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

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.

Figure 1

The flow of the patients through the study.

During a run-in period, the patients were titrated to an acceptable level of pain relief (the average pain intensity ≤30 on a 100 mm 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 4 mg/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 20 mg (Seroxat^® 20 mg, GlaxoSmithKline, Mayenne, France) orally once daily in the morning. Pain intensity (average during the period; VAS 100 mm) 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 (10 ml 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 12 h later. Lunch was served at noon (4 h after drug intake). Pain intensity and relief were assessed on a 100 mm 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 100 mm 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 30 min, 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 (2.1 mm × 100 mm, 3.5 μm I.D.) analytical column protected by an XBridge C18 (2.1 mm × 10 mm, 3.5 μm I.D.) guard column (Waters Corp., Milford, MASS). The mobile phase consisted of (channel A) 5 mM ammonium formate (pH 9.4, adjusted with 25% ammonium hydroxide solution) and (channel B) methanol, and the mobile phase flow rate was kept at 180 μL/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 0.1 ng/ml for oxycodone and oxymorphone, 0.25 ng/ml for noroxycodone, noroxymorphone, and 1.0 ng/ml for paroxetine. The interday coefficient of variation (CV) at the concentrations of 0.1, 5.0 and 100 ng/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 100 ng/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 100 ng/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 (C_max ) and area under the plasma concentration–time curve from 0 to 12 h (AUC_0–12 ). The pharmacokinetic calculations were performed with the program Prism 4.0 (GraphPad Software Inc., San Diego, CA, USA).

2.4 Genotyping methods

Blood samples (10 ml) 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^TM 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.

Figure 2

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

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.

3.1 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).

Figure 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).

Compared with placebo, paroxetine increased the mean peak (dose-adjusted) plasma concentration (C_max ) of oxycodone by 26% (range −12 to 130%; P = 0.001) and the mean area under plasma (dose-adjusted) concentration–time curve (AUC_{0–12 h} ) of oxycodone by 19% (range −23 to 113%; P = 0.003) (Fig. 4a, Table 2).

Paroxetine increased the mean (dose-adjusted) C_max of noroxycodone by 102% (2–267%; P < 0.0001) and its mean AUC_{0–12 h} 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) C_max and AUC_{0–12 h} of oxymorphone by 57% (P < 0.0001) and 67% (P < 0.0001), respectively (Fig. 4c, Table 2). Also the mean (dose-adjusted) C_max and AUC_{0–12 h} 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.

Figure 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 (20 mg/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.

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).