| | Does co-administration of paroxetine change oxycodone analgesia: An interaction study in chronic pain patients
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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)
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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 (20 mg/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. 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. 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. | | |  | Patient | Gender | Age (years) | Type of pain | Daily dose of oxycodone (mg) | Non-opioid co-analgesics (daily dose) | Other medications (daily dose) | As needed-medications (dose) | |
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| 1 | f | 56 | Neuropathic | 40 | Paracetamol 1.5g | Alendronate 70mg/week, amlodipine 5mg, furosemide 40mg, warfarin | Lidocain-gel | | | 3 | m | 76 | Ca. pancreas | 20 | Paracetamol 1.5g | – | – | | | 4 | m | 68 | Ca. pancreas | 320 | – | Metoclopramide 30mg, osmotic laxative, sodium picosulphate 22.5mg | – | | | 5 | m | 65 | Ca. rectum | 40 | – | haloperidol 1.5mg, lactulose 20ml | – | | | 6 | f | 49 | CRPS | 50 | Etoricoxib 90mg, gabapentin 2400mg, phenoxybenzamine 20mg, venlafaxine 75mg | Montelucast 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 18μg | Acrivastatine 8mg+pseudoephedrine 60mg, phenylpropanolamine–HCl, budesonide 100μg, ipratropium bromide+fenoterole hydrobromide 40/100μg | | | 7 | f | 36 | Neuropathic | 30 | Etoricoxib 90mg, gabapentin 300mg | – | Ondansetron 4mg | | | 9 | m | 58 | Neuropathic | 80 | – | 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, warfarin | Salbutamol 200μg | | | 10 | f | 29 | Neuropathic | 80 | Pregabalin 600mg | Amiloride 2.5mg, budesonide 160μg, formoterole 4.5μg, hydrochlortiazide 25mg, tizanidine 4mg | Osmotic laxative | | | 12 | m | 65 | Neuropathic | 100 | Gabapentin 2000mg | Alendronate 70mg/week, bisoprolol 2.5mg, budesonide 400μg, diazepam 5mg, ferrosulphate 100mg, leflunomide 20mg, prednisolone 7.5mg, tamsulosine 0.4mg, verapamil 160mg | Glyceryl nitrate 0.5mg, omeprazol 20mg | | | 14 | m | 59 | Neuropathic | 120 | Gabapentin 3600mg, mirtazapin 15mg | Acetosalicylic acid 100mg, atorvastatin 20mg, bisoprolol 2.5mg, budesonide 320μg, formoterole 4.5μg, metformin 750mg, pantoprazole 40mg, sodium picosulphate 3.75mg, tamsulosine 0.4mg | Salbutamol 200μg | | | 15 | m | 58 | Low back pain | 40 | Amitriptyline 70mg, gabapentin 3600mg | Enalapril 20mg, folic acid 5mg/week, lactulose 20ml, leflunomide 20mg, methotrexate 10mg/week, metoprolol 95mg, prednisolone 5mg, rosuvastatin 10mg, zolpidem 10mg | – | | | 16 | f | 58 | Neuropathic | 40 | Amitriptyline 37.5mg, chlordiazepoxide 15mg, ibuprofen 2400mg, pregabalin 600mg | Bisoprolol 10mg, levothyroxin 0.1mg, sulphasalazine 3g, temazepam 20mg, tizanidine 12mg | Lactulose 20ml, zyclizine 10mg | | | 19 | m | 57 | Ischemic pain | 80 | Paracetamol 3g, pregabalin 300mg | Bisoprolol 5mg, diazepam 20mg, kefalexine 1.5g, Rosuvastatin 10mg, zopiclone 15mg | – | | | 20 | m | 38 | Neuropathic | 80 | Amitriptyline 120mg, gabapentin 3600mg | Lactulose 20ml | – | | | 21 | f | 45 | Neuropathic | 40 | – | Plantago seed laxative 12g | – | | | 23 | m | 63 | Ca. pancreas | 40 | – | Hydroxizine 25mg, pancreatine 900mg, tamsulosine 0.4mgmg | Lactulose 20ml, zyclizine 10mg | | | 24 | m | 51 | Neuropathic | 60 | Paracetamol 2g, pregabalin 150mg | Acetosalicylic acid 100mg, bisoprolol 5mg, furosemide 40mg, montelucaste 10mg, potassium chloride 1g, ramipril 7.5mg | – | | | 25 | f | 49 | Neuropathic | 20 | – | – | – | | | 27 | m | 57 | Low back pain | 40 | Amitriptyline 50mg, gabapentin 3600mg | Bisoprolol 5mg, glyburide 1.75mg, hydrochlortiazide 12.5mg, lisinopril 20mg, metformin 1.5g | Metoclopramide 10mg, lactulose 20ml | | | 28 | f | 61 | Ca. rectum | 40 | Mirtazapin 30mg, paracetamol 4g | Sodium picosulphate 3.75mg | Ondansetron 5mg | | | | |
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. 3. Results Twenty-eight patients were recruited to the study. Twenty patients completed the whole trial. Their demographic data are given in Table 1. 3.2. 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). 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). 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. 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). 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. 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. 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a Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland b Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland c Department of Clinical Pharmacology, Helsinki University Central Hospital, Helsinki, Finland d Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden  Corresponding author at: Institute of Biomedicine/Pharmacology, P.O. Box 63, FIN-00014 University of Helsiki, Finland. Tel.: +358 50 5950009; fax: +358 9 19125364.
PII: S1877-8860(09)00004-4 doi:10.1016/j.sjpain.2009.09.003 © 2009 Scandinavian Association for the Study of Pain. Published by Elsevier Inc. All rights reserved. | |
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