Decreased Analgesic Effect of Tramadol in Japanese Patients with CYP2D6 Intermediate Metabolizers after Orthopedic Surgery

Abstract

Tramadol is metabolized by CYP2D6 to an active metabolite, which in turn acts as an analgesic. This study aimed to investigate the impact of CYP2D6 genotype on the analgesic effect of tramadol in clinical practice. A retrospective cohort study was performed in patients treated with tramadol for postoperative pain after arthroscopic surgery for rotator cuff injury during April 2017–March 2019. The impact of CYP2D6 genotypes on the analgesic effects was assessed by the numeric rating scale (NRS) pain scoring and analyzed by the Mann–Whitney U test. Stepwise multiple linear regression analysis was performed to identify predictive factors for the area under the time-NRS curve (NRS-AUC), which was calculated using the linear trapezoidal method. Among the 85 enrolled Japanese patients, the number of phenotypes with CYP2D6 normal metabolizer (NM) and intermediate metabolizer (IM) was n = 69 (81.1%) and n = 16 (18.9%), respectively. The NRS and NRS-AUC in the IM group were significantly higher than those in the NM group until Day 7 (p < 0.05). The multiple linear regression analysis indicated that the CYP2D6 polymorphism was a prediction factor of the high NRS-AUC levels in Days 0–7 (β = 9.52, 95% CI 1.30–17.7). In IM patients, the analgesic effect of tramadol was significantly reduced one week after orthopedic surgery in clinical practice. Therefore, dose escalation of tramadol or the use of alternative analgesic medications can be recommended for IM patients.

INTRODUCTION

Pharmacogenomic (PGx) testing can predict therapeutic responses or adverse effects based on genetic variants and is expected to be an effective clinical test for precision medicine patient management.^1,2) The number of drugs recommended for PGx testing by regulatory agencies or consortiums are increasing, and the Food and Drug Administration (FDA) and the European Medicines Agency provided distinct guidelines for conducting PGx tests.^3,4)

Tramadol is an orally available, centrally acting, weak-opioid analgesic drug, which is metabolized by the CYP2D6 enzyme to its primary active metabolite O-desmethyltramadol (ODT) via O-demethylation or by CYP3A4 and CYP2B6 to other metabolites.^5,6) ODT which is converted from tramadol by CYP2D6 is a major active metabolite, which binds to the μ-opioid receptors and exhibits analgesic effects. In addition, tramadol has adjuvant analgesic effects by inhibiting the reuptake of monoamine neurotransmitters such as 5-hydroxytryptamine and noradrenaline. Therefore, wide interindividual differences are found in analgesic effects due to the highly polymorphic nature of CYP2D6.^2,7–9) CYP2D6 is one of the major drug-metabolizing enzymes that is responsible for the metabolism of up to 25% of common drugs, such as antipsychotics and antidepressants.^10,11) Over 100 polymorphisms of CYP2D6 allelic variants and subvariants have already been reported.¹⁰⁾

An individualized administration strategy of tramadol has been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) based on clinical trials performed in Western countries. Tramadol is defined as CPIC level A, indicating that genetic information should be used to change prescribing of any related drug. Consequently, CPIC positively recommended dosage adjustment or the use of alternative medications with respect to the CYP2D6 genotypes. In general, the patients were stratified into four phenotypes: ultra-rapid metabolizer (UM), normal metabolizer (NM), intermediate metabolizer (IM), and poor metabolizer (PM).¹²⁾ Previous studies demonstrated that exposure of the active metabolite of tramadol was significantly higher in UMs compared with NMs (p = 0.005),¹³⁾ and tramadol loading dose for postoperative analgesia was significantly lower in NMs compared with PMs (p < 0.001).⁷⁾ In contrast, marked racial differences are found in the frequency of CYP2D6 alleles. A previous study showed that the CYP2D6*4 allele occurs in approximately 20% of Caucasians compared with only 0.3% in the Japanese people.¹⁴⁾ In contrast, the frequency of the CYP2D6*10 allele is known to be very high in Japanese.¹⁵⁾ Thus, the individualized administration strategy published by the CPIC may not be directly applicable to the Japanese population. The frequency of the CYP2D6 IM category is higher among Asians, including the Japanese, than among Europeans and admixed Americans, whereas the frequency of the CYP2D6 PM category is rare.¹⁶⁾ Therefore, introducing specific recommendations for tramadol therapy to the CYP2D6 IM category of patients based on clinical studies that will be performed in Asian patients is necessary. The plasma concentration of ODT is significantly decreased in IM patients.¹⁷⁾ Also, tamoxifen is metabolically activated by CYP2D6, and the plasma concentration is affected by CYP2D6 polymorphisms,¹⁸⁾ whereas Tamura et al. reported that an administration design based on PGx did not affect the subsequent therapeutic effects.¹⁹⁾

