1.1 Background

Carpal tunnel syndrome (CTS) is one of the most frequently encountered diseases of the hand.¹ CTS is a neuropathic entrapment disease caused by compression of the median nerve, leading to symptoms such as numbness in the fingers and nocturnal pain, and is associated with neuropathic pain.^2,3 The impact of neuropathic pain on activities of daily living and quality of life (QOL) is significant, and reducing this pain is an important treatment goal.^2,4–6 The guidelines for the pharmacological treatment of neuropathic pain created by the Japan Society of Pain Clinicians recommend calcium channel α₂δ ligands, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants as first-line medications.⁷ Gabapentinoids (gabapentin and pregabalin) exert analgesic effects on neuropathic pain by binding to the α₂δ subunit of voltage-dependent calcium channels, thereby inhibiting neuronal excitation. However, these medications are also associated with a high incidence of side effects, such as drowsiness, dizziness, and headache.^8,9

Mirogabalin besylate (hereafter referred to as mirogabalin [MGB]), a novel gabapentinoid, became available in Japan in 2019. MGB has binding affinities for the α2δ-1 subunit, which is involved in analgesic effects, and for the α2δ-2 subunit, which is associated with side effects, comparable to those of pregabalin.^10,11 However, MGB exhibits a slower dissociation rate than pregabalin, particularly with the α2δ-1 subunit. Due to these unique binding characteristics, the analgesic effects of MGB are superior to those of pregabalin, with fewer central nervous system-related side effects. The dosage of MGB is determined based on creatinine clearance (CrCl) levels¹²: for CrCl ≥60 mL/min, the dosage is 10–30 mg/day; for CrCl 30–60 mL/min, the dosage is 5–15 mg/day; and for CrCl <30 mL/min, the dosage is 2.5–7.5 mg/day. Treatment is initiated with an initial dose based on CrCl levels (≥60 mL/min, 5 mg twice daily; 30–60 mL/min, 2.5 mg twice daily; and <30 mL/min, 2.5 mg once daily). After at least one week from the initial administration, the dosage is increased to the effective dose, based on CrCl levels (≥60 mL/min, 10 mg twice daily; 30–60 mL/min, 5 mg twice daily; and <30 mL/min, 5 mg once daily). After an additional interval of at least one week, the dosage is further increased to the maximum dose based on CrCl levels (≥60 mL/min, 15 mg twice daily; 30–60 mL/min, 7.5 mg twice daily; and <30 mL/min, 7.5 mg once daily).

1.2 Rationale

MBG has shown favorable treatment outcomes for various neuropathic pain conditions, including spinal disorders such as lumbar spinal stenosis and lumbar disc herniation, as well as diabetic peripheral neuropathy.^13–16 However, no reports have focused solely on the treatment outcomes of MGB for patients with CTS, and its effectiveness remains unclear.

The purpose of this study was to investigate the short-term clinical outcomes of MGB for CTS and to report the findings as a pilot study.

2.1 Study design

This single-center, retrospective observational pilot study was conducted in accordance with the Declaration of Helsinki and with the approval of the ethics committee of our institution. Informed consent was obtained using an opt-out method due to the retrospective nature of the study. This study adheres to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines.¹⁷

2.2 Participants and selection criteria

The study included 38 patients (15 males, 23 females; mean age 73 ± 12.6 years) who began conservative treatment with MGB for CTS between April 2022 and March 2023. The exclusion criteria were as follows: discontinuation of MGB within 12 weeks of treatment initiation; lack of evaluation using the designated numeric scales both before treatment and at 12 weeks; and prior use of MGB for the treatment of other conditions (Fig. 1).

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Fig. 1 Flowchart of inclusion and exclusion criteria for the analysis. Thirty-eight cases of CTS treated with MGB were included. Eight cases who discontinued MGB within 12 weeks after the start of treatment, six cases whose treatment outcomes were not evaluated with the numeric scale, and three cases who were already taking MGB were excluded. CTS, carpal tunnel syndrome; MGB, mirogabalin.

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2.3 Investigation of patient backgrounds

The following patient background data were investigated: age, sex, body mass index (BMI), affected hand, atrophy of the abductor pollicis brevis muscle, CrCl, daily dosage of MGB at 12 weeks, comorbidities, concomitant drugs used before the initiation of MGB administration, adverse drug reactions (ADRs), newly added non-MGB analgesics, and implementation of other conservative treatments. The ADR severity was assessed and classified as follows: mild, easily tolerable; moderate, interfered with daily activities; and severe, made daily activities impossible.

