Clinica Chimica Acta 429 (2014) 175–180
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Impact of genetic and non-genetic factors on clinical responses to prochlorperazine in oxycodone-treated cancer patients Masaki Tashiro a,b, Takafumi Naito a, Kazunori Ohnishi c, Yoshiyuki Kagawa b, Junichi Kawakami a,⁎ a b c
Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan Department of Clinical Pharmaceutics and Pharmacy Practice, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Shizuoka, Japan Oncology Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
a r t i c l e
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Article history: Received 4 October 2013 Received in revised form 11 November 2013 Accepted 10 December 2013 Available online 17 December 2013 Keywords: Prochlorperazine DRD2 OPRM1 Oxycodone Cancer patients
a b s t r a c t Background: The contributions of DRD2 and OPRM1 genetic variants to clinical responses to prochlorperazine remain to be clarified in opioid-treated patients. We evaluated the clinical responses to prochlorperazine based on non-genetic and genetic factors in oxycodone-treated patients. Methods: Seventy Japanese cancer patients starting oral prochlorperazine together with oxycodone were enrolled. Predose plasma prochlorperazine concentrations and serum prolactin concentrations were determined. The incidences of oxycodone-induced nausea and vomiting were monitored for 2 weeks. Results: Plasma prochlorperazine concentration and oxycodone daily dose were not associated with the incidences of nausea and vomiting. The incidence of nausea was significantly higher in the DRD2 TaqIA A1A2 + A1A1 group than in the A2A2 group. The incidence of vomiting was significantly higher in females than in males. Before and after the prochlorperazine administration, the serum prolactin concentration was significantly higher in female patients than in male patients. The serum prolactin concentration was weakly correlated with prochlorperazine concentration and was significantly higher in the OPRM1 118AA group than in the AG + GG group. Conclusions: DRD2 TaqIA and female gender altered the prophylactic antiemetic efficacy of prochlorperazine. OPRM1 A118G together with plasma exposure of prochlorperazine and gender affected prolactin secretion in oxycodone-treated patients. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Opioid analgesics including morphine, oxycodone and fentanyl are widely used for the treatment of cancer and chronic non-cancer pain [1,2]. Although opioids possess a strong analgesic potency, patients receiving opioids frequently experience adverse effects leading to noncompliance [3,4]. Nausea and vomiting are the most common adverse effects in the early phase after starting opioids [4,5]. Most patients develop tolerance to the emetic effect within a week [6]. Opioids produce analgesia via an action at the opioid receptor mu1 (OPRM1) [7]. The mechanisms for opioid-induced nausea and vomiting include direct stimulation of the chemoreceptor trigger zone, reduced gastrointestinal motility, or enhanced vestibular sensitivity [8]. Prochlorperazine is a dopamine D2 receptor (DRD2) antagonist with a piperazinyl phenothiazine structure. Prochlorperazine has a high potency antiemetic effect based on inhibiting DRD2 at a chemoreceptor trigger zone and is commonly used for the treatment of nausea and
Abbreviations: DRD2, dopamine receptor D2; OPRM1, opioid receptor mu 1. ⁎ Corresponding author at: Department of Hospital Pharmacy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan. Tel.: +81 53 435 2762; fax: +81 53 435 2764. E-mail address: [email protected] (J. Kawakami). 0009-8981/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cca.2013.12.011
vomiting in clinical settings [9]. Clinical responses to prochlorperazine vary in opioid-treated patients. The diversity in the responses to prochlorperazine can occasionally cause inadequate antiemetic efficacy or adverse effects such as hyperprolactinemia, extrapyramidal symptoms, and drowsiness [10–12]. Opioid-treated patients exhibit the interindividual variability in the plasma concentration of prochlorperazine [13], however, its contribution to clinical responses remains to be clarified. Prochlorperazine increases the serum prolactin concentration via the blockade of dopaminergic pathways in the anterior pituitary gland [14,15]. Prolactin, a lactogenic hormone, is released from the pituitary lactotrophs. The hypothalamus controls prolactin secretion into the blood stream via dopamine as a prolactin inhibiting factor and thyrotropin-releasing hormone as a prolactin releasing factor [16]. Opioids bind to OPRM1 on the hypothalamus and subsequently cause the blockade of dopaminergic pathways [17,18]. Morphine administration has been found to elevate the serum prolactin concentration in humans [19,20]. The influence of opioids on prolactin secretion has not been fully evaluated in DRD2 antagonist-treated patients. Several important genetic variants of DRD2 and OPRM1 have been identified in humans [21,22]. DRD2 TaqIA (rs1800497) affected the incidences of postoperative nausea and vomiting [23] and the clinical responses to antipsychotics [24]. DRD2 TaqIA is associated with a
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reduction of DRD2 gene expression, resulting in diminishing dopaminergic activity [25,26]. A genetic variant of OPRM1 has been shown to affect postoperative morphine consumption after hysterectomy [27] and lessened the analgesic effect of oxycodone in healthy subjects [28]. OPRM1 A118G (rs1799971) is a functional genetic variant with deleterious effects on both mRNA and protein yield and is associated with brain OPRM1 binding potential [21,22]. There is still controversy concerning the clinical implications of these genetic variants in clinical settings. The contributions of DRD2 and OPRM1 genetic variants to the prophylactic antiemetic efficacy of prochlorperazine and serum prolactin elevation remain to be clarified in opioid-treated patients. 2. Materials and methods 2.1. Ethics The study was performed in accordance with the Declaration of Helsinki and its amendments, and the protocol was approved by the Ethics Committee of Hamamatsu University School of Medicine. The patients were briefed about the scientific aim of the study and each patient provided written informed consent. 2.2. Patients and study schedule The study was an observational study (UMIN-CTR, UMIN000011323) conducted at a single site at Hamamatsu University Hospital. Seventy patients receiving oral prochlorperazine (Novamin®, Shionogi & Co.,) for the prevention of opioid-induced nausea and vomiting at Hamamatsu University Hospital were enrolled. Each patient started oral prochlorperazine together with oxycodone extended-release tablets (OxyContin®, Shionogi & Co.) for cancer pain. They received 5 mg prochlorperazine 3 times daily at 8:00, 14:00, and 20:00 and 5 mg oxycodone as an initial dose twice daily at 8:00 and 20:00. Exclusion criteria were as follows: Patients who (1) discontinued oral prochlorperazine or oxycodone during the study; (2) were being co-treated with anticancer drugs; (3) were being co-treated with other DRD2 antagonists; (4) were being co-treated with triazole antifungal agents, rifampin, or macrolide antibiotics; (5) were diagnosed as having prolactinproducing adenoma or brain tumors; and (6) were difficult to evaluate with respect to nausea and vomiting. Blood specimens were drawn into tubes containing EDTA disodium salt and serum separators at 12 h after the evening dosing on day 6 or later within 2 weeks after starting prochlorperazine administration and the predose concentrations of prochlorperazine and prolactin were evaluated. In addition, some patients donated stored serum specimens before starting the prochlorperazine administration. 2.3. Determination of plasma prochlorperazine concentration Prochlorperazine maleate and amitriptyline hydrochloride as an internal standard were purchased from Sigma Aldrich. All other reagents were analytical grade and commercially available. Plasma was separated by centrifugation of the EDTA-treated blood samples at 1670 ×g at 4 °C for 10 min. Plasma concentrations of prochlorperazine were determined by isocratic LC-MS/MS as previously described [13]. Chromatographic separation of each analyte was performed on an ODS column (TSKgel ODS-100 V, 3 μm, 150 × 2.0 mm, Tosoh). The mobile phase consisted of 40% acetonitrile containing 5 mmol/l ammonium acetate at pH 4.25. The flow rate was 0.3 ml/min and the column oven temperature was set at 60 °C. The MS/MS analysis was performed with an electrospray source. The heated capillary was maintained at 240 °C in positive ion mode. The collision energies for prochlorperazine and amitriptyline were set at −22 and −25 eV, respectively. The ion transitions were monitored using a dwell time of 0.5 s for each compound: prochlorperazine, m/z 374.1/140.9; and amitriptyline, m/z 278.1/116.8. The calibration curves in human plasma were linear over the