Consequently, investigating the impact of CYP2D6 polymorphisms on tramadol pharmacokinetics but also on its pharmacodynamics (analgesic effect) is necessary. This study aimed to investigate the impact of CYP2D6 genotypes on the analgesic effect of tramadol in real-world clinical practice.

PATIENTS AND METHODS

Subjects and Research Methods

We retrospectively analyzed data from patients treated with tramadol hydrochloride/acetaminophen combination tablets, who underwent arthroscopic rotator cuff repair (ARCR) at the Department of Orthopedics in Shiga University of Medical Science Hospital and were hospitalized between April 2017 and March 2019. Data collected included information on patient characteristics, such as sex, age, body weight, body mass index, total protein, albumin (Alb), C-reactive protein, blood urea nitrogen (BUN), serum creatinine (Cre), aspartate aminotransferase (AST), alanine aminotransferase (ALT) at hospital admission, and administration of analgesics. We determined the exclusion criteria as follows: patients who exhibited no genomic information of CYP2D6 alleles; patients who did not record the self-reported NRS.

Table 1 shows the clinical pathway of pain management after ARCR surgery in Shiga University of Medical Science Hospital. In principle, this pathway was applied to all patients while considering anamnesis and the degree of preoperational pain. In this study, subjective evaluation of pain was performed according to the numeric rating scale (NRS). The NRS is a segmented numeric version of the visual analog scale (VAS), in which respondents select a number (0–10 integers) that best reflects the intensity of their pain. Similar to the VAS, the NRS is anchored by terms describing pain severity extremes. We collected self-reported NRS scores before and at 1, 2, 3, 7, 14, 21, and 28 d after the operation, and we evaluated time-dependent changes. We assessed the relationships between CYP2D6 alleles and changes in NRS. With respect to the CYP2D6 genotypes, the patients were grouped into four phenotypes; UM, NM, IM, and PM based on PGx clinical practice guidelines, such as CPIC and the Dutch Pharmacogenetics Working Group.^12,20) As a cumulative evaluation of pain control, the area under the NRS-time curve during the first 7 d (Days 0–7) and 28 d (Days 0–28) after tramadol administration were calculated using the linear trapezoidal method.

Table 1. Clinical Pathway of Pain Management after Arthroscopic Rotator Cuff Repair Surgery

	Days 1–7 after surgery	Days 8–14 after surgery	After Day 15 post-surgery
Tramadol 37.5 mg/Acetaminophen 325 mg combination tablet	One tablet, once a day before bedtime	If pain control is adequate, the same dose is continued; if pain control is not adequate, the dose is increased.	The dose is continued, reduced, or discontinued depending on the effect and side effects.
Celecoxib tablet 100 mg	Two tablets, twice a day after breakfast and dinner	Administration is finished. (If postoperative pain increases, analgesics are added as appropriate.)

CYP2D6 polymorphisms (*2, 2850C > T, rs16947; *4, 1846G > A, rs3892097; *10, 100C > T, rs1065852; *14, 1758G > A, rs5030865) and copy number (Intron 6, Hs04502391_cm; Exon 9, Hs00010001_cm; reference to RNaseP, 4403236) were analyzed by the TaqMan PCR method or copy number assay. Copy number of Intron indicates all alleles, whereas that of Exon 9 indicates all alleles except for CY2D6*36.

Ethical Considerations

This study was conducted in accordance with the Declaration of Helsinki, and it was approved by the Ethics Board of the Shiga University of Medical Science (Approval Number: 29-254) and Ritsumeikan University (Approval Number: BKC-2018-001).

Statistical Analysis

Comparisons of the NRS scores, patient characteristics, renal and liver function, and administration of analgesics between NM and IM patients were performed by the nonparametric Mann–Whitney U test and the Fisher’s exact test. Stepwise multiple linear regression analysis was performed to identify predictive factors for the area under the time-NRS curve (NRS-AUC) calculated using the linear trapezoidal method. The explanatory variables used were sex and age, which may affect the NRS assessment, ALT was used to assess liver function, and eGFR was used to evaluate renal function to influence the adjustment of the analgesic dose.

