmacol. 1991;32:516–518
  40. Pöyhiä R, Seppälä T, Olkkola KT, Kalso E. The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects. Br J Clin Pharmacol. 1992;33:617–621
  41. Rang ST, Irving C. Serotonin toxicity caused by an interaction between fentanyl and paroxetine. Can J Anaesth. 2008;55:521–525
  42. Rosebraucgh CJ, Flockhart DA, Yasuda SU, Woosley RL. Visual hallucination and tremor induced by sertraline and oxycodone in a bone marrow transplant patient. J Clin Pharmacol. 2001;41:224–227
  43. Schinkel AH. P-glycoprotein, a gatekeeper in the blood–brain barrier. Adv Drug Deliv Rev. 1999;36:179–194
  44. Silvasti M, Rosenberg P, Seppälä T, Svartling N, Pitkänen M. Comparison of analgesic efficacy of oxycodone and morphine in postoperative intravenous patient-controlled analgesia. Acta Anaesthesiol Scand. 1998;142:576–580
  45. Sindrup SH, Gram LF, Brøsen K, Eshoj E, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990;42:135–144
  46. Sindrup SH, Brøsen K, Gram LF, Hallas J, Sjelbo E, Allen A, et al. The relation between paroxetine and sparteine oxidation polymorphism. Clin Pharmacol Ther. 1992;51:278–287
  47. Steijns LS, Van Der Weide J. Ultrarapid drug metabolism: PCR-based detection of CYP2D6 gene duplication. Clin Chem. 1998;44:914–917
  48. Thompson SJ, Koszdin K, Bernards CM. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology. 2000;92:1392–1399
  49. Thompson CM, Wojno H, Greiner E, May EL, Rice KC, Selley DE. Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors. J Pharmacol Exp Ther. 2004;308:547–554
  50. van Schaik RH, de Wildt SN, van Iperen NM, Uitterlinden AG, van den Anker JN, Lindemans J. CYP3A4-V polymorphism detection by PCR-restriction fragment length polymorphism analysis and its allelic frequency among 199 Dutch Caucasians. Clin Chem. 2000;46:1834–1836
  51. van Schaik RH, de Wildt SN, Brosens R, van Fessem M, van den Anker JN, Lindemans J. The CYP3A4*3 allele: is it really rare?. Clin Chem. 2001;47:1104–1106
  52. van Schaik RH, van der Heiden IP, van den Anker JN, Lindemans J. CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem. 2002;48:1668–1671
  53. Wang A, Yu BN, Luo CH, Tan ZR, Zhou G, Wang LS, et al. Ile118Val genetic polymorphism of CYP3A4 and its effects on lipid-lowering efficacy of simvastatin in Chinese hyperlipidemic patients. Eur J Clin Pharmacol. 2005;60:843–848
  54. Weinstein SH, Gaylord JC. Determination of oxycodone in plasma and identification of a major metabolite. J Pharm Sci. 1979;68:527–528
  55. Yanagidate F, Dohi S. Epidural oxycodone or morphine following gynaecological surgery. Br J Anaesth. 2004;93:362–367
  56. Zwisler ST, Enggaard TP, Noehr-Jensen L, Pedersen RS, Mikkelsen S, Nielsen F, et al. The hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism. Basic Clin Pharmacol Toxicol. 2009;104:335–344

PII: S1877-8860(09)00004-4

doi:10.1016/j.sjpain.2009.09.003

Refers to article:

  • Investigation of drug–drug interactions and pain—From volunteer studies to randomized controlled trials in patients with chronic pain

    Klaus T. Olkkola, Nora M. Hagelberg
    Scandinavian Journal of Pain January 2010 (Vol. 1, Issue 1, Page 5)

Scandinavian Journal of Pain
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