Cost-Effectiveness of Monotherapy versus Polypharmacy in Cervicobrachial Symptoms: A Nationwide Multicenter Analysis

Abstract

Introduction

Cervicobrachial symptoms are common causes of disability worldwide, yet the cost-effectiveness of combination therapy versus monotherapy remains unclear. In this nationwide multicenter study, we aimed to compare the economic value of multiple-drug therapy with that of monotherapy for cervicobrachial symptoms.

Methods

This prospective observational study, conducted through the Japanese Society for Spine Surgery and Related Research, included 261 adults with cervicobrachial symptoms across 28 institutions (July 2020 to July 2022). Patients received monotherapy (n=112) or multiple-drug therapy (n=149) using five pre-specified agents: loxoprofen, celecoxib, acetaminophen, tramadol-acetaminophen, and pregabalin. The primary outcome was quality-adjusted life years (QALYs), calculated from monthly EuroQol 5-Dimension 5-Level assessments over six months. The secondary outcomes were drug costs and incremental cost-effectiveness ratios (ICERs), evaluated against Japan's reference threshold of 5,000,000 JPY per QALY.

Results

Mean QALY gains were similar between the monotherapy (0.00267±0.00544) and multiple-drug therapy (0.00284±0.00774) groups, with no statistically significant difference (p>0.05). However, total drug costs were substantially higher with multiple-drug therapy (19,243 JPY vs. 8,275 JPY). ICERs were more favorable for monotherapy (3,093,957 JPY/QALY) than for multiple-drug therapy (6,781,101 JPY/QALY). Among agents used as monotherapy, loxoprofen (744,409 JPY/QALY) and acetaminophen (781,293 JPY/QALY) showed the most favorable cost-effectiveness profiles, whereas tramadol-acetaminophen (6,370,451 JPY/QALY) and pregabalin (10,995,651 JPY/QALY) had the least favorable cost-effectiveness. Most QALY gains occurred during the first three months in both groups.

Conclusions

Multiple-drug therapy approximately doubled pharmaceutical costs without providing additional QALY gains over six months. Monotherapy, particularly with non-steroidal anti-inflammatory drugs or acetaminophen, offers superior cost-effectiveness and should be prioritized as first-line treatment. These findings underscore the need for restraint in polypharmacy and provide real-world evidence to guide clinical decision-making and national healthcare policy.

Introduction

Cervicobrachial symptoms, such as pain in the neck, shoulder, and upper limbs, are common causes of disability and impaired quality of life (QOL) worldwide, and their population burden is increasing with aging societies¹⁾. Contemporary clinical practice guidelines emphasize multimodal conservative care while noting that the long-term benefits of pharmacotherapy remain uncertain and medication escalation should be judicious²⁾. Against this background, a nationwide Japanese multicenter study by the Japanese Society for Spine Surgery and Related Research (JSSR) reported that six months of pharmacotherapy across five commonly used agents for cervicobrachial symptoms yielded modest quality-adjusted life year (QALY) gains concentrated in the first three months and an overall incremental cost-effectiveness ratio (ICER) above Japan's reference willingness-to-pay threshold, suggesting limited cost-effectiveness for routine prolonged use³⁾. In contrast, a previous JSSR study on chronic low back pain reported pharmacological management to be cost-effective, underscoring that cost-utility may differ by pain phenotype and baseline QOL⁴⁾. Japan's health technology assessment program formally introduced cost-effectiveness evaluation in pricing decisions, with a reference threshold of approximately 5,000,000 JPY per quality-adjusted life year (QALY)⁵⁾, and QALYs are commonly calculated using the EuroQol five-dimensional five-level (EQ-5D-5L) Japanese value set^6,7).

In clinical practice, combination (multiple drugs) therapy is frequently used to address mixed nociceptive and neuropathic mechanisms. However, high-quality syntheses show little convincing evidence that commonly used combinations outperform their constituent monotherapies and highlight overlapping adverse-event profiles that can offset incremental benefit^8,9). Economic evaluations of neuropathic pain further demonstrate wide variations in modeling approaches and persistent uncertainties, particularly around translating short-term pain relief into utility gains and the impact of multi-line or combination therapy, underscoring the need for transparent, real-world cost-utility evidence^10,11).

To address these gaps, we aimed to directly compare the cost-effectiveness of monotherapy versus multiple-drug therapy for cervicobrachial symptoms in a nationwide multicenter cohort. We also evaluated the cost-utility of individual drugs used as monotherapy, providing insights relevant to clinical practice and healthcare policies.