All statistical analyses were performed with SPSS, version 22. A p-value of <0.05 was considered to be statistically significant.

RESULTS

Study Population and Patient Characteristics

In total, 100 patients were enrolled in the study, of which 15 patients were excluded in accordance with the predefined exclusion criteria-the genetic polymorphisms of eight patients were not analyzed, and seven patients did not compete their self-reported NRS. Consequently, 85 patients were included in the subsequent analysis.

Patient characteristics and CYP2D6 genotype distribution in the study population are shown in Table 2. Significant differences were found in the sex, age, and BUN between the groups, but no differences were found in other characteristics. The observed genetic variants of the CYP2D6 genotype were as follows: *1/*10–*36 (n = 27), *1/*1 (n = 12), *1/*10 (n = 9), and *1/*2 (n = 8). The number of CYP2D6 NM and IM phenotypes were 69 (81.1%) and 16 (18.9%), respectively. UM and PM phenotypes were not detected.

Table 2. Patient Characteristics and CYP2D6 Phenotype and Genotype Distribution

	Normal metabolizer (n = 69)		Intermediate metabolizer (n = 16)		p-Value
Sex (Male)	42 (61.0%)		5 (31.3%)		p < 0.05†
Age	66 (41–83)		72 (45–82)		p < 0.05
Body weight (kg)	64.1 (38.7–106.7)		61.7 (46.9–86.5)		N.S.
Body mass index (kg/m2)	24.7 (16.4–33.8)		25.2 (19.5–34.9)		N.S.
Total protein(g/dL)	7.1 (5.5–8.2)		7.1 (6.4–7.5)		N.S.
Albumin (g/dL)	4.3 (3.4–4.8)		4.1 (3.8–4.6)		N.S.
White blood cell (103/µL)	5.7 (3.3–12.7)		6.0 (3.5–7.7)		N.S.
C-reaction protein (mg/dL)	0.06 (0.01–4.10)		0.06 (0.02–0.33)		N.S.
BUN (mg/dL)	15.6 (7.7–26.8)		18.4 (10.9–30.3)		p < 0.05
Creatinine (mg/dL)	0.76 (0.48–1.24)		0.67 (0.45–1.28)		N.S.
eGFR (mL/min/1.73 m2)	74.0 (36.7–120.3)		71.5 (36.9–105.1)		N.S.
AST (U/L)	23 (13–123)		25 (11–116)		N.S.
ALT (U/L)	22 (9–98)		22 (9–170)		N.S.
CYP2D6 genotype number (frequency (%))	*1/*10–*36	27 (31.8)	*10–*36/*10–*36	6 (7.1)
	*1/*1	12 (14.1)	*10/*10	4 (4.7)
	*1/*10	9 (10.6)	*10–*36/*10	2 (4.7)
	*1/*2	8 (9.4)	*4/*10–*36	2 (2.4)
	*2/*10–*36	5 (5.9)	*5/*10	1 (2.4)
	*1/*5	3 (3.5)	*10–*36/*10–*36–*36	1 (1.2)
	*2/*10	2 (2.4)
	*2/*2	2 (2.4)
	*1/*10 × 2	1 (1.2)

Median (min–max). ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate. ^† Fisher’s exact test.

Postoperative Analgesics Profile

Table 3 shows the comparison of the administration duration of tramadol, tramadol/acetaminophen combination tablets, and other analgesics between the groups and provides a comparison of the daily analgesic dose each postoperative period (Days 1–7, Days 8–14, and Days 15–28). The initial dose of tramadol was not statistically significant. However, the duration of tramadol/acetaminophen combination use and duration of concomitant analgesics use were significantly prolonged in the IM group.