concentration ranges of 0.01–40 μg/l (r N 0.999). The intra- and interassay CVs and accuracies were within 5.8% and 100–104% and within 7.8% and 99–103%, respectively. The lower limit of quantification in human plasma was 10 ng/l. The precision and accuracy of the lower limit of quantification were 7.6% and 105%, respectively. 2.4. Determination of serum prolactin concentration Serum prolactin concentrations were measured using chemiluminescent immunoassay according to the manufacturer's protocol (Architect® Prolactin, Abbott) using an automated immunoassay analyzer (Architect® i1000 SR,). The intra- and inter-assay precisions and accuracies were within 1.8% and 99–100% and within 2.6% and 97–100%, respectively. The serum prolactin concentration was calculated from the calibration information stored in the instrument memory. The lower limit of quantification in human serum was 0.6 μg/l. 2.5. Genotyping of DRD2 and OPRM1 Genomic DNA was extracted from peripheral whole blood from each patient using a DNA Extractor WB Kit (Wako Pure Chemicals) and stored at − 20 °C until analysis. The primer sequences and conditions of the polymerase chain reaction-fragment length polymorphism used for analyses of DRD2 TaqIA, TaqIB (rs1079597) and OPRM1 A118G were as described previously, with some modifications [29–31]. 2.6. Evaluation of prophylactic antiemetic efficacy The prophylactic antiemetic efficacy of prochlorperazine for oxycodone-induced nausea and vomiting was monitored for 2 weeks after starting prochlorperazine administration. The prophylactic antiemetic efficacy was evaluated by the incidences of nausea and vomiting. The incidence and severity were obtained from the medical records. The incidences and severities of nausea and vomiting in each patient were assessed using the grading system of the Common Terminology Criteria for Adverse Events (CTCAE v4.0). 2.7. Statistical analysis All statistical analyses were performed using SPSS (15.0 J, SPSS Japan Inc., Tokyo). The genetic variants of DRD2 TaqIA, TaqIB, and OPRM1 evaluated were as follows: DRD2 TaqIA (A2A2 and A1A2 + A1A1), DRD2 TaqIB (B2B2 and B1B2 + B1B1), and OPRM1 (AA and AG + GG). The influences of the plasma prochlorperazine concentration and oxycodone daily dose on the incidences of nausea and vomiting were tested using the Mann–Whitney U test. The influences of gender and genetic variants of DRD2 and OPRM1 on the incidences of nausea and vomiting were tested using Fisher's exact test. Stepwise multiple logistic regression analysis was performed to evaluate the influences of the plasma prochlorperazine concentration, oxycodone daily dose, gender, and genetic variants of DRD2 and OPRM1 on the incidences of nausea and vomiting. The changes in serum prolactin concentration before and after prochlorperazine administration were tested by the Wilcoxon signed rank test. The correlations between the plasma prochlorperazine concentration or oxycodone daily dose and serum prolactin concentration were tested by Spearman's rank correlation coefficient analysis. The influences of gender and genetic variants of DRD2 and OPRM1 on the serum prolactin concentration were tested using the Mann–Whitney U test. Multiple regression analysis was performed to evaluate the influences of the plasma prochlorperazine concentration, oxycodone daily dose, gender, and genetic variants of DRD2 and OPRM1 on the serum prolactin concentration following prochlorperazine administration. All values are expressed as the median and interquartile range (IQR) unless otherwise stated. A P b 0.05 was considered to indicate statistical significance.
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Table 1 shows the patient demographic characteristics. The patient population consisted of 45 males and 25 females. The patients had slightly lower serum concentrations of total protein (median, 6.4 g/dl; and IQR, 6.1–7.0 g/dl) and albumin (median, 3.5 g/dl; IQR, 3.2–3.8 g/dl). No patient had severe hepatic and/or renal function impairment according to Table 1. The patients had pharyngeal cancer (n = 26), lung cancer (n = 7), multiple myeloma (n = 6), malignant lymphoma (n = 6), esophageal cancer (n = 5), gastric cancer (n = 2), prostate cancer (n = 2), bladder cancer (n = 2), and other types of cancer (n = 14). The present study was performed in a Japanese population. The allele frequencies of the observed genetic variants of DRD2 and OPRM1 were as follows: DRD2 TaqIA A1 (0.357), TaqIB B1 (0.371), and OPRM1 118G (0.421), respectively. 3.2. Plasma prochlorperazine concentration and oxycodone daily dose The median of the predose plasma concentration of prochlorperazine at 12 h after the evening dosing after starting prochlorperazine administration was 1.90 μg/l and interindividual variation was also observed (IQR, 1.03–4.07 μg/l). The median and IQR of the oxycodone daily dose were 10 and 10–20 mg, respectively. 3.3. Non-genetic factors related to prophylactic antiemetic efficacy The incidences of nausea and vomiting in the study population were 36% and 17%, respectively. The grades of the adverse events of nausea and vomiting were categorized into 1 or 2. No significant difference was observed in the plasma prochlorperazine concentration between the patients with and without nausea or vomiting (Fig. 1). There was no significant difference in the oxycodone daily dose between the patients with and without nausea (median and IQR, 10 and 10–20 vs. 10 and 10–20 mg, respectively) or vomiting (10 and 10–20 vs. 10 and 10–20 mg, respectively). The incidences of nausea and vomiting were 31% and 7% in males and 44% and 36% in females, respectively (Table 2). The incidence of vomiting was significantly higher in female patients than in male patients (P = 0.006), while gender was not associated with the incidence of nausea. 3.4. Non-genetic factors related to serum prolactin concentration The serum prolactin concentration increased after the treatments (median and IQR, 11.0 and 9.2–17.4 vs. 31.8 and 20.5–52.3 μg/l, P b 0.001) in 26 patients who donated serum specimens before starting prochlorperazine administration. The median of the serum prolactin concentration was 35.3 μg/l after prochlorperazine administration in 70 cancer patients. There was interindividual variation in the serum prolactin concentration in this study population (IQR, 26.8–50.0 μg/l). The serum prolactin concentration was weakly correlated with the
B) 25
Plasma prochlorperazine concentration (µg/l)
3.1. Patient demographic characteristics
Plasma prochlorperazine concentration (µg/l)
A)
3. Results
20
15
10
5
0
Without (n = 45)
With (n = 25)
20
15
10
5
0
Without (n = 58)
plasma prochlorperazine concentration (ρ = 0.243, P = 0.043). The serum prolactin concentration was not significantly correlated with the oxycodone daily dose (ρ = −0.024, P = 0.846). The serum prolactin concentration was significantly higher in female patients than in male patients before and after prochlorperazine administration (P = 0.006 and P = 0.007, respectively, Fig. 2). 3.5. Genetic factors related to clinical responses The incidence of nausea was higher in the DRD2 TaqIA A1A2 + A1A1 group than in the A2A2 group (P = 0.042), while the incidence of vomiting was not (Table 2). The incidence of nausea was higher in the DRD2 TaqIB B1B2 + B1B1 group than in the B2B2 group (P = 0.042), while the incidence of vomiting was not. No significant differences were observed in the incidences of nausea and vomiting between the OPRM1 genetic variants. DRD2 TaqIA and TaqIB were not associated with the serum prolactin concentration (Fig. 3). The serum prolactin concentration was significantly higher in the OPRM1 118AA group than in the 118AG + GG group (P = 0.005). 3.6. Multivariate analysis of several factors related to clinical responses Multiple logistic regression analysis demonstrated that the DRD2 TaqIA A1 allele was correlated with the incidence of nausea (P = 0.031, Table 2 The influences of gender and OPRM1 and DRD2 genetic variants on the incidences of nausea and vomiting in cancer patients. Nausea
70, 45/25 66 (58–72) 53.8 (45.8–61.3) 6.4 (6.1–7.0) 3.5 (3.2–3.8) 0.8 (0.6–0.9) 16.1 (12.1–19.4) 0.6 (0.5–0.8) 26 (19–34) 22 (16–34) 10 (10–20)
Data are expressed as median with interquartile range in parentheses.
With (n = 12)
Fig. 1. Influence of plasma prochlorperazine concentration on the incidences of nausea (A) and vomiting (B) in oxycodone-treated patients. Box plots represent the median, 25th, and 75th percentiles. The whiskers indicate the range and extend within 1.5 times the length of the inner quartiles. Outliers, or those which lie N1.5 times the length of the inner quartiles, are indicated by the presence of open circles.
Table 1 Demographics of cancer patients receiving oxycodone. Number of patients, male/female Age (y) Body weight (kg) Total protein (g/dl) Serum albumin (g/dl) Serum creatinine (mg/dl) Blood urea nitrogen (mg/dl) Total bilirubin (mg/dl) Aspartate aminotransferase (IU/l) Alanine aminotransferase (IU/l) Oxycodone daily dose (mg)
25
Vomiting
n
n
(%)
P
n
Male Female
45 25
14 11
31 44
NS
AA AG + GG
25 45
11 14
44 31
NS
A2/A2 A1/A2 + A1/A1 B2/B2 B1/B2 + B1/B1
29 41 29 41
6 19 6 19
21 46 21 46
0.042†
(%)
P
3 9
7 36
0.006†
5 7
20 16
NS
2 10 2 10
7 24 7 24
NS
Gender
OPRM1 A118G DRD2 TaqIA TaqIB †
P b 0.05, Fisher's exact test.