Materials and Methods

Study design

This nationwide, multicenter, prospective observational study was conducted by the JSSR Project Committee at 28 institutions in Japan (July 2020 to July 2022). The JSSR Ethics Committee and institutional review boards at all sites approved this study, and all participants provided written informed consent. This sub-analysis was performed using the same design, data items, and follow-up schedule as the parent nationwide study to ensure direct comparability of outcomes and economic endpoints³⁾.

Participants

Eligible individuals were adults aged 20-85 years with cervicobrachial symptoms for whom pharmacotherapy was initiated. The inclusion criteria included the ability to complete patient-reported outcomes (EQ-5D-5L, Short-Form-8 physical and mental component summaries [SF-8 PCS/MCS], and a 100-mm visual analog scale [VAS]) at baseline and monthly. Similar to the parent study, we excluded individuals with shoulder pathology on examination; cervical surgery within the preceding three months; severe cardiac, hepatic, renal, or hematological disease; active malignancy within five years; alcohol/substance abuse; dementia; and a Brief Scale for Psychiatric Problems in Orthopedic Patients score indicating significant psychiatric problems (physician version ≥10 or patient version ≥15)³⁾. Overall, 322 individuals were registered; as in the parent study, 12 were excluded owing to initial data loss at baseline (“initial data loss/baseline data missing”), and 37 discontinued before three months, leaving 273 eligible subjects. For the present sub-analysis, we further restricted the cohort to 261 individuals with complete longitudinal EQ-5D-5L utilities and drug exposure necessary for the prespecified cost-effectiveness and sensitivity analyses (Figure 1).

Figure 1.

Study population schema.

Treatment regimens and groups

Pharmacotherapy was administered at the discretion of the treating physician using five pre-specified agents widely used for cervicobrachial symptoms: loxoprofen, celecoxib, acetaminophen, tramadol-acetaminophen, and pregabalin. Patients were categorized as receiving monotherapy (single agent) or multiple-drug therapy (two or more agents during follow-up, either concurrently or sequentially). Changes within the five drugs were permitted; individuals requiring off-protocol drugs were excluded from this analysis to maintain internal validity³⁾.

Outcomes

The primary outcome was QALY, derived from the EQ-5D-5L using the Japanese value set⁶⁾. The secondary outcomes included (i) total six-month drug cost (Japanese yen [JPY]) calculated from the National Health Insurance drug prices (2017 tariff)³⁾, (ii) ICER, and (iii) trajectories of VAS and SF-8 PCS/MCS.

Economic evaluation

Utilities were measured monthly. Base-case QALY gain (“acquired QALY”) was calculated as the area under the curve (AUC) of monthly utilities above baseline over six months using linear interpolation between visits, consistent with the parent study³⁾. The total drug cost reflected the dispensed doses priced at the 2017 National Health Insurance schedule; costs of consultations and diagnostic tests were not included³⁾. ICERs were evaluated against Japan's reference willingness-to-pay of 5,000,000 JPY per QALY⁵⁾.

Statistical analysis

Continuous variables (utilities, QALYs, and costs) are summarized as mean (standard deviation) and were compared using Mann-Whitney U tests. Categorical variables were compared using chi-square tests. Subgroup analyses within the monotherapy cohort compared individual drugs. Missing monthly utilities were imputed using last observation carried forward, consistent with the parent study³⁾. Analyses were conducted with SAS 9.4 (SAS Institute, Cary, NC, USA). All tests were two-sided with α=0.05.

Results

Baseline characteristics

In this study, the analytical cohort comprised 261 individuals (monotherapy=112; multiple-drug therapy=149).

Baseline demographic and clinical characteristics were comparable between the two treatment groups, except for symptom duration, SF-8 PCS score at baseline, and current smoking status, which showed statistically significant differences between the two treatment groups (Table 1). The significantly longer symptom duration observed in the multiple-drug therapy group (760.15±1,418.68 days vs. 330.80±669.12 days, p=0.001) may reflect a clinical tendency to prescribe combination therapy for individuals with more chronic or potentially treatment-refractory symptoms, representing a potential confounding by indication.

Table 1.

Baseline Demographic and Clinical Characteristics (n=261).