Table 3. Comparison of the Administration Conditions and the Median Daily Dose of Analgesics in Each Duration

			Normal metabolizer (n = 69)		Intermediate metabolizer (n = 16)		p-Value
Duration of tramadol/acetaminophen combination use (d)			26 (2–28)		28 (3–28)		p < 0.05
Initial dose of tramadol		37.5 mg	64		16		N.S.
		75 mg	4		0
		112.5 mg	1		0
Duration of concomitant analgesics use (d)			15 (0–28)		25.5 (4–28)		p < 0.05
Details of concomitant analgesics			CE	51	CE	11	—
			CE, APAP	7	CE, APAP	2
			CE, LO	3	CE, DI	1
			APAP	4	DI	1
			LO	2
			CE, LO, DI	1
Days 1–7	Tramadol (mg)		37.5 (16.1–107.1)		37.5 (16.1–37.5)		N.S.
	APAP (mg)		325.0 (139.3–2125.0)		325.0 (139.3–2382.0)		N.S.
	CE (mg)		200.0 (0–400.0)		400.0 (0–400.0)		N.S.
Days 8–14	Tramadol (mg)		37.5 (0–133.9)		37.5 (0–75.0)		N.S.
	APAP (mg)		325.0 (0–2125.0)		325.0 (0–2725.0)		N.S.
	CE (mg)		28.6 (0–400.0)		214.3 (0–400.0)		N.S.
Days 15–28	Tramadol (mg)		37.5 (0–150.0)		37.5 (0–75.0)		N.S.
	APAP (mg)		325.0 (0–2125.0)		325.0 (0–2841.0)		N.S.
	CE (mg)		0 (0–400.0)		64.3 (0–400.0)		p < 0.05

CE; celecoxib, LO; loxoprofen, DI; diclofenac, APAP; acetaminophen, Median (min–max).

The daily dose of analgesics, including tramadol, at Days 1–7 and Days 8–14 was not significantly different between the IM and NM groups. In addition, tramadol and acetaminophen doses at Days 15–28 were also not statistically different between the IM and NM groups. However, the celecoxib dose in the IM group was significantly higher than that in the NM group.

Tramadol Pharmacodynamics

Figure 1a shows the time-dependent profile of NRS after ARCR surgery. The peak NRS was observed at Day 1, and the NRS was reduced time-dependently in both groups. The NRS in the IM group was significantly higher compared to the NM group until Day 7 (p < 0.05). Figures 1b and c show the comparison of the NRS-AUC of the initial tramadol treatment post-operation (Days 0–7) and the whole treatment throughout the clinical pathway (Days 0–28) between NM and IM. The NRS-AUCs of the IM group were significantly high in both durations.

Fig. 1. Effect of CYP2D6 Phenotype on NRS of Patients Treated with Tramadol Undergoing Arthroscopic Rotator Cuff Repair

(a) Time-dependent changes in NRSs of CYP2D6 phenotypes. Open and close circles represent normal metabolizer (NM, n = 69) and intermediate metabolizer (IM, n = 16), respectively. Mean ± standard deviation (S.D.). * p < 0.05 vs. NM group by the Mann–Whitney U test. (b, c) Area under the time-numeric rating scale of CYP2D6 normal metabolizer (NM, n = 69) and intermediate metabolizer (IM, n = 16) in initial administration duration (NRS-AUC₀₋₇; b) and whole administration duration (NRS-AUC₀₋₂₈; c). Solid line in the middle of each plot represents the median. Boxes represent the interquartile ranges (25th–75th percentiles), and whiskers represent the 10th–90th percentiles. Data falling outside the lower–upper range are plotted as outliers of the data.

Relationship between the NRS and the Analgesics

As the evaluation index to compare analgesic efficacy and dose in each subject, the dose-adjusted NRS values were calculated by multiplying the NRS average (NRS_ave) and the analgesic doses in each period. The comparisons of the dose-adjusted NRS values between the NM and IM groups were shown in Fig. 2. During the initial treatment phase of post-operation (Days 1–7), the NRS_ave·tramadol dose in the IM group was significantly higher than that in the NM group, but there was no significant difference during the other periods (Fig. 2a). The NRS_ave·acetaminophen dose were no significant difference in all periods (Fig. 2b). The NRS_ave·celecoxib dose showed a significant difference between the two groups on Days 15–28 (Fig. 2c), the variabilities of analgesic doses were large in the period (Days 15–28), as described in Table 3.

Fig. 2. Comparison of the Dose-Adjusted NRS Values Calculated by Multiplying the NRS Average (NRS_ave) and the Dose of the Analgesics in Each Period between the Normal Metabolizer (NM) and Intermediate Metabolizer (IM) Groups

Mean ± S.D. * p < 0.05 vs. the NM group by the Mann–Whitney U test. APAP (Acetaminophen), CE (Celecoxib). Solid line in the middle of each plot represents the median. Boxes represent the interquartile ranges (25th–75th percentiles), and whiskers represent the 10th–90th percentiles. Data falling outside the lower–upper range are plotted as outliers of the data.