2.4 Evaluation of treatment outcomes

The CTS treatment outcomes were evaluated using the following numeric scales: the Japanese Society for Surgery of the Hand (JSSH) version of the Carpal Tunnel Syndrome Instrument (CTSI),^18,19 the Quick Disabilities of the Arm, Shoulder and Hand (Quick DASH) questionnaire developed by the JSSH,^20,21 and the Visual Analog Scale (VAS). The CTSI was evaluated using the Symptom Severity Scale (CTSI-SS), the Functional Status Scale (CTSI-FS), and their total scores (CTSI-total). The CTSI-SS and CTSI-FS were scored from 1 to 5, and the DASH and VAS from 0 to 100. For all scales, lower scores indicated better outcomes.

The primary outcome measure was the change in CTSI-total scores from baseline after 12 weeks of MGB administration. Secondary outcome measures included the changes in CTSI-SS, CTSI-FS, DASH, and VAS scores from baseline after 12 weeks of MGB administration.

2.5 Statistical analysis

Due to the small number of cases, non-parametric tests were used for analyses. For the analysis of within-group differences, the Wilcoxon signed-rank test was used. Statistical analysis was performed using EZR statistical software (Saitama Medical Center, Jichi Medical University, Saitama, Japan),²² with the significance level set at p<0.05. The responsiveness of the instruments was examined by calculating the standardized response mean (SRM) and effect size (ES). SRM was defined as small (<0.5), medium (0.5–0.8), or large (≥0.8). For the non-parametric test, ES was defined as small (0.1–0.3), medium (0.3–0.5), or large (≥0.5).

3.1 The short-term clinical outcomes of MGB for CTS

The treatment outcomes are shown in Fig. 2. The primary outcome measure, CTSI-total scores, showed a significant improvement (p=0.022). Both SRM and ES were medium (Table 2).

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Fig. 2 Changes in primary and secondary outcome measures with the initiation of treatment. A. CTSI-total, total of CTSI-SS and CTSI-FS; B. CTSI-SS, Carpal Tunnel Syndrome Instrument Symptom Severity Scale; C. CTSI-FS, Carpal Tunnel Syndrome Instrument Functional Status Scale; D. DASH, Disabilities of the Arm, Shoulder and Hand; E. VAS, Visual Analog Scale; n.s., not significant. ∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001 for Wilcoxon's signed-rank test.

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3.2 The effect of MGB on CTS symptom severity and subjective pain level

For the secondary outcome measures, CTSI-SS (p<0.01) and VAS (p<0.001) showed significant improvements. No significant differences were observed in CTSI-FS (p=0.349) and DASH (p=0.102) scores. Both the SRM and ES for the CTSI-SS scores were medium, while both the SRM and ES for VAS scores were large. For CTSI-FS and DASH scores, the SRM and ES values were small. In a post-hoc exploratory analysis, the statistical power was 0.638.

3.3 The ADRs associated with MGB in patients with CTS

ADRs occurred in nine cases (42.9 %), and most were mild (Table 3).

4.1 The short-term clinical outcomes of MGB for CTS

In this study, the CTSI-total scores of patients who were administered MGB for 12 weeks significantly improved. Although these are short-term results, the treatment outcomes of MGB for CTS appear to be favorable. Previous studies involving Asian patients with diabetes by Baba et al.¹³ and Kato et al.¹¹ reported that MGB improves symptoms of neuropathic pain in a dose-dependent manner. In this study, the MGB dosage was maintained at the maximum dose in 20 of 21 cases and at an effective dose in 1 case, indicating a high administered dosage. This may account for the similar favorable results observed, which are consistent with existing reports. In contrast, in this study, no patients continued receiving a low dose, and we were unable to closely monitor the longitudinal changes in clinical outcomes. Therefore, comparing the treatment effects based on dosage or investigating the timing of symptom improvement was difficult. Nevertheless, the findings from this study suggest that increasing the MGB dosage to a high level based on the CrCl and continuing the administration for 12 weeks results in favorable treatment outcomes.