†
0.042
NS
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A)
B)
†
† 140
Serum prolactin concentration (µg/l)
Serum prolactin concentration (µg/l)
40
30
20
10
0
120 100 80 60 40 20 0
Male (n = 20)
Male (n = 45)
Female (n = 6)
Female (n = 25)
Fig. 2. Comparison of serum prolactin concentration between male and female cancer patients before (A) and after (B) prochlorperazine administration. Box plots represent the median, 25th, and 75th percentiles. The whiskers indicate the range and extend within 1.5 times the length of the inner quartiles. Outliers, or those which lie N1.5 times the length of the inner quartiles, are indicated by the presence of open circles. †P b 0.05.
odds ratio, OR: 3.31; 95% confidence interval, 1.11–9.83). Multiple logistic regression analysis demonstrated that being female was correlated with the incidence of vomiting (P = 0.008, OR: 7.26; 95% confidence interval, 1.70–31.12). Multiple regression analysis demonstrated that plasma prochlorperazine concentration (standardized partial regression coefficient (β) = 0.263, P = 0.015), female gender (β = 0.279, P = 0.013), and OPRM1 118G allele carrier (β = −0.284, P = 0.013) were significantly correlated with the serum prolactin concentration. 4. Discussion The clinical implications of DRD2 and OPRM1 genetic variants for the management of opioid-induced nausea and vomiting using phenothiazine derivatives have not been fully clarified in cancer patients. This study evaluated the interindividual variation in clinical responses to prochlorperazine based on non-genetic and genetic factors in oxycodone-treated patients. Being female and having the DRD2 TaqIA A1 allele were 2 parameters that were correlated with the incidence of nausea and vomiting. OPRM1 A118G together with plasma prochlorperazine concentration and gender were associated with the serum prolactin concentration. These findings indicate that genetic
A)
B)
C)
120 100 80 60 40 20 0
†
140
Serum prolactin concentration (µg/l)
140
Serum prolactin concentration (µg/l)
140
Serum prolactin concentration (µg/l)
variants of DRD2 and OPRM1 affect the dopaminergic pathways in prochlorperazine-treated cancer patients receiving oxycodone. To the best of our knowledge, this is the first report that has evaluated the interindividual variations of clinical responses to prochlorperazine based on genetic variants of DRD2 and OPRM1 in cancer patients receiving oxycodone. The incidences of nausea and vomiting in cancer patients receiving oxycodone were 36% and 17%, respectively, in this study. Vomiting is usually proceeded with nausea. In this study, the patient group with vomiting included the patients with nausea. Patients have tolerance to the opioid-induced nausea and vomiting within 2 weeks [9]. This study had evaluated the incidences and severities of nausea and vomiting during only 2 weeks. A large variation was observed in the predose plasma prochlorperazine concentration. In a previous report we also observed interindividual variation in the plasma exposure of prochlorperazine [13]. In the present study population, the plasma concentration of prochlorperazine was not associated with the incidences of nausea and vomiting and the antiemetic effect of prochlorperazine was not responsible for the plasma prochlorperazine concentration. The plasma exposure to oxycodone may also affect opioid-induced nausea and vomiting. The oxycodone daily dose was not related to the incidences of nausea and vomiting in our study. In addition, there was little difference in the oxycodone daily dose because the patients enrolled were in the induction phase. These data indicate that the difference in plasma exposure to oxycodone was associated with our results. The serum prolactin concentration was elevated after coadministration of oxycodone and prochlorperazine, and was weakly correlated with the plasma prochlorperazine concentration in this study. Several studies have showed that prochlorperazine treatment elevated the serum prolactin concentration [32]. The time–concentration profile of serum prolactin after the prochlorperazine administration was similar to that of plasma prochlorperazine in healthy adults [11]. In the preliminary observation for several patients, the serum concentration of prolactin had not changed largely on day 6 or later during the observation period. Opioid analgesic morphine also raised the serum prolactin concentration [18,19]. Our results suggest that each administration of prochlorperazine and oxycodone is associated with the elevation of the serum prolactin concentration. In the present study, the serum prolactin concentrations in females were higher than those in males before and after co-treatment with prochlorperazine and oxycodone. David et al. reported that the elevation of serum prolactin concentration caused by the administration of a DRD2 antagonist was higher in female than in male schizophrenia patients [33]. Although our study enrolled elderly postmenopausal cancer patients, the serum
120 100 80 60 40 20 0
120 100 80 60 40 20 0
A2A2
A1A2+A1A1
B2B2
B1B2+B1B1
AA
AG+GG
(n = 29)
(n = 41)
(n = 29)
(n = 41)
(n = 25)
(n = 45)
Fig. 3. Influence of DRD2 and OPRM1 genetic variants on the serum prolactin concentration in prochlorperazine-treated cancer patients. (A) DRD2 TaqIA, (B) DRD2 TaqIB, and (C) OPRM1 A118G. Box plots represent the median, 25th, and 75th percentiles. The whiskers indicate the range and extend within 1.5 times the length of the inner quartiles. Outliers, or those which lie N1.5 times the length of the inner quartiles, are indicated by the presence of open circles. †P b 0.05.
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prolactin concentration was higher in females than in males. Our results indicate that gender and plasma prochlorperazine concentration are non-genetic factors affecting serum prolactin concentrations in elderly cancer patients receiving oxycodone and prochlorperazine. DRD2 TaqIA and TaqIB genetic variants increased the incidence of nausea and vomiting in cancer patients receiving oxycodone in this study. The TaqIB genetic variant has linkage disequilibrium with the TaqIA genetic variant [34]. The B1 allele of the TaqIB genetic variant as well as the A1 allele of the TaqIA genetic variant decreased the density of DRD2 in brain in vitro and in vivo [25,26]. DRD2 TaqIA and TaqIB genetic variants may be associated with the sensitivity to nausea and vomiting by reducing DRD2 gene expression. Sora et al. demonstrated that DRD2 TaqIA and TaqIB were involved in the onset of gastrointestinal symptoms caused by oxycodone [35]. In contrast, Nakagawa et al. reported that the DRD2 TaqIA A2 allele was a risk factor for postoperative nausea and vomiting [23]. The opioid-induced nausea and vomiting observed in our study were evaluated in cancer patients and the patients received prophylactic prochlorperazine when the oxycodone was started. The difference in patient backgrounds may have altered the effects of the DRD2 TaqIA genetic variants on nausea and vomiting. The OPRM1 genetic variant lowered the serum prolactin concentration in the present study. Opioids bind to OPRM1 on the hypothalamus and cause the inhibition of dopaminergic pathways, resulting in elevation of the serum prolactin concentration. OPRM1 A118G is a functional genetic variant with deleterious effects on both mRNA and protein yield and is associated with OPRM1 binding potential in the brain [21,22]. In the present study, the oxycodone daily dose was not associated with serum prolactin concentrations in cancer patients. Opioids indirectly cause the secretion of prolactin via OPRM1 mediated dopaminergic pathways [18,19]. Functional OPRM1 may synergistically cause the elevation of serum prolactin concentrations through the inhibition of dopamine neurons by opioids together with the DRD2 inhibition by prochlorperazine in the anterior pituitary. This study employed the multivariate analyses to clarify the impact of genetic variants in each gender. Using multiple logistic regression analyses, DRD2 TaqIA A1 allele was associated with the incidence of nausea (OR: 3.3) and female gender increased the incidence of vomiting (OR: 7.2). Using multiple regression analyses, the β value of female gender (β = 0.279) was similar to that of plasma prochlorperazine concentration (β = 0.263) and OPRM1 118G allele carrier (β = −0.284). Our data suggest that female gender together with genetic variants of DRD2 and OPRM1 strongly influence the prophylactic antiemetic efficacy and prolactin secretion under the prochlorperazine administration. The DRD2 TaqIA and TaqIB genetic variants were not correlated with the serum prolactin concentrations. Young et al. reported that serum prolactin concentrations were twice as high in the DRD2 TaqIA A1 allele group than in the A2 allele group in patients with schizophrenia receiving DRD2 antagonist [36]. In contrast, Yasui-Furukori et al. showed that there was no association between serum prolactin concentrations and the DRD2 TaqIA genetic variant in patients with schizophrenia [37]. To date, there is still no consensus on the effect of the DRD2 genetic variant on serum prolactin concentrations. Opioid analgesics together with a DRD2 antagonist were also shown to elevate serum prolactin concentrations [18,19]. This study encountered difficulty with evaluating the influence of DRD2 genetic variants on serum prolactin concentrations in cancer patients receiving both prochlorperazine and oxycodone. The study has several limitations. First, it was difficult to observe extrapyramidal symptoms, which are known to be an adverse effect of prochlorperazine. One patient was diagnosed as having severe extrapyramidal symptoms. The study population consisted of mostly elderly patients with low activity concentrations, which may have masked the extrapyramidal symptoms. Evaluations with a focused population with higher activities may clarify the relationship with extrapyramidal symptoms. Second, half of the patients enrolled in this study had pharyngeal cancer or lung cancer. There were no differences in the incidences of nausea and vomiting, or the serum prolactin concentration
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between pharyngeal cancer, lung cancer, and other cancer types. The data indicate that the difference in cancer types did not strongly affect our findings. Third, the impact of DRD2 genetic variants on the antiemetic effect was not clarified in this study. Earlier reports did not distinguish between the incidences of nausea and vomiting. DRD2 genetic variants may be more sensitive to nausea than vomiting in oxycodone-treated patients. Fourth, this study was underpowered to perform the subgroups analysis. The subgroup analysis by consideration of gender is needed in order to clarify the impact of the genetic variants in each gender. As alternative analyses, we employed the multivariate analyses to clarify the impact of the genetic variants in each gender. The clinical implications of DRD2 and OPRM1 genetic variants on the management of opioid-induced adverse effects using prochlorperazine have not been fully clarified in cancer patients. Based on our clinical data, DRD2 genetic variants may be a predictive factor for nausea in cancer patients receiving prochlorperazine and oxycodone. OPRM1 118A allele may be a risk factor for hyperprolactinemia caused by prochlorperazine. Our data indicate that additional treatments are needed to manage the prochlorperazine prophylaxis in cancer patients receiving oxycodone. Our study enrolled only patients receiving oxycodone. Earlier reports showed that morphine and fentanyl also elevated the serum prolactin concentration via OPRM1 [19,20,38]. If we take into consideration the mechanism of action, similar results may be observed in cancer patients receiving other opioids.