Multiple Linear Regression Analysis

Table 4 summarizes the results of the multiple linear regression analysis for NRS-AUC (as the response variable) and age, sex, eGFR, ALT, and CYP2D6 phenotypes (as the explanatory variable). NRS-AUC analysis during Days 0–7 revealed that CYP2D6 phenotype was a significant predictive factor, even when adjusted by renal function, liver function, age, and sex.

Table 4. Stepwise Multiple Linear Regression Analysis for NRS-AUC as the Response Variable

Explanatory variables	NRS-AUC0−7			NRS-AUC0−28
	β	95%CI	p-Value	β	95%CI	p-Value
Intercept	18.4	−14.2–50.9	0.264	63.6	−45.9–173.1	0.251
ALT	0.001	−0.150–0.152	0.989	0.062	−0.445–0.570	0.807
eGFR	−0.006	−0.209–0.198	0.956	−0.191	−0.877–0.494	0.580
CYP2D6 phenotype†	9.52	1.30–17.7	0.024	20.9	−6.77–48.5	0.137
Sex‡	−0.401	−6.67–5.87	0.899	1.58	−19.5–22.7	0.882
Age	0.093	−0.255–0.441	0.596	0.132	−1.04–1.30	0.823
R2	0.0806			0.0454

^† CYP2D6 phenotype (1 = intermediate metabolizer group, 0 = normal metabolizer group). ^‡ Sex (0 = male, 1 = female). ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; NRS, numeric rating scale; NRS-AUC, the area under the time-NRS curve; R, correlation coefficient.

DISCUSSION

This study aimed to investigate the impact of the CYP2D6 genotype on the analgesic effect of tramadol during the early postoperative phase in clinical practice. The NRS and the NRS-AUC in the IM group were significantly higher than in the NM group until Day 7. Furthermore, the multiple linear regression analysis revealed that the CYP2D6 genotype should be very useful as a predictive factor, even when adjusted by other factors.

We considered that the study population reflects the clinical practice, because the fact that the CYP2D6 allele frequency was similar to that reported in previous studies.^14,21) In this study, only NM and IM were compared because PM and UM were not observed. In general, postoperative pain greatly depends on the underlying disease and surgical procedure. Therefore, we investigated the effect of CYP2D6 polymorphisms on the pain levels of patients treated with tramadol after arthroscopic rotator cuff repair.

Previous studies showed that the pharmacokinetics of active metabolites are affected by CYP2D6 gene polymorphisms.^17,22) Tanaka et al. reported that the plasma concentration of ODT and its ratio to tramadol were significantly lower in the CYP2D6 IM and PM groups compared to the NM group.¹⁷⁾ Researchers also been reported that the concentration of ODT decreases to approximately 50% in the IM group. In the present study, the average daily dosage of tramadol was not significantly different between the two groups (Table 3). The plasma concentration of the active metabolite in the IM group was likely to be lower than that in the NM group. The NRS and the NRS-AUC of the IM group were significantly higher compared to the NM group from Day 0 to Day 7 (Fig. 1). In contrast, the NRSs between Days 14–28 were not significantly different between the two groups. In our clinical pathway, the analgesic dosage used after Day 7 was adjusted based on the patients’ NRS including their chief complaints. Consequently, the analgesic effect from Day 14 was equivalent between both groups. In the late postoperative period, the median dose of tramadol was 37.5 mg, and no difference was found between the two groups, whereas the median dose of celecoxib in the IM group was significantly higher than the NM group (NM vs IM = 0 mg vs 64.3 mg, p < 0.05). On the other hand, when considering the relationship of the individual NRS_ave and analgesics, the dose of tramadol and celecoxib at Days 15–28 was highly variable and the individual differences were large. It is difficult to say that changing analgesics are useful based only on this result. However, tramadol at Days 1–7 was significantly different in the IM group even when the individual NRSave and analgesics are considered. A previous study reported that the analgesic effect of a 200-mg daily dose of celecoxib was equal to that of a 100-mg daily dose of tramadol.²³⁾ However, the exposure of the active metabolite of tramadol may have been reduced in the IM group. To compensate for the reduced analgesic effect of tramadol, celecoxib was additionally administrated at an approximately two-fold dose of tramadol in the IM group. This, in turn, ensured that the results of this study remained consistent with the findings of the previous report.