Variable	All (n=261)	Monotherapy (n=112)	Multiple-drug (n=149)	p-Value (mono vs multi)
Age (years)	60.67±13.44	62.48±13.90	59.30±12.96	0.054
BMI (kg/m2)	23.80±4.28	23.37±4.02	24.14±4.45	0.130
Symptom duration (days)	511.93±1,071.34	760.15±1,418.68	330.80±669.12	0.001
BS-POP (physician total)	9.68±1.96	9.52±1.59	9.80±2.19	0.559
BS-POP (patient total)	16.07±3.24	15.93±3.30	16.16±3.21	0.525
EQ-5D-5L index (Baseline)	0.74±0.16	0.75±0.17	0.73±0.16	0.361
EQ-VAS (0-100, Baseline)	61.59±19.73	63.72±19.71	60.06±19.68	0.118
SF-8 PCS (Baseline)	40.12±6.64	41.71±6.58	38.91±6.46	0.001
SF-8 MCS (Baseline)	48.50±7.21	48.06±6.87	48.84±7.47	0.326
Exercise frequency (ordinal 1-4)	1.01±1.13	1.10±1.15	0.95±1.12	0.262
Family conversation time (min/day)	64.24±75.17	64.85±80.53	63.79±71.20	0.698
Friend conversation time (min/day)	28.19±52.50	27.79±43.98	28.49±58.24	0.375
Female (%)	134 (51.3%)	63 (56.2%)	71 (47.7%)	0.211
Hypertension (%)	61 (23.5%)	25 (22.5%)	36 (24.2%)	0.873
Diabetes (%)	33 (12.7%)	12 (10.8%)	21 (14.1%)	0.550
Dyslipidemia (%)	25 (9.6%)	10 (9.0%)	15 (10.1%)	0.941
Coronary artery disease (%)	5 (1.9%)	3 (2.7%)	2 (1.3%)	0.739
Cerebrovascular disease (%)	3 (1.2%)	1 (0.9%)	2 (1.3%)	1.000
Renal dysfunction (%)	4 (1.5%)	3 (2.7%)	1 (0.7%)	0.420
Liver dysfunction (%)	11 (4.2%)	5 (4.5%)	6 (4.0%)	1.000
Respiratory disease (%)	8 (3.1%)	1 (0.9%)	7 (4.7%)	0.164
Endocrine disease (%)	5 (1.9%)	3 (2.7%)	2 (1.3%)	0.740
Rheumatoid arthritis (%)	6 (2.3%)	4 (3.6%)	2 (1.3%)	0.433
Other immune disease (%)	3 (1.2%)	2 (1.8%)	1 (0.7%)	0.797
Depression (%)	3 (1.2%)	0 (0.0%)	3 (2.0%)	0.359
Other psychiatric/neurologic disease (%)	2 (0.8%)	1 (0.9%)	1 (0.7%)	1.000
Other diseases (%)	34 (13.1%)	11 (9.9%)	23 (15.4%)	0.262
History of malignancy (%)	8 (3.1%)	2 (1.8%)	6 (4.0%)	0.506
Current smoker (%)	12 (5.8%)	1 (1.1%)	11 (9.3%)	0.027

Notes: Continuous variables are mean±SD (Mann-Whitney U test); categorical variables are n (%), tested with chi-square.

BMI: body mass index; BS-POP: Brief Scale for Psychiatric Problems in Orthopedic Patients; EQ-VAS: EuroQol Visual Analog Scale; MCS: mental component summary; PCS: physical component summary; SF-8: Short Form-8 Health Survey

QALY and time course

Over six months, the mean QALY gain was 0.00267±0.00544 and 0.00284±0.00774 in the monotherapy and multiple-drug groups, respectively (Table 2); the between-group difference was not statistically significant. In both groups, most QALY gains accrued during 0-3 months, with a plateau thereafter (Figure 2). In the monotherapy cohort, loxoprofen achieved the largest early QALY gains, followed by celecoxib and acetaminophen, whereas tramadol-acetaminophen and pregabalin showed modest improvements (Table 3).

Table 2.

Average Acquired QALY (6 Months): Monotherapy vs Multiple-Drug Therapy.

Group	n	Average acquired QALY (six months)
Monotherapy	112	0.002674±0.005445
Multiple-drug therapy	149	0.002838±0.007740

QALY: quality adjusted life year

Figure 2.

Cumulative acquired QALY over 6 months (AUC method) (solid=Mono; dashed=Poly).