5. Conclusions DRD2 TaqIA and being female altered the prophylactic antiemetic efficacy of prochlorperazine in cancer patients receiving prochlorperazine and oxycodone. In addition, OPRM1 A118G together with plasma prochlorperazine concentration and gender affected the serum prolactin concentration. These findings suggest that genetic variants of DRD2 and OPRM1 affected the interindividual variation of clinical responses to prochlorperazine in these oxycodone-treated cancer patients.
Financial disclosure This work was supported by JSPS KAKENHI Grant Number 23790181.
References [1] Cohen MZ, Easley MK, Ellis C, et al. Cancer pain management and the JCAHO's pain standards: an institutional challenge. J Pain Symptom Manage 2003;25:519–27. [2] Trescot AM, Boswell MV, Atluri SL, et al. Opioid guidelines in the management of chronic non-cancer pain. Pain Physician 2006;9:1–39. [3] McNicol E, Horowicz-Mehler N, Fisk RA, et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain 2003;4:231–56. [4] Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 2001;19:2542–54. [5] Cepeda MS, Farrar JT, Baumgarten M, Boston R, Carr DB, Strom BL. Side effects of opioids during short-term administration: effect of age, gender, and race. Clin Pharmacol Ther 2003;74:102–12. [6] Lloyd RS, Costello F, Eves MJ, James IG, Miller AJ. The efficacy and tolerability of controlled-release dihydrocodeine tablets and combination dextropropoxyphene/ paracetamol tablets in patients with severe osteoarthritis of the hips. Curr Med Res Opin 1992;13:37–48. [7] Pasternak GW. Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 1993;16:1–18. [8] Bhargava KP, Dixit KS, Gupta YK. Enkephalin receptors in the emetic chemoreceptor trigger zone of the dog. Br J Pharmacol 1981;72:471–5. [9] Ishihara M, Iihara H, Okayasu S, et al. Pharmaceutical interventions facilitate premedication and prevent opioid-induced constipation and emesis in cancer patients. Support Care Cancer 2010;18:1531–8. [10] Bateman DN, Darling WM, Boys R, Rawlins MD. Extrapyramidal reactions to metoclopramide and prochlorperazine. Q J Med 1989;71:307–11. [11] Isah AO, Rawlins MD, Bateman DN. Clinical pharmacology of prochlorperazine in healthy young males. Br J Clin Pharmacol 1991;32:677–84. [12] Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med 2004;26:265–70.
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[13] Tashiro M, Naito T, Kagawa Y, Kawakami J. Simultaneous determination of prochlorperazine and its metabolites in human plasma using isocratic liquid chromatography tandem mass spectrometry. Biomed Chromatogr 2012;26:754–60. [14] Baron JC, Martinot JL, Cambon H, et al. Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacology (Berl) 1989;99:463–72. [15] Ben-Jonathan N. Dopamine: a prolactin-inhibiting hormone. Endocr Rev 1985;6:564–89. [16] Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev 2000;80:1523–631. [17] Bero LA, Kuhn CM. Differential ontogeny of opioid, dopaminergic and serotonergic regulation of prolactin secretion. J Pharmacol Exp Ther 1987;240:825–30. [18] Flores CM, Hulihan-Giblin BA, Hornby PJ, Lumpkin MD, Kellar KJ. Partial characterization of a neurotransmitter pathway regulating the in vivo release of prolactin. Neuroendocrinology 1992;55:519–28. [19] Delitala G, Grossman A, Besser GM. The participation of hypothalamic dopamine in morphine-induced prolactin release in man. Clin Endocrinol (Oxf) 1983;19:437–44. [20] Hemmings R, Fox G, Tolis G. Effect of morphine on the hypothalamic-pituitary axis in postmenopausal women. Fertil Steril 1982;37:389–91. [21] Zhang Y, Wang D, Johnson AD, Papp AC, Sadee W. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 2005;280:32618–24. [22] Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 1998;95:9608–13. [23] Nakagawa M, Kuri M, Kambara N, et al. Dopamine D2 receptor Taq IA polymorphism is associated with postoperative nausea and vomiting. J Anesth 2008;22:397–403. [24] Zahari Z, Teh LK, Ismail R, Razali SM. Influence of DRD2 polymorphisms on the clinical outcomes of patients with schizophrenia. Psychiatr Genet 2011;21:183–9. [25] Thompson J, Thomas N, Singleton A, et al. D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics 1997;7:479–84. [26] Jonsson EG, Nothen MM, Grunhage F, et al. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 1999;4:290–6.
[27] Chou WY, Wang CH, Liu PH, Liu CC, Tseng CC, Jawan B. Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology 2006;105:334–7. [28] Zwisler ST, Enggaard TP, Noehr-Jensen L, et al. The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes. Fundam Clin Pharmacol 2010;24:517–24. [29] Nakazono Y, Abe H, Murakami H, et al. Association between neuroleptic druginduced extrapyramidal symptoms and dopamine D2-receptor polymorphisms in Japanese schizophrenic patients. Int J Clin Pharmacol Ther 2005;43:163–71. [30] Grandy DK, Zhang Y, Civelli O. PCR detection of the TaqA RFLP at the DRD2 locus. Hum Mol Genet 1993;2:2197. [31] Romberg RR, Olofsen E, Bijl H, et al. Polymorphism of mu-opioid receptor gene (OPRM1:c.118A N G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology 2005;102:522–30. [32] Taylor WB, Bateman DN. Preliminary studies of the pharmacokinetics and pharmacodynamics of prochlorperazine in healthy volunteers. Br J Clin Pharmacol 1987;23:137–42. [33] David SR, Taylor CC, Kinon BJ, Breier A. The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther 2000;22:1085–96. [34] Hauge XY, Grandy DK, Eubanks JH, Evans GA, Civelli O, Litt M. Detection and characterization of additional DNA polymorphisms in the dopamine D2 receptor gene. Genomics 1991;10:527–30. [35] Sora I, Komatsu H, Igari M, Ide S, Ikeda K, Shimoyama N. Side effects of opioid and gene variants. Masui 2009;58:1109–11. [36] Young RM, Lawford BR, Barnes M, et al. Prolactin levels in antipsychotic treatment of patients with schizophrenia carrying the DRD2*A1 allele. Br J Psychiatry 2004;185:147–51. [37] Yasui-Furukori N, Saito M, Tsuchimine S, et al. Association between dopaminerelated polymorphisms and plasma concentrations of prolactin during risperidone treatment in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1491–5. [38] Pan JT, Teo KL. Fentanyl stimulates prolactin release through mu-opiate receptors, but not the serotonergic system. Endocrinology 1989;125:1863–9.