It is known that in addition to the CYP2D6 genotype, patient characteristics, including sex, age, liver function, renal function, and concomitant drugs, affect the analgesic effect of tramadol.^24,25) Our findings revealed that significant differences in sex, age, and BUN were found between the two groups. Although BUN, an index of renal function, was slightly higher in the IM group, the median values of BUN were within the normal range in both groups. Furthermore, the values of both serum creatinine and eGFR were not significantly different between the two groups, indicating a similar renal excretion. In contrast, the self-regulating dose of opioids can be vary as a result of different pain tolerance which may be sex- and age-dependent,²⁶⁾ since elderly patients may be more sensitive to mechanically-evoked pain.²⁷⁾ Therefore, correcting the subsequent analysis by considering these confounding is important. Multiple linear regression analysis in the NRS-AUC estimated CYP2D6 phenotype as a significant factor in AUC₀₋₇ (Table 4). Even when variable factors, such as sex and age, were considered, these results suggested that CYP2D6 genotype testing is a reliable predictable biomarker of analgesic effect of tramadol. However, no significant factors were found in AUC₀₋₂₈, during which dose adjustment was included based on the NRS. Although dose adjustment based on the NRS provided an appropriate analgesic effect also to IM patients, the delayed dose-titration remains a significant issue. Therefore, drug selection and initial dose setting according to the preemptive CYP2D6 genotype determination may be useful for pain relief in the early postoperative phase. In the case of CYP2D6 IM patients, increasing the initial dose of tramadol or preferentially using celecoxib instead of tramadol could be considered as alternative analgesic strategies.

Prolongation of a high NRS score may lead to the prolongation of hospital stay due to the slow rehabilitation progress after orthopedic surgery. In addition, for cancer patients using tramadol, continuous cancer pain is a fatal problem that directly leads to QOL deterioration. The results of this study suggest that tramadol dosage may be independent of liver and renal function, sex, and age. Confirmation of the genetic polymorphism in advance, and the use of tramadol for postoperative pain management in the NM group is recommended. On the other hand, if the gene mutation that applies to the IM group can be confirmed, more rapid pain relief can be expected by changing the treatment options to include changing to other analgesics or adjusting the tramadol dosage.

This study exhibits some limitations. First, interindividual differences in the population should not be completely excluded, because the NRS is a subjective numerical scale. In contrast, the intra-individual variability could be evaluated through continuous NRS assessment during the postoperative period.²⁸⁾ Furthermore, patient’s-reported-outcome has been reported to be effective in Orthopedics.²⁹⁾ The NRS is useful to evaluate the effects of drug treatment and to adjust pharmaceutical approaches. Second, the analgesic effects of tramadol and acetaminophen were not differentiated in this study because they were both used as a combination tablet. The main metabolic pathway of acetaminophen is reported to be glucuronidation and not CYP2D6,^30,31) and liver function was not different between the two groups. Therefore, the difference in the analgesic effect between the two CYP2D6 phenotype groups is likely due to the pharmacokinetic variation of tramadol and its metabolite. Third, this study is a single-center retrospective observational study. Limitations of this study include the small sample size, and data analysis was not extensively corrected to include the patient background, such as comorbidities and concomitant medications. It is difficult to completely exclude the problem that the NRS-AUC grows proportionally as the explanatory variables increase in the statistical analysis of this study. The number of patients, especially of the IM, are small and this may cause inaccurate estimation in the statistical evaluation. For accurate modeling such as individualized dosing design, collecting additional data and planning the population pharmacokinetics and pharmacodynamics modeling are needed.

CONCLUSION

This study reveals that CYP2D6 IM patients treated with tramadol may experience insufficient analgesic effects one week after orthopedic surgeries. The results suggested that preemptive and effective personalized precision medicine in postoperative pain management could be achieved by measuring gene polymorphisms.

Acknowledgments

This work was supported by the JSPS KAKENHI Grant Numbers: 17K15504, 18K06782, and 20K07211.

Funding

This work was supported by the Nakatomi Foundation.