The cumulative QALY profiles are shown for the overall cohort, as well as the Monotherapy and Multiple-drug therapy groups. The AUC method integrates monthly EuroQol 5-Dimension utilities (Japanese value set) using a trapezoidal rule with the LOCF for the missing months. In both regimens, most QALY gains accrued during months 0-3 with a subsequent plateau.

AUC: area-under-the-curve; LOCF: last-observation-carried-forward; QALY: quality adjusted life year

Table 3.

Average Acquired QALY (6 Months) by Monotherapy Drug.

Monotherapy drug	n	Average acquired QALY (6 months)
Loxoprofen	39	0.003639±0.006592
Acetaminophen	11	0.003318±0.004615
Celecoxib	15	0.003319±0.004963
Tramadol-Acetaminophen	15	0.002053±0.004369
Pregabalin	32	0.001267±0.004745

QALY: quality adjusted life year

Drug costs

The total drug cost over six months averaged 8,275 JPY in the monotherapy group versus 19,243 JPY in the multiple-drug therapy group (Table 4).

Table 4.

Drug Cost Summary at 6 Months (JPY).

Group	Cost 6 mo (JPY)
Monotherapy	8,275
Multiple-drug therapy	19,243

JPY: Japanese yen

Among monotherapies, acetaminophen had the lowest mean cost (2,526 JPY), while pregabalin had the highest mean cost (13,931 JPY) (Table 5).

Table 5.

Monotherapy Drug Cost Summary at 6 Months (JPY).

Drug	N	Cost 6mo (JPY) – brand
Loxoprofen	39	2,709
Celecoxib	15	10,093
Acetaminophen	11	2,526
Tramadol-acetaminophen	15	13,077
Pregabalin	32	13,931

JPY: Japanese yen

Figure 3 depicts cumulative six-month costs by treatment group and by drug.

Figure 3.

Cumulative 6-month drug costs (JPY) by treatment group and by monotherapy drug (solid=Mono; dashed=Poly).

Drug prices were calculated using the 2017 National Health Insurance tariff, and consultation and test costs were excluded.

JPY: Japanese yen

Cost-effectiveness (ICER)

Using the study's primary scenario (2017 National Health Insurance brand prices and AUC-based QALY), the ICER was 3,093,957 JPY/QALY for monotherapy and 6,781,101 JPY/QALY for multiple-drug therapy. Notably, multiple-drug therapy yielded costs exceeding Japan's reference willingness-to-pay threshold of 5,000,000 JPY per QALY, whereas monotherapy yielded costs below this threshold. Within the monotherapy group, loxoprofen (744,409 JPY/QALY) and acetaminophen (781,293 JPY/QALY) were most favorable, both well below the reference threshold. Celecoxib (3,040,645 JPY/QALY) was in the intermediate range but remained acceptable. Tramadol-acetaminophen (6,370,451 JPY/QALY) and pregabalin (10,995,651 JPY/QALY) were the least favorable, both exceeding the reference willingness-to-pay threshold.

Pain and health status (VAS, EQ-5D-5L, SF-8)

Over six months, VAS (0-100 mm) changed by +11.3 mm and +7.1 mm in the monotherapy and multiple-drug therapy groups, respectively (Figure 4).

Figure 4.

Time-course profiles of VAS over 6 months. Curves are shown in monochrome (solid=Mono; dashed=Poly).

Group differences were small.

VAS: visual analog scale

Mean EQ-5D-5L index showed a small increase in both groups (Figure 5). SF-8 PCS/MCS modestly improved through month three and then stabilized (Figures 6a and b).

Figure 5.

Time-course profiles of patient-reported outcomes (EuroQol 5-Dimensions, 5-Level index) over 6 months (solid=Mono; dashed=Poly).

The curves are shown as monochromes. Group differences were small; most improvements occurred by month 3 and then stabilized.

Safety

No severe drug-related adverse events requiring additional interventions were documented during the observation period.

This aligns with the parent cohort's safety profile.

Discussion

In this nationwide multicenter analysis of 261 individuals with cervicobrachial symptoms, multiple-drug therapy delivered no additional QALY gain over monotherapy despite substantially higher drug costs, yielding less favorable ICERs. Within the monotherapy group, non-steroidal anti-inflammatory drugs (NSAIDs) (loxoprofen and celecoxib) and acetaminophen had the most favorable economic profiles, whereas tramadol-acetaminophen and pregabalin were the least favorable. These findings extend the parent cohort's observation that QALY accrues primarily during the first three months with minimal utility thereafter, and that the overall cost-effectiveness of cervicobrachial drug therapy is modest³⁾.