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Impact of genetic and non-genetic factors on clinical responses to prochlorperazine in oxycodone-treated cancer patients Masaki Tashiro a,b, Takafumi Naito a, Kazunori Ohnishi c, Yoshiyuki Kagawa b, Junichi Kawakami a,⁎ a b c
Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan Department of Clinical Pharmaceutics and Pharmacy Practice, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Shizuoka, Japan Oncology Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
a r t i c l e
i n f o
Article history: Received 4 October 2013 Received in revised form 11 November 2013 Accepted 10 December 2013 Available online 17 December 2013 Keywords: Prochlorperazine DRD2 OPRM1 Oxycodone Cancer patients
a b s t r a c t Background: The contributions of DRD2 and OPRM1 genetic variants to clinical responses to prochlorperazine remain to be clarified in opioid-treated patients. We evaluated the clinical responses to prochlorperazine based on non-genetic and genetic factors in oxycodone-treated patients. Methods: Seventy Japanese cancer patients starting oral prochlorperazine together with oxycodone were enrolled. Predose plasma prochlorperazine concentrations and serum prolactin concentrations were determined. The incidences of oxycodone-induced nausea and vomiting were monitored for 2 weeks. Results: Plasma prochlorperazine concentration and oxycodone daily dose were not associated with the incidences of nausea and vomiting. The incidence of nausea was significantly higher in the DRD2 TaqIA A1A2 + A1A1 group than in the A2A2 group. The incidence of vomiting was significantly higher in females than in males. Before and after the prochlorperazine administration, the serum prolactin concentration was significantly higher in female patients than in male patients. The serum prolactin concentration was weakly correlated with prochlorperazine concentration and was significantly higher in the OPRM1 118AA group than in the AG + GG group. Conclusions: DRD2 TaqIA and female gender altered the prophylactic antiemetic efficacy of prochlorperazine. OPRM1 A118G together with plasma exposure of prochlorperazine and gender affected prolactin secretion in oxycodone-treated patients. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Opioid analgesics including morphine, oxycodone and fentanyl are widely used for the treatment of cancer and chronic non-cancer pain [1,2]. Although opioids possess a strong analgesic potency, patients receiving opioids frequently experience adverse effects leading to noncompliance [3,4]. Nausea and vomiting are the most common adverse effects in the early phase after starting opioids [4,5]. Most patients develop tolerance to the emetic effect within a week [6]. Opioids produce analgesia via an action at the opioid receptor mu1 (OPRM1) [7]. The mechanisms for opioid-induced nausea and vomiting include direct stimulation of the chemoreceptor trigger zone, reduced gastrointestinal motility, or enhanced vestibular sensitivity [8]. Prochlorperazine is a dopamine D2 receptor (DRD2) antagonist with a piperazinyl phenothiazine structure. Prochlorperazine has a high potency antiemetic effect based on inhibiting DRD2 at a chemoreceptor trigger zone and is commonly used for the treatment of nausea and
Abbreviations: DRD2, dopamine receptor D2; OPRM1, opioid receptor mu 1. ⁎ Corresponding author at: Department of Hospital Pharmacy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan. Tel.: +81 53 435 2762; fax: +81 53 435 2764. E-mail address: [email protected] (J. Kawakami). 0009-8981/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cca.2013.12.011
vomiting in clinical settings [9]. Clinical responses to prochlorperazine vary in opioid-treated patients. The diversity in the responses to prochlorperazine can occasionally cause inadequate antiemetic efficacy or adverse effects such as hyperprolactinemia, extrapyramidal symptoms, and drowsiness [10–12]. Opioid-treated patients exhibit the interindividual variability in the plasma concentration of prochlorperazine [13], however, its contribution to clinical responses remains to be clarified. Prochlorperazine increases the serum prolactin concentration via the blockade of dopaminergic pathways in the anterior pituitary gland [14,15]. Prolactin, a lactogenic hormone, is released from the pituitary lactotrophs. The hypothalamus controls prolactin secretion into the blood stream via dopamine as a prolactin inhibiting factor and thyrotropin-releasing hormone as a prolactin releasing factor [16]. Opioids bind to OPRM1 on the hypothalamus and subsequently cause the blockade of dopaminergic pathways [17,18]. Morphine administration has been found to elevate the serum prolactin concentration in humans [19,20]. The influence of opioids on prolactin secretion has not been fully evaluated in DRD2 antagonist-treated patients. Several important genetic variants of DRD2 and OPRM1 have been identified in humans [21,22]. DRD2 TaqIA (rs1800497) affected the incidences of postoperative nausea and vomiting [23] and the clinical responses to antipsychotics [24]. DRD2 TaqIA is associated with a
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reduction of DRD2 gene expression, resulting in diminishing dopaminergic activity [25,26]. A genetic variant of OPRM1 has been shown to affect postoperative morphine consumption after hysterectomy [27] and lessened the analgesic effect of oxycodone in healthy subjects [28]. OPRM1 A118G (rs1799971) is a functional genetic variant with deleterious effects on both mRNA and protein yield and is associated with brain OPRM1 binding potential [21,22]. There is still controversy concerning the clinical implications of these genetic variants in clinical settings. The contributions of DRD2 and OPRM1 genetic variants to the prophylactic antiemetic efficacy of prochlorperazine and serum prolactin elevation remain to be clarified in opioid-treated patients. 2. Materials and methods 2.1. Ethics The study was performed in accordance with the Declaration of Helsinki and its amendments, and the protocol was approved by the Ethics Committee of Hamamatsu University School of Medicine. The patients were briefed about the scientific aim of the study and each patient provided written informed consent. 2.2. Patients and study schedule The study was an observational study (UMIN-CTR, UMIN000011323) conducted at a single site at Hamamatsu University Hospital. Seventy patients receiving oral prochlorperazine (Novamin®, Shionogi & Co.,) for the prevention of opioid-induced nausea and vomiting at Hamamatsu University Hospital were enrolled. Each patient started oral prochlorperazine together with oxycodone extended-release tablets (OxyContin®, Shionogi & Co.) for cancer pain. They received 5 mg prochlorperazine 3 times daily at 8:00, 14:00, and 20:00 and 5 mg oxycodone as an initial dose twice daily at 8:00 and 20:00. Exclusion criteria were as follows: Patients who (1) discontinued oral prochlorperazine or oxycodone during the study; (2) were being co-treated with anticancer drugs; (3) were being co-treated with other DRD2 antagonists; (4) were being co-treated with triazole antifungal agents, rifampin, or macrolide antibiotics; (5) were diagnosed as having prolactinproducing adenoma or brain tumors; and (6) were difficult to evaluate with respect to nausea and vomiting. Blood specimens were drawn into tubes containing EDTA disodium salt and serum separators at 12 h after the evening dosing on day 6 or later within 2 weeks after starting prochlorperazine administration and the predose concentrations of prochlorperazine and prolactin were evaluated. In addition, some patients donated stored serum specimens before starting the prochlorperazine administration. 2.3. Determination of plasma prochlorperazine concentration Prochlorperazine maleate and amitriptyline hydrochloride as an internal standard were purchased from Sigma Aldrich. All other reagents were analytical grade and commercially available. Plasma was separated by centrifugation of the EDTA-treated blood samples at 1670 ×g at 4 °C for 10 min. Plasma concentrations of prochlorperazine were determined by isocratic LC-MS/MS as previously described [13]. Chromatographic separation of each analyte was performed on an ODS column (TSKgel ODS-100 V, 3 μm, 150 × 2.0 mm, Tosoh). The mobile phase consisted of 40% acetonitrile containing 5 mmol/l ammonium acetate at pH 4.25. The flow rate was 0.3 ml/min and the column oven temperature was set at 60 °C. The MS/MS analysis was performed with an electrospray source. The heated capillary was maintained at 240 °C in positive ion mode. The collision energies for prochlorperazine and amitriptyline were set at −22 and −25 eV, respectively. The ion transitions were monitored using a dwell time of 0.5 s for each compound: prochlorperazine, m/z 374.1/140.9; and amitriptyline, m/z 278.1/116.8. The calibration curves in human plasma were linear over the
