mirogabalin and Neuralgia

Neuropathic pain is a complex sort of pain that is detrimental to individuals' health, both physically and mentally, but merely a small portion of them could witness pain alleviation. Mirogabalin, by distinctive binding characteristics of voltage-gated calcium channels, has won approval from the Japanese authority as a third member of gabapentinoids in Japan. Our review was aimed at encompassing the bulk of clinical research on mirogabalin, which included clinical trials, special considerations, coadministration studies, case reports, and cost-effectiveness studies.. A review was carried out on a series of platforms, such as PubMed, MEDLINE, and Scopus, up to December 2021 using the keywords as follows: "mirogabalin OR mirogabalin besylate OR Tarlige OR DS-5565" AND "neuropathic pain OR Neuropathy.". Mirogabalin demonstrated analgesic activity and manageable adverse reactions and provides a new alternative for individuals with PHN or DPNP in 3 phase II and 4 III trials. Mirogabalin alleviated pain markedly in comparison with placebo. Administration of mirogabalin on a long-term basis is a flexible dosage regimen for patients with PHN. It is noteworthy that mirogabalin should be administrated cautiously when combined with probenecid and cimetidine on account of a slight increase in pharmacodynamics effects of mirogabalin.. The development of mirogabalin allows further optimization of individual treatment strategies so as to provide more therapeutic choices in this medical domain.

Topics: Analgesics; Bridged Bicyclo Compounds; Cimetidine; Humans; Neuralgia

We aimed to perform a systematic review and meta-analysis to examine the efficacy and safety of mirogabalin in patients with diabetic peripheral neuropathic pain (DPNP).. We searched four databases from inception to 1st July 2020. We included all randomised controlled trials (RCTs) which assessed the effectiveness and safety of mirogabalin in patients with DPNP. We evaluated the quality of the included RCTs using the Cochrane risk of bias assessment tool. We pooled dichotomous outcomes as risk ratios and continuous outcomes as mean differences with 95% confidence intervals, both under the random- or fixed-effects model.. Three RCTs matched our inclusion criteria with a total of 1732 patients with DPNP: 1057, 534 and 141 patients received mirogabalin, placebo and pregabalin, respectively. The quality of included RCTs was marked as moderate-to-high. Mirogabalin treatment was significantly associated with a significant reduction in the average daily pain score (ADPS) compared with placebo over 7 weeks. Compared with pregabalin, mirogabalin was significantly associated with more decrease in ADPS only after 3, 4 and 5 weeks. The proportion of patients with ≥30% and ≥50% reduction in the ADPS was significantly higher in the mirogabalin vs placebo and pregabalin groups. Compared with placebo, mirogabalin was significantly associated with more adverse events of dizziness, increased weight, peripheral oedema and somnolence. The safety profile was comparable between mirogabalin and pregabalin.. Our systematic review and meta-analysis revealed that in patients with DPNP, mirogabalin treatment was superior to placebo and pregabalin in decreasing the ADPS over time. Besides, mirogabalin was largely safe and associated with some adverse events that could be managed conservatively.

Topics: Analgesics; Bridged Bicyclo Compounds; Diabetes Mellitus; Humans; Neuralgia; Pregabalin; Randomized Controlled Trials as Topic; Treatment Outcome

To assess the cost-effectiveness of 30 mg of mirogabalin versus no treatment or 300 mg of pregabalin in patients with diabetic peripheral neuropathic pain (DPNP) from a third-party perspective in Taiwan.. A Markov model, developed with cycles of 2-week and a 1-year timeframes, consisted of 3 health states: mild, moderate, and severe pain. Average daily pain score (ADPS) was assessed at the end of each 2-week cycle. All patients entered the model in moderate (4 ≤ ADPS < 7) or severe (7 ≤ ADPS ≤ 10) pain health states. At the end of each cycle, patients remained in their assigned health state or transitioned to a different health state according to their pain score change. Efficacy data were informed by the pivotal phase III clinical trial (J303, NCT02318706) or by a network meta-analysis. Utility values were obtained from published literature, and resource use and cost data from Taiwanese clinical experts and Taiwan National Health Insurance Administration. One-way sensitivity, scenario, and probabilistic analyses were conducted to test the robustness of the results.. A head-to-head analysis demonstrated that 30 mg of mirogabalin is a cost-effective treatment option versus placebo for DPNP. The base-case deterministic analysis estimated quality-adjusted life years (QALY) gains of 0.02 at an incremental cost of 9697 New Taiwan dollars (NT$) (equal to $323) versus placebo (incremental cost-effectiveness ratio [ICER]: 489 310 NT$/QALY [$15 860/QALY]). Mirogabalin was also cost-effective compared with 300 mg of pregabalin (ICER: 18 476 NT$/QALY [$600/QALY]). Sensitivity and scenario analyses results confirmed the robustness.. Economic analysis suggests that mirogabalin 30 mg, a potent and selective α2δ ligand, is a cost-effective treatment option for DPNP in Taiwan, with an ICER below the willingness-to-pay threshold.

Topics: Bridged Bicyclo Compounds; Cost-Benefit Analysis; Diabetes Mellitus; Diabetic Neuropathies; Humans; Neuralgia; Taiwan

Neuropathic pain (NeP) is a chronic and refractory condition in many patients, and its treatment is a challenge for physicians. A new voltage-gated Ca. The purpose of this article is to review the pharmacological characteristics, pharmacokinetics, and efficacy and safety of mirogabalin for NeP based on the results of non-clinical and clinical studies.. Although there are several first-line therapies for NeP, insufficient efficacy and adverse drug reactions of NeP drugs often cause patient dissatisfaction. Mirogabalin was effective and well tolerated with a step-wise dose increase in clinical studies on P-NeP patients. Thus, mirogabalin is expected to be a useful treatment option for patients with P-NeP.

Topics: Animals; Bridged Bicyclo Compounds; Humans; Ligands; Neuralgia; Pregabalin

Topics: Bridged Bicyclo Compounds; Clinical Trials, Phase III as Topic; Double-Blind Method; Fibromyalgia; Gabapentin; Humans; Neuralgia

Neuropathic pain (NeP) is a global cause of suffering and debilitation leading to significant morbidity and reduced quality of life. New treatments are needed to address the growing prevalence of NeP and its impact on sleep, mood and functionality. Mirogabalin besylate (mirogabalin, Tarlige) is a gabapentinoid therapy developed by Daiichi Sankyo which is approved in Japan for the treatment of postherpetic neuralgia and painful diabetic peripheral neuropathy. Mirogabalin has a potent pain-modulating effect with a unique high affinity and prolonged dissociation rate for the a2delta-1 subunit of voltage-gated calcium (Ca2+) channels (VGCCs) on the dorsal root ganglion resulting in more sustained analgesia compared with traditional gabapentinoids. Additionally, mirogabalin has a superior adverse events (AEs) profile due to a rapid dissociation from the a2delta-2 subunit of VGCCs potentially implicated in central nervous system-specific AEs. The most common AEs for mirogabalin are dizziness (approximately 8-16%), somnolence (approximately 6-24%) and headache (approximately 6-14%), with a lower incidence of constipation, nausea, diarrhea, vomiting, edema, fatigue and weight gain. Postmarketing studies are required to evaluate its analgesic durability and efficacy when combined with other antineuropathic agents such as tricyclics, duloxetine and tramadol/tapentadol.

Topics: Analgesics; Bridged Bicyclo Compounds; Humans; Neuralgia

Mirogabalin besylate (