4.2 The effect of MGB on CTS symptom severity and subjective pain level

The CTSI-SS, an indicator of CTS severity, and the VAS, which evaluates subjective CTS symptoms, showed significant improvements during this study. Therefore, MGB appears to have a short-term effect on improving both the severity and subjective symptoms of CTS, which likely contributes to the overall improvement in treatment outcomes. In contrast, CTSI-FS, an indicator of functional impairment due to CTS, and DASH, an assessment of upper limb function, did not show significant differences. Kanatani et al.²⁷ evaluated CTSI in patients with CTS one year after surgery and reported significant improvements in CTSI-total, CTSI-SS, and CTSI-FS, with CTSI-SS showing a greater improvement than CTSI-FS. Although the observation period in this study differs from that reported previously, the significant improvement in CTSI-total and the greater improvement in CTSI-SS compared with CTSI-FS are similar findings. While comparing the degree of improvement with surgical treatment is difficult, oral treatment with MGB may also result in greater improvement in CTSI-SS than in CTSI-FS. Additionally, Uchiyama et al.²⁸ evaluated the treatment outcomes of patients with CTS three months after surgery and observed significant improvements in CTSI, DASH, body pain (a subscale of the Short Form-36, which is a health-related QOL measure), and VAS scores. They also reported that CTSI-SS and CTSI-FS scores showed greater improvements than VAS scores. In this study, significant improvements were observed in CTSI-SS and VAS scores but not in CTSI-FS scores. Notably, VAS scores showed substantial improvements. This difference from the postoperative improvement trajectory suggests that the observed improvement may be a characteristic of the treatment effect of MGB. However, given the short follow-up period and reliance on short-term results, this conclusion remains speculative. To understand the long-term effects and true characteristics of MGB, long-term prospective studies are required.

4.3 The ADRs associated with MGB in patients with CTS

The incidence of ADRs from oral administration of MGB ranges from 27.6 % to 52.1 %,^15,29–32 with the most common being drowsiness, dizziness, and weight gain. The occurrence and types of ADRs in this study were similar to those previously reported. Regarding the dosage-related incidence of ADRs, Baba et al.¹³ conducted a clinical trial with 834 patients and reported that side effects occurred in 2.4 % of patients in the 15 mg/day group, 4.8 % in the 20 mg/day group, and 6.7 % in the 30 mg/day group. In this study, ADRs occurred in 2 of 11 patients (18.2 %) in the 15 mg/day group and in 7 of 10 patients (70 %) in the 30 mg/day group. The higher incidence in the 30 mg/day group is similar to the findings reported by Baba et al.¹³ However, due to the small sample size in this study, comparison with previous reports is difficult. To understand the incidence of ADRs by MGB dosage in patients with CTS, long-term studies are needed. In contrast, regarding severity, based on the results of a Phase III clinical trial of Asian patients with diabetic neuropathic pain, Kato et al.¹¹ found mostly mild-to-moderate side effects of MGB. They also noted that MGB is safe and effective, considering its tolerability. Our study also involved Asian patients (all Japanese), and most side effects were mild, with similar findings regarding severity. Therefore, MGB may be safe and effective for Asian patients with CTS.

4.4 Other observations

Kanbayashi et al.³³ have stated that the concomitant use of MGB and opioids may exacerbate ADRs and should be avoided. However, they reported that neurotropin, which has few side effects and is effective against neuropathic pain, may provide additional therapeutic benefits when used in combination with MGB. In our study, four patients were taking concomitant medications prior to the initiation of MGB, including acetaminophen and nonsteroidal anti-inflammatory drugs (celecoxib and zaltoprofen). However, it remains unclear whether these medications influenced the treatment outcomes or side effects of MGB. To accurately determine the specific treatment effects of MGB on CTS, a prospective study with meticulously controlled conditions is required. Furthermore, since no patients in our study received other conservative treatments, the clinical effect of combining conservative treatments with MGB remains unknown. Future studies should investigate the efficacy of combining MGB with conservative therapies.

4.5 Limitations

This study had several limitations. It was a retrospective study with a small sample size and short-term outcomes. In particular, the lack of a control group and comparison with other medications are major weaknesses. Additionally, the study included patients who were taking other analgesics or had comorbidities that could cause neurological symptoms, which created a selection bias. Furthermore, cases where medication was discontinued within 12 weeks were not examined. Further large-scale studies are necessary to address these issues.

4.6 Conclusion

We retrospectively investigated the short-term clinical outcomes of MGB for CTS. Continuation of oral administration for 12 weeks significantly improved CTSI-total, CTSI-SS, and VAS scores. ADRs occurred at a high rate, though most were mild. While preliminary, this is the first report on the clinical outcomes of MGB focusing exclusively on patients with CTS. We believe this report represents a valuable step forward in exploring new therapies for CTS.