concentration ranges of 0.01–40 μg/l (r N 0.999). The intra- and interassay CVs and accuracies were within 5.8% and 100–104% and within 7.8% and 99–103%, respectively. The lower limit of quantification in human plasma was 10 ng/l. The precision and accuracy of the lower limit of quantification were 7.6% and 105%, respectively. 2.4. Determination of serum prolactin concentration Serum prolactin concentrations were measured using chemiluminescent immunoassay according to the manufacturer's protocol (Architect® Prolactin, Abbott) using an automated immunoassay analyzer (Architect® i1000 SR,). The intra- and inter-assay precisions and accuracies were within 1.8% and 99–100% and within 2.6% and 97–100%, respectively. The serum prolactin concentration was calculated from the calibration information stored in the instrument memory. The lower limit of quantification in human serum was 0.6 μg/l. 2.5. Genotyping of DRD2 and OPRM1 Genomic DNA was extracted from peripheral whole blood from each patient using a DNA Extractor WB Kit (Wako Pure Chemicals) and stored at − 20 °C until analysis. The primer sequences and conditions of the polymerase chain reaction-fragment length polymorphism used for analyses of DRD2 TaqIA, TaqIB (rs1079597) and OPRM1 A118G were as described previously, with some modifications [29–31]. 2.6. Evaluation of prophylactic antiemetic efficacy The prophylactic antiemetic efficacy of prochlorperazine for oxycodone-induced nausea and vomiting was monitored for 2 weeks after starting prochlorperazine administration. The prophylactic antiemetic efficacy was evaluated by the incidences of nausea and vomiting. The incidence and severity were obtained from the medical records. The incidences and severities of nausea and vomiting in each patient were assessed using the grading system of the Common Terminology Criteria for Adverse Events (CTCAE v4.0). 2.7. Statistical analysis All statistical analyses were performed using SPSS (15.0 J, SPSS Japan Inc., Tokyo). The genetic variants of DRD2 TaqIA, TaqIB, and OPRM1 evaluated were as follows: DRD2 TaqIA (A2A2 and A1A2 + A1A1), DRD2 TaqIB (B2B2 and B1B2 + B1B1), and OPRM1 (AA and AG + GG). The influences of the plasma prochlorperazine concentration and oxycodone daily dose on the incidences of nausea and vomiting were tested using the Mann–Whitney U test. The influences of gender and genetic variants of DRD2 and OPRM1 on the incidences of nausea and vomiting were tested using Fisher's exact test. Stepwise multiple logistic regression analysis was performed to evaluate the influences of the plasma prochlorperazine concentration, oxycodone daily dose, gender, and genetic variants of DRD2 and OPRM1 on the incidences of nausea and vomiting. The changes in serum prolactin concentration before and after prochlorperazine administration were tested by the Wilcoxon signed rank test. The correlations between the plasma prochlorperazine concentration or oxycodone daily dose and serum prolactin concentration were tested by Spearman's rank correlation coefficient analysis. The influences of gender and genetic variants of DRD2 and OPRM1 on the serum prolactin concentration were tested using the Mann–Whitney U test. Multiple regression analysis was performed to evaluate the influences of the plasma prochlorperazine concentration, oxycodone daily dose, gender, and genetic variants of DRD2 and OPRM1 on the serum prolactin concentration following prochlorperazine administration. All values are expressed as the median and interquartile range (IQR) unless otherwise stated. A P b 0.05 was considered to indicate statistical significance.
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Table 1 shows the patient demographic characteristics. The patient population consisted of 45 males and 25 females. The patients had slightly lower serum concentrations of total protein (median, 6.4 g/dl; and IQR, 6.1–7.0 g/dl) and albumin (median, 3.5 g/dl; IQR, 3.2–3.8 g/dl). No patient had severe hepatic and/or renal function impairment according to Table 1. The patients had pharyngeal cancer (n = 26), lung cancer (n = 7), multiple myeloma (n = 6), malignant lymphoma (n = 6), esophageal cancer (n = 5), gastric cancer (n = 2), prostate cancer (n = 2), bladder cancer (n = 2), and other types of cancer (n = 14). The present study was performed in a Japanese population. The allele frequencies of the observed genetic variants of DRD2 and OPRM1 were as follows: DRD2 TaqIA A1 (0.357), TaqIB B1 (0.371), and OPRM1 118G (0.421), respectively. 3.2. Plasma prochlorperazine concentration and oxycodone daily dose The median of the predose plasma concentration of prochlorperazine at 12 h after the evening dosing after starting prochlorperazine administration was 1.90 μg/l and interindividual variation was also observed (IQR, 1.03–4.07 μg/l). The median and IQR of the oxycodone daily dose were 10 and 10–20 mg, respectively. 3.3. Non-genetic factors related to prophylactic antiemetic efficacy The incidences of nausea and vomiting in the study population were 36% and 17%, respectively. The grades of the adverse events of nausea and vomiting were categorized into 1 or 2. No significant difference was observed in the plasma prochlorperazine concentration between the patients with and without nausea or vomiting (Fig. 1). There was no significant difference in the oxycodone daily dose between the patients with and without nausea (median and IQR, 10 and 10–20 vs. 10 and 10–20 mg, respectively) or vomiting (10 and 10–20 vs. 10 and 10–20 mg, respectively). The incidences of nausea and vomiting were 31% and 7% in males and 44% and 36% in females, respectively (Table 2). The incidence of vomiting was significantly higher in female patients than in male patients (P = 0.006), while gender was not associated with the incidence of nausea. 3.4. Non-genetic factors related to serum prolactin concentration The serum prolactin concentration increased after the treatments (median and IQR, 11.0 and 9.2–17.4 vs. 31.8 and 20.5–52.3 μg/l, P b 0.001) in 26 patients who donated serum specimens before starting prochlorperazine administration. The median of the serum prolactin concentration was 35.3 μg/l after prochlorperazine administration in 70 cancer patients. There was interindividual variation in the serum prolactin concentration in this study population (IQR, 26.8–50.0 μg/l). The serum prolactin concentration was weakly correlated with the
B) 25
Plasma prochlorperazine concentration (µg/l)
3.1. Patient demographic characteristics
Plasma prochlorperazine concentration (µg/l)
A)
3. Results
20
15
10
5
0
Without (n = 45)
With (n = 25)
20
15
10
5
0
Without (n = 58)
plasma prochlorperazine concentration (ρ = 0.243, P = 0.043). The serum prolactin concentration was not significantly correlated with the oxycodone daily dose (ρ = −0.024, P = 0.846). The serum prolactin concentration was significantly higher in female patients than in male patients before and after prochlorperazine administration (P = 0.006 and P = 0.007, respectively, Fig. 2). 3.5. Genetic factors related to clinical responses The incidence of nausea was higher in the DRD2 TaqIA A1A2 + A1A1 group than in the A2A2 group (P = 0.042), while the incidence of vomiting was not (Table 2). The incidence of nausea was higher in the DRD2 TaqIB B1B2 + B1B1 group than in the B2B2 group (P = 0.042), while the incidence of vomiting was not. No significant differences were observed in the incidences of nausea and vomiting between the OPRM1 genetic variants. DRD2 TaqIA and TaqIB were not associated with the serum prolactin concentration (Fig. 3). The serum prolactin concentration was significantly higher in the OPRM1 118AA group than in the 118AG + GG group (P = 0.005). 3.6. Multivariate analysis of several factors related to clinical responses Multiple logistic regression analysis demonstrated that the DRD2 TaqIA A1 allele was correlated with the incidence of nausea (P = 0.031, Table 2 The influences of gender and OPRM1 and DRD2 genetic variants on the incidences of nausea and vomiting in cancer patients. Nausea
70, 45/25 66 (58–72) 53.8 (45.8–61.3) 6.4 (6.1–7.0) 3.5 (3.2–3.8) 0.8 (0.6–0.9) 16.1 (12.1–19.4) 0.6 (0.5–0.8) 26 (19–34) 22 (16–34) 10 (10–20)
Data are expressed as median with interquartile range in parentheses.
With (n = 12)
Fig. 1. Influence of plasma prochlorperazine concentration on the incidences of nausea (A) and vomiting (B) in oxycodone-treated patients. Box plots represent the median, 25th, and 75th percentiles. The whiskers indicate the range and extend within 1.5 times the length of the inner quartiles. Outliers, or those which lie N1.5 times the length of the inner quartiles, are indicated by the presence of open circles.
Table 1 Demographics of cancer patients receiving oxycodone. Number of patients, male/female Age (y) Body weight (kg) Total protein (g/dl) Serum albumin (g/dl) Serum creatinine (mg/dl) Blood urea nitrogen (mg/dl) Total bilirubin (mg/dl) Aspartate aminotransferase (IU/l) Alanine aminotransferase (IU/l) Oxycodone daily dose (mg)
25
Vomiting
n
n
(%)
P
n
Male Female
45 25
14 11
31 44
NS
AA AG + GG
25 45
11 14
44 31
NS
A2/A2 A1/A2 + A1/A1 B2/B2 B1/B2 + B1/B1
29 41 29 41
6 19 6 19
21 46 21 46
0.042†
(%)
P
3 9
7 36
0.006†
5 7
20 16
NS
2 10 2 10
7 24 7 24
NS
Gender
OPRM1 A118G DRD2 TaqIA TaqIB †
P b 0.05, Fisher's exact test.