Author Contributions

Takaki Kamiya, Daiki Hira, and Ryo Nakajima substantially contributed to the study conceptualization. Takaki Kamiya, and Daiki Hira developed the statistical analysis plan and conducted statistical analyses. Takaki Kamiya, Kazuha Shinoda, Atsuko Motomochi, Aya Morikochi, Yoshito Ikeda, Tetsuichiro Isono, and Michiya Akabane contributed to data collection and measurement. Kazuha Shinoda, Satoshi Ueshima, Mikio Kakumoto, Shinji Imai, Shin-ya Morita, and Tomohiro Terada significantly contributed to data analysis and interpretation. Takaki Kamiya drafted the original manuscript. Daiki Hira, Shin-ya Morita, and Tomohiro Terada substantially reviewed to the manuscript drafting. Tomohiro Terada supervised the conduct of this study. All authors critically reviewed and revised the manuscript draft and approved the final version for submission. The authors confirm that the Principal Investigator for this paper is Tomohiro Terada, Ph.D. and that he demonstrated direct clinical responsibility for patients.

Conflict of Interest

The authors declare no conflict of interest.

Data Availability

All data analyzed during this study are included in this published article.

REFERENCES

• 1) Hess GP, Fonseca E, Scott R, Fagerness J. Pharmacogenomic and pharmacogenetic-guided therapy as a tool in precision medicine: current state and factors impacting acceptance by stakeholders. Genet. Res. (Camb.), 97, e13 (2015).
• 2) Gleason PP, Frye RF, O’Toole T. Debilitating reaction following the initial dose of tramadol. Ann. Pharmacother., 31, 1150–1152 (1997).
• 3) Maliepaard M, Nofziger C, Papaluca M, Zineh I, Uyama Y, Prasad K, Grimstein C, Pacanowski M, Ehmann F, Dossena S, Paulmichl M. Pharmacogenetics in the evaluation of new drugs: a multiregional regulatory perspective. Nat. Rev. Drug Discov., 12, 103–115 (2013).
• 4) Green DJ, Mummaneni P, Kim IW, Oh JM, Pacanowski M, Burckart GJ. Pharmacogenomic information in FDA-approved drug labels: Application to pediatric patients. Clin. Pharmacol. Ther., 99, 622–632 (2016).
• 5) Saarikoski T, Saari TI, Hagelberg NM, Backman JT, Neuvonen PJ, Scheinin M, Olkkola KT, Laine K. Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol. Eur. J. Clin. Pharmacol., 71, 321–327 (2015).
• 6) Ryan NM, Isbister GK. Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely. Clin. Toxicol. (Phila.), 53, 545–550 (2015).
• 7) Stamer UM, Lehnen K, Hothker F, Bayerer B, Wolf S, Hoeft A, Stuber F. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain, 105, 231–238 (2003).
• 8) Wang G, Zhang H, He F, Fang X. Effect of the CYP2D6*10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population. Eur. J. Clin. Pharmacol., 62, 927–931 (2006).
• 9) Stamer UM, Stuber F, Muders T, Musshoff F. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth. Analg., 107, 926–929 (2008).
• 10) Twist GP, Gaedigk A, Miller NA, Farrow EG, Willig LK, Dinwiddie DL, Petrikin JE, Soden SE, Herd S, Gibson M, Cakici JA, Riffel AK, Leeder JS, Dinakarpandian D, Kingsmore SF. Constellation: a tool for rapid, automated phenotype assignment of a highly polymorphic pharmacogene, CYP2D6, from whole-genome sequences. NPJ Genom. Med., 1, 15007 (2016).
• 11) Friedrich DC, Genro JP, Sortica VA, Suarez-Kurtz G, de Moraes ME, Pena SD, dos Santos AK, Romano-Silva MA, Hutz MH. Distribution of CYP2D6 alleles and phenotypes in the Brazilian population. PLOS ONE, 9, e110691 (2014).
• 12) Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, Rongen GA, van Schaik RH, Schalekamp T, Touw DJ, van der Weide J, Wilffert B, Deneer VH, Guchelaar HJ. Pharmacogenetics: from bench to byte—an update of guidelines. Clin. Pharmacol. Ther., 89, 662–673 (2011).
• 13) Kirchheiner J, Keulen JT, Bauer S, Roots I, Brockmoller J. Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. J. Clin. Psychopharmacol., 28, 78–83 (2008).