Evidence syntheses on combination pharmacotherapy for neuropathic pain show no consistent superiority over monotherapy, with comparable adverse-event rates—results mirrored here when comparing multiple-drug therapy to monotherapy^8,9). Guidelines also favor a stepwise approach (trial including a single agent and switching rather than routinely combining treatment agents), recommending amitriptyline, duloxetine, gabapentin, or pregabalin as initial choices for neuropathic pain and discouraging escalation to polypharmacy in non-specialist settings without clear indications¹²⁾. Our real-world data, showing no utility improvement commensurate with increased cost, are consistent with prior reports and recommendations.

The cost-effectiveness ranking within monotherapy—loxoprofen ≈, acetaminophen ≻, celecoxib, tramadol-acetaminophen, pregabalin—likely reflects the interaction between price and realized utility over a six-month horizon. Meta-analyses of neuropathic pain pharmacotherapy show modest average efficacy and frequent tolerability trade-offs; therefore, small incremental utilities can be overwhelmed by cost differences¹³⁾. In the past, JSSR programs on chronic spinal pain, similar temporal patterns were observed: early improvements predominate; thereafter, marginal gains flatten, limiting incremental QALY even when pain scores increase slightly⁴⁾.

Notably, several industry-sponsored or model-based evaluations have reported favorable ICERs for pregabalin, including approximately 970,000 JPY per QALY in Japan and even lower values from a societal perspective, as well as demonstrated cost-effectiveness for refractory neuropathic pain in European settings^14-16).

The divergent findings in our study can be attributed to several key factors. First, there are fundamental differences in patient populations between studies. Previous evaluations focused exclusively on individuals with confirmed neuropathic pain phenotypes, whereas our study encompassed a broader, clinically heterogeneous population with cervicobrachial symptoms that were not necessarily limited to neuropathic etiologies. This broader inclusion likely diluted the potential benefits of pregabalin, which is specifically indicated for neuropathic pain. Second, adherence patterns and treatment persistence differed markedly between idealized model assumptions and real-world practice. While previous studies assumed optimal medication adherence throughout the treatment period, our pragmatic observational data—which permitted treatment modifications and discontinuations at the physician's discretion based on clinical response and tolerability—revealed variable treatment patterns in both groups, which substantially dampened the realized therapeutic utility compared with theoretical projections from controlled trials with strict adherence monitoring. Third, the perspective and scope of cost calculations varied significantly between studies. Previous evaluations have often adopted a societal perspective that incorporated broader economic benefits, including productivity gains from individuals returning to work and reduced healthcare utilization. In contrast, our analysis employed a more restrictive payer-only perspective, focusing solely on direct drug costs, which provides a more conservative but arguably more relevant assessment for healthcare decision makers concerned with pharmaceutical budgets.

Methodologically, cost-effective models for neuropathic pain are inherently sensitive to several critical assumptions that can substantially influence outcomes. These include how pain relief translates into utility improvements, the sequencing of treatment options, and the magnitude of disutility associated with adverse events. The variability in these modeling assumptions has been consistently identified as a major source of heterogeneity and potential bias in systematic reviews of economic evaluations of neuropathic pain treatments^10,11). Thus, our real-world findings provide valuable empirical data to inform these often theoretical modeling assumptions and highlight the importance of validating economic models against observed clinical practice patterns.

Japan's formal health technology assessment program, which was implemented nationally in 2019, uses a reference threshold of approximately 5 million JPY per QALY when considering price adjustments⁵⁾. In this context, monotherapy in our cohort often fell at or below this reference (depending on the drug), whereas multiple-drug therapy tended to exceed it while offering no additional QALY benefit, arguing against routine polypharmacy and for time-limited trials with stopping rules when the response is inadequate. These conclusions are in accordance with the parent cervicobrachial study and the JSSR chronic low-back-pain program, where cost-effectiveness was strongest in subgroups with greater baseline impairment and headroom for improvement^3,4).

A practical, value-conscious pathway is to prioritize monotherapy—NSAIDs or acetaminophen for nociceptive-dominant presentations, and a single first-line neuropathic agent when a neuropathic phenotype is likely—before considering add-on therapy. If insufficient benefit is observed by 8-12 weeks (the window during which most QALY accrual occurred), clinicians should consider switching drug class or pivoting to non-pharmacological modalities (supervised exercise/rehabilitation, education, and psychological support) instead of escalating to combination pharmacotherapy¹²⁾.