†
0.042
NS
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A)
B)
†
† 140
Serum prolactin concentration (µg/l)
Serum prolactin concentration (µg/l)
40
30
20
10
0
120 100 80 60 40 20 0
Male (n = 20)
Male (n = 45)
Female (n = 6)
Female (n = 25)
Fig. 2. Comparison of serum prolactin concentration between male and female cancer patients before (A) and after (B) prochlorperazine administration. Box plots represent the median, 25th, and 75th percentiles. The whiskers indicate the range and extend within 1.5 times the length of the inner quartiles. Outliers, or those which lie N1.5 times the length of the inner quartiles, are indicated by the presence of open circles. †P b 0.05.
odds ratio, OR: 3.31; 95% confidence interval, 1.11–9.83). Multiple logistic regression analysis demonstrated that being female was correlated with the incidence of vomiting (P = 0.008, OR: 7.26; 95% confidence interval, 1.70–31.12). Multiple regression analysis demonstrated that plasma prochlorperazine concentration (standardized partial regression coefficient (β) = 0.263, P = 0.015), female gender (β = 0.279, P = 0.013), and OPRM1 118G allele carrier (β = −0.284, P = 0.013) were significantly correlated with the serum prolactin concentration. 4. Discussion The clinical implications of DRD2 and OPRM1 genetic variants for the management of opioid-induced nausea and vomiting using phenothiazine derivatives have not been fully clarified in cancer patients. This study evaluated the interindividual variation in clinical responses to prochlorperazine based on non-genetic and genetic factors in oxycodone-treated patients. Being female and having the DRD2 TaqIA A1 allele were 2 parameters that were correlated with the incidence of nausea and vomiting. OPRM1 A118G together with plasma prochlorperazine concentration and gender were associated with the serum prolactin concentration. These findings indicate that genetic
A)
B)
C)
120 100 80 60 40 20 0
†
140
Serum prolactin concentration (µg/l)
140
Serum prolactin concentration (µg/l)
140
Serum prolactin concentration (µg/l)
variants of DRD2 and OPRM1 affect the dopaminergic pathways in prochlorperazine-treated cancer patients receiving oxycodone. To the best of our knowledge, this is the first report that has evaluated the interindividual variations of clinical responses to prochlorperazine based on genetic variants of DRD2 and OPRM1 in cancer patients receiving oxycodone. The incidences of nausea and vomiting in cancer patients receiving oxycodone were 36% and 17%, respectively, in this study. Vomiting is usually proceeded with nausea. In this study, the patient group with vomiting included the patients with nausea. Patients have tolerance to the opioid-induced nausea and vomiting within 2 weeks [9]. This study had evaluated the incidences and severities of nausea and vomiting during only 2 weeks. A large variation was observed in the predose plasma prochlorperazine concentration. In a previous report we also observed interindividual variation in the plasma exposure of prochlorperazine [13]. In the present study population, the plasma concentration of prochlorperazine was not associated with the incidences of nausea and vomiting and the antiemetic effect of prochlorperazine was not responsible for the plasma prochlorperazine concentration. The plasma exposure to oxycodone may also affect opioid-induced nausea and vomiting. The oxycodone daily dose was not related to the incidences of nausea and vomiting in our study. In addition, there was little difference in the oxycodone daily dose because the patients enrolled were in the induction phase. These data indicate that the difference in plasma exposure to oxycodone was associated with our results. The serum prolactin concentration was elevated after coadministration of oxycodone and prochlorperazine, and was weakly correlated with the plasma prochlorperazine concentration in this study. Several studies have showed that prochlorperazine treatment elevated the serum prolactin concentration [32]. The time–concentration profile of serum prolactin after the prochlorperazine administration was similar to that of plasma prochlorperazine in healthy adults [11]. In the preliminary observation for several patients, the serum concentration of prolactin had not changed largely on day 6 or later during the observation period. Opioid analgesic morphine also raised the serum prolactin concentration [18,19]. Our results suggest that each administration of prochlorperazine and oxycodone is associated with the elevation of the serum prolactin concentration. In the present study, the serum prolactin concentrations in females were higher than those in males before and after co-treatment with prochlorperazine and oxycodone. David et al. reported that the elevation of serum prolactin concentration caused by the administration of a DRD2 antagonist was higher in female than in male schizophrenia patients [33]. Although our study enrolled elderly postmenopausal cancer patients, the serum
120 100 80 60 40 20 0
120 100 80 60 40 20 0
A2A2
A1A2+A1A1
B2B2
B1B2+B1B1
AA
AG+GG
(n = 29)
(n = 41)
(n = 29)
(n = 41)
(n = 25)
(n = 45)
Fig. 3. Influence of DRD2 and OPRM1 genetic variants on the serum prolactin concentration in prochlorperazine-treated cancer patients. (A) DRD2 TaqIA, (B) DRD2 TaqIB, and (C) OPRM1 A118G. Box plots represent the median, 25th, and 75th percentiles. The whiskers indicate the range and extend within 1.5 times the length of the inner quartiles. Outliers, or those which lie N1.5 times the length of the inner quartiles, are indicated by the presence of open circles. †P b 0.05.
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prolactin concentration was higher in females than in males. Our results indicate that gender and plasma prochlorperazine concentration are non-genetic factors affecting serum prolactin concentrations in elderly cancer patients receiving oxycodone and prochlorperazine. DRD2 TaqIA and TaqIB genetic variants increased the incidence of nausea and vomiting in cancer patients receiving oxycodone in this study. The TaqIB genetic variant has linkage disequilibrium with the TaqIA genetic variant [34]. The B1 allele of the TaqIB genetic variant as well as the A1 allele of the TaqIA genetic variant decreased the density of DRD2 in brain in vitro and in vivo [25,26]. DRD2 TaqIA and TaqIB genetic variants may be associated with the sensitivity to nausea and vomiting by reducing DRD2 gene expression. Sora et al. demonstrated that DRD2 TaqIA and TaqIB were involved in the onset of gastrointestinal symptoms caused by oxycodone [35]. In contrast, Nakagawa et al. reported that the DRD2 TaqIA A2 allele was a risk factor for postoperative nausea and vomiting [23]. The opioid-induced nausea and vomiting observed in our study were evaluated in cancer patients and the patients received prophylactic prochlorperazine when the oxycodone was started. The difference in patient backgrounds may have altered the effects of the DRD2 TaqIA genetic variants on nausea and vomiting. The OPRM1 genetic variant lowered the serum prolactin concentration in the present study. Opioids bind to OPRM1 on the hypothalamus and cause the inhibition of dopaminergic pathways, resulting in elevation of the serum prolactin concentration. OPRM1 A118G is a functional genetic variant with deleterious effects on both mRNA and protein yield and is associated with OPRM1 binding potential in the brain [21,22]. In the present study, the oxycodone daily dose was not associated with serum prolactin concentrations in cancer patients. Opioids indirectly cause the secretion of prolactin via OPRM1 mediated dopaminergic pathways [18,19]. Functional OPRM1 may synergistically cause the elevation of serum prolactin concentrations through the inhibition of dopamine neurons by opioids together with the DRD2 inhibition by prochlorperazine in the anterior pituitary. This study employed the multivariate analyses to clarify the impact of genetic variants in each gender. Using multiple logistic regression analyses, DRD2 TaqIA A1 allele was associated with the incidence of nausea (OR: 3.3) and female gender increased the incidence of vomiting (OR: 7.2). Using multiple regression analyses, the β value of female gender (β = 0.279) was similar to that of plasma prochlorperazine concentration (β = 0.263) and OPRM1 118G allele carrier (β = −0.284). Our data suggest that female gender together with genetic variants of DRD2 and OPRM1 strongly influence the prophylactic antiemetic efficacy and prolactin secretion under the prochlorperazine administration. The DRD2 TaqIA and TaqIB genetic variants were not correlated with the serum prolactin concentrations. Young et al. reported that serum prolactin concentrations were twice as high in the DRD2 TaqIA A1 allele group than in the A2 allele group in patients with schizophrenia receiving DRD2 antagonist [36]. In contrast, Yasui-Furukori et al. showed that there was no association between serum prolactin concentrations and the DRD2 TaqIA genetic variant in patients with schizophrenia [37]. To date, there is still no consensus on the effect of the DRD2 genetic variant on serum prolactin concentrations. Opioid analgesics together with a DRD2 antagonist were also shown to elevate serum prolactin concentrations [18,19]. This study encountered difficulty with evaluating the influence of DRD2 genetic variants on serum prolactin concentrations in cancer patients receiving both prochlorperazine and oxycodone. The study has several limitations. First, it was difficult to observe extrapyramidal symptoms, which are known to be an adverse effect of prochlorperazine. One patient was diagnosed as having severe extrapyramidal symptoms. The study population consisted of mostly elderly patients with low activity concentrations, which may have masked the extrapyramidal symptoms. Evaluations with a focused population with higher activities may clarify the relationship with extrapyramidal symptoms. Second, half of the patients enrolled in this study had pharyngeal cancer or lung cancer. There were no differences in the incidences of nausea and vomiting, or the serum prolactin concentration
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between pharyngeal cancer, lung cancer, and other cancer types. The data indicate that the difference in cancer types did not strongly affect our findings. Third, the impact of DRD2 genetic variants on the antiemetic effect was not clarified in this study. Earlier reports did not distinguish between the incidences of nausea and vomiting. DRD2 genetic variants may be more sensitive to nausea than vomiting in oxycodone-treated patients. Fourth, this study was underpowered to perform the subgroups analysis. The subgroup analysis by consideration of gender is needed in order to clarify the impact of the genetic variants in each gender. As alternative analyses, we employed the multivariate analyses to clarify the impact of the genetic variants in each gender. The clinical implications of DRD2 and OPRM1 genetic variants on the management of opioid-induced adverse effects using prochlorperazine have not been fully clarified in cancer patients. Based on our clinical data, DRD2 genetic variants may be a predictive factor for nausea in cancer patients receiving prochlorperazine and oxycodone. OPRM1 118A allele may be a risk factor for hyperprolactinemia caused by prochlorperazine. Our data indicate that additional treatments are needed to manage the prochlorperazine prophylaxis in cancer patients receiving oxycodone. Our study enrolled only patients receiving oxycodone. Earlier reports showed that morphine and fentanyl also elevated the serum prolactin concentration via OPRM1 [19,20,38]. If we take into consideration the mechanism of action, similar results may be observed in cancer patients receiving other opioids.