• 14) Hosono N, Kato M, Kiyotani K, Mushiroda T, Takata S, Sato H, Amitani H, Tsuchiya Y, Yamazaki K, Tsunoda T, Zembutsu H, Nakamura Y, Kubo M. CYP2D6 genotyping for functional-gene dosage analysis by allele copy number detection. Clin. Chem., 55, 1546–1554 (2009).
• 15) Ebisawa A, Hiratsuka M, Sakuyama K, Konno Y, Sasaki T, Mizugaki M. Two novel single nucleotide polymorphisms (SNPs) of the CYP2D6 gene in Japanese individuals. Drug Metab. Pharmacokinet., 20, 294–299 (2005).
• 16) Zhou Y, Ingelman-Sundberg M, Lauschke VM. Worldwide distribution of cytochrome P450 alleles: a meta-analysis of population-scale sequencing projects. Clin. Pharmacol. Ther., 102, 688–700 (2017).
• 17) Tanaka H, Naito T, Sato H, Hiraide T, Yamada Y, Kawakami J. Impact of CYP genotype and inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patients. Eur. J. Clin. Pharmacol., 74, 1461–1469 (2018).
• 18) Irvin WJ Jr, Walko CM, Weck KE, et al. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study. J. Clin. Oncol., 29, 3232–3239 (2011).
• 19) Tamura K, Imamura CK, Takano T, Saji S, Yamanaka T, Yonemori K, Takahashi M, Tsurutani J, Nishimura R, Sato K, Kitani A, Ueno NT, Mushiroda T, Kubo M, Fujiwara Y, Tanigawara Y. CYP2D6 genotype-guided tamoxifen dosing in hormone receptor-positive metastatic breast cancer (TARGET-1): a randomized, open-label, phase II study. J. Clin. Oncol., 38, 558–566 (2020).
• 20) Caudle KE, Sangkuhl K, Whirl-Carrillo M, Swen JJ, Haidar CE, Klein TE, Gammal RS, Relling MV, Scott SA, Hertz DL, Guchelaar HJ, Gaedigk A. Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the clinical pharmacogenetics implementation consortium and Dutch pharmacogenetics working group. Clin. Transl. Sci., 13, 116–124 (2020).
• 21) Fukunaga K, Hishinuma E, Hiratsuka M, Kato K, Okusaka T, Saito T, Ikeda M, Yoshida T, Zembutsu H, Iwata N, Mushiroda T. Determination of novel CYP2D6 haplotype using the targeted sequencing followed by the long-read sequencing and the functional characterization in the Japanese population. J. Hum. Genet., 66, 139–149 (2021).
• 22) Lee J, Yoo HD, Bae JW, Lee S, Shin KH. Population pharmacokinetic analysis of tramadol and O-desmethyltramadol with genetic polymorphism of CYP2D6. Drug Des. Devel. Ther., 13, 1751–1761 (2019).
• 23) O’Donnell JB, Ekman EF, Spalding WM, Bhadra P, McCabe D, Berger MF. The effectiveness of a weak opioid medication versus a cyclo-oxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug in treating flare-up of chronic low-back pain: results from two randomized, double-blind, 6-week studies. J. Int. Med. Res., 37, 1789–1802 (2009).
• 24) Allegaert K, Holford N, Anderson BJ, Holford S, Stuber F, Rochette A, Troconiz IF, Beier H, de Hoon JN, Pedersen RS, Stamer U. Tramadol and o-desmethyl tramadol clearance maturation and disposition in humans. a pooled pharmacokinetic study. Clin. Pharmacokinet., 54, 167–178 (2015).
• 25) Xia DY, Wang YH, Guo T, Li XL, Su XY, Zhao LS. Pharmacokinetics of tramadol in a diverse healthy Chinese population. J. Clin. Pharm. Ther., 37, 599–603 (2012).
• 26) Pisanu C, Franconi F, Gessa GL, Mameli S, Pisanu GM, Campesi I, Leggio L, Agabio R. Sex differences in the response to opioids for pain relief: A systematic review and meta-analysis. Pharmacol. Res., 148, 104447 (2019).
• 27) El Tumi H, Johnson MI, Dantas PBF, Maynard MJ, Tashani OA. Age-related changes in pain sensitivity in healthy humans: A systematic review with meta-analysis. Eur. J. Pain, 21, 955–964 (2017).
• 28) Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J. Pain, 17, 131–157 (2016).
• 29) Gagnier JJ. Patient reported outcomes in orthopaedics. J. Orthop. Res., 35, 2098–2108 (2017).
• 30) Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Br. J. Clin. Pharmacol., 10 (Suppl. 2), 291S–298S (1980).
• 31) Patel M, Tang BK, Kalow W. Variability of acetaminophen metabolism in Caucasians and Orientals. Pharmacogenetics, 2, 38–45 (1992).