Our study had some limitations that should be acknowledged when interpreting our findings. First, the observational nature of this study with non-randomized treatment allocation introduces the potential for confounding by indication, whereby treatment decisions may have been influenced by unmeasured patient characteristics, disease severity, or physician preferences that could systematically differ between the monotherapy and multiple-drug therapy groups. We adjusted for the measured baseline characteristics; however, residual confounding factors cannot be entirely excluded. Additionally, we did not systematically capture prior pharmacotherapy history before study entry, which may have influenced physician treatment selection and patient response patterns. This unmeasured confounding could partially explain differences in drug utilization between groups and represents an important limitation when interpreting our comparative findings. Second, our analysis adopted a restrictive payer-only cost perspective that focuses exclusively on direct drug acquisition costs. This approach excludes other potentially relevant healthcare resource utilizations, such as physician visits, diagnostic procedures, hospitalizations, and emergency department visits, as well as indirect costs related to productivity losses or caregiver burden. A broader societal perspective may yield different cost-effective conclusions, particularly if individuals receiving multiple-drug therapy require fewer healthcare contacts or experience greater functional improvements that translate into productivity gains. Third, our study population exhibited limited phenotypic granularity in distinguishing between neuropathic and nociceptive pain mechanisms. This heterogeneity may have obscured differential treatment effects, as specific pharmacological agents may demonstrate superior efficacy for particular pain phenotypes. The lack of detailed pain characterization using validated neuropathic pain screening tools may have contributed to suboptimal treatment matching and potentially underestimated the benefits of targeted therapies, such as pregabalin, in appropriate patient subgroups. Despite these limitations, our core findings remain robust across numerous sensitivity analyses and uncertainty scenarios, with the qualitative conclusion of no incremental value from polytherapy over monotherapy during the six-month observation period consistently upheld across different analytical approaches and assumptions.

Figure 6.

a. SF-8 PCS over 6 months by treatment strategy (0=baseline) (solid=Mono; dashed=Poly).

PCS improved mainly through month 3 and then stabilized in both groups.

b. SF-8 MCS over 6 months by treatment strategy (0=baseline) (solid=Mono; dashed=Poly).

MCS showed modest early gains and plateaued.

MCS: mental component summary; PCS: physical component summary; SF-8: Short Form-8 Health Survey

Conclusions

In routine clinical care for cervicobrachial symptoms, multiple-drug therapy approximately doubles pharmaceutical costs without providing additional QALY gains over six months. Monotherapy, particularly with NSAIDs or acetaminophen, offers a more favorable balance between clinical benefit and economic value and should be prioritized as first-line treatment. When individuals demonstrate a suboptimal response, clinicians should consider early reassessment and redirection toward non-pharmacological strategies rather than switching to combination pharmacotherapy. These findings reinforce the national clinical guidance and broader messages from our parent cohort studies. Based on our findings, a time-limited, phenotype-guided approach with restraint in polypharmacy prescribing is warranted^3,12). Our results support evidence-based resource allocation and provide real-world data to inform clinical decision-making and health policies for managing cervicobrachial pain syndromes.

Author Contributions: Contributed to conceptualization, methodology, data collection, formal analysis, and original draft preparation, S.I. and H.N.; participated in conceptualization, methodology, data collection, formal analysis, and manuscript review and editing, T.F., T.Y., H.A., Y.Y., S.I., Y.I., H.M., G.I., M.M., S.K., Y.I., H.C., K.W., K.K., M.T., M.M., M.Y., S.S., M.T., M.H., M.K., K.N., K.M., A.S., and T.K.; participated in conceptualization, methodology, formal analysis, and manuscript review and editing, K.M.; conceptualization, methodology, supervision, and manuscript review and editing, N.O., S.I., N.M., H.H., Y.M., M.K., H.H.; all authors have approved the final version of the manuscript.

Conflicts of Interest: The authors declare that there are no relevant conflicts of interest.

Ethical Approval: This study was approved by the Ethics and Conflict of Interest Committee of the Japanese Society for Spine Surgery and Related Research (JSSR) (191202#6).

Informed Consent: All participants provided written informed consent.

Data Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Disclaimer: Kei Watanabe, Masao Koda, Naohisa Miyakoshi, Hiroshi Hashizume, and Mamoru Kawakami are the Editors of Spine Surgery and Related Research and on the journal's Editorial Committee. They were not involved in the editorial evaluation or decision to accept this article for publication at all.