5. Conclusions DRD2 TaqIA and being female altered the prophylactic antiemetic efficacy of prochlorperazine in cancer patients receiving prochlorperazine and oxycodone. In addition, OPRM1 A118G together with plasma prochlorperazine concentration and gender affected the serum prolactin concentration. These findings suggest that genetic variants of DRD2 and OPRM1 affected the interindividual variation of clinical responses to prochlorperazine in these oxycodone-treated cancer patients.
Financial disclosure This work was supported by JSPS KAKENHI Grant Number 23790181.
References [1] Cohen MZ, Easley MK, Ellis C, et al. Cancer pain management and the JCAHO's pain standards: an institutional challenge. J Pain Symptom Manage 2003;25:519–27. [2] Trescot AM, Boswell MV, Atluri SL, et al. Opioid guidelines in the management of chronic non-cancer pain. Pain Physician 2006;9:1–39. [3] McNicol E, Horowicz-Mehler N, Fisk RA, et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain 2003;4:231–56. [4] Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 2001;19:2542–54. [5] Cepeda MS, Farrar JT, Baumgarten M, Boston R, Carr DB, Strom BL. Side effects of opioids during short-term administration: effect of age, gender, and race. Clin Pharmacol Ther 2003;74:102–12. [6] Lloyd RS, Costello F, Eves MJ, James IG, Miller AJ. The efficacy and tolerability of controlled-release dihydrocodeine tablets and combination dextropropoxyphene/ paracetamol tablets in patients with severe osteoarthritis of the hips. Curr Med Res Opin 1992;13:37–48. [7] Pasternak GW. Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 1993;16:1–18. [8] Bhargava KP, Dixit KS, Gupta YK. Enkephalin receptors in the emetic chemoreceptor trigger zone of the dog. Br J Pharmacol 1981;72:471–5. [9] Ishihara M, Iihara H, Okayasu S, et al. Pharmaceutical interventions facilitate premedication and prevent opioid-induced constipation and emesis in cancer patients. Support Care Cancer 2010;18:1531–8. [10] Bateman DN, Darling WM, Boys R, Rawlins MD. Extrapyramidal reactions to metoclopramide and prochlorperazine. Q J Med 1989;71:307–11. [11] Isah AO, Rawlins MD, Bateman DN. Clinical pharmacology of prochlorperazine in healthy young males. Br J Clin Pharmacol 1991;32:677–84. [12] Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med 2004;26:265–70.
180
M. Tashiro et al. / Clinica Chimica Acta 429 (2014) 175–180
[13] Tashiro M, Naito T, Kagawa Y, Kawakami J. Simultaneous determination of prochlorperazine and its metabolites in human plasma using isocratic liquid chromatography tandem mass spectrometry. Biomed Chromatogr 2012;26:754–60. [14] Baron JC, Martinot JL, Cambon H, et al. Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacology (Berl) 1989;99:463–72. [15] Ben-Jonathan N. Dopamine: a prolactin-inhibiting hormone. Endocr Rev 1985;6:564–89. [16] Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev 2000;80:1523–631. [17] Bero LA, Kuhn CM. Differential ontogeny of opioid, dopaminergic and serotonergic regulation of prolactin secretion. J Pharmacol Exp Ther 1987;240:825–30. [18] Flores CM, Hulihan-Giblin BA, Hornby PJ, Lumpkin MD, Kellar KJ. Partial characterization of a neurotransmitter pathway regulating the in vivo release of prolactin. Neuroendocrinology 1992;55:519–28. [19] Delitala G, Grossman A, Besser GM. The participation of hypothalamic dopamine in morphine-induced prolactin release in man. Clin Endocrinol (Oxf) 1983;19:437–44. [20] Hemmings R, Fox G, Tolis G. Effect of morphine on the hypothalamic-pituitary axis in postmenopausal women. Fertil Steril 1982;37:389–91. [21] Zhang Y, Wang D, Johnson AD, Papp AC, Sadee W. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 2005;280:32618–24. [22] Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 1998;95:9608–13. [23] Nakagawa M, Kuri M, Kambara N, et al. Dopamine D2 receptor Taq IA polymorphism is associated with postoperative nausea and vomiting. J Anesth 2008;22:397–403. [24] Zahari Z, Teh LK, Ismail R, Razali SM. Influence of DRD2 polymorphisms on the clinical outcomes of patients with schizophrenia. Psychiatr Genet 2011;21:183–9. [25] Thompson J, Thomas N, Singleton A, et al. D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics 1997;7:479–84. [26] Jonsson EG, Nothen MM, Grunhage F, et al. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 1999;4:290–6.
[27] Chou WY, Wang CH, Liu PH, Liu CC, Tseng CC, Jawan B. Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology 2006;105:334–7. [28] Zwisler ST, Enggaard TP, Noehr-Jensen L, et al. The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes. Fundam Clin Pharmacol 2010;24:517–24. [29] Nakazono Y, Abe H, Murakami H, et al. Association between neuroleptic druginduced extrapyramidal symptoms and dopamine D2-receptor polymorphisms in Japanese schizophrenic patients. Int J Clin Pharmacol Ther 2005;43:163–71. [30] Grandy DK, Zhang Y, Civelli O. PCR detection of the TaqA RFLP at the DRD2 locus. Hum Mol Genet 1993;2:2197. [31] Romberg RR, Olofsen E, Bijl H, et al. Polymorphism of mu-opioid receptor gene (OPRM1:c.118A N G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology 2005;102:522–30. [32] Taylor WB, Bateman DN. Preliminary studies of the pharmacokinetics and pharmacodynamics of prochlorperazine in healthy volunteers. Br J Clin Pharmacol 1987;23:137–42. [33] David SR, Taylor CC, Kinon BJ, Breier A. The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther 2000;22:1085–96. [34] Hauge XY, Grandy DK, Eubanks JH, Evans GA, Civelli O, Litt M. Detection and characterization of additional DNA polymorphisms in the dopamine D2 receptor gene. Genomics 1991;10:527–30. [35] Sora I, Komatsu H, Igari M, Ide S, Ikeda K, Shimoyama N. Side effects of opioid and gene variants. Masui 2009;58:1109–11. [36] Young RM, Lawford BR, Barnes M, et al. Prolactin levels in antipsychotic treatment of patients with schizophrenia carrying the DRD2*A1 allele. Br J Psychiatry 2004;185:147–51. [37] Yasui-Furukori N, Saito M, Tsuchimine S, et al. Association between dopaminerelated polymorphisms and plasma concentrations of prolactin during risperidone treatment in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1491–5. [38] Pan JT, Teo KL. Fentanyl stimulates prolactin release through mu-opiate receptors, but not the serotonergic system. Endocrinology 1989;125:1863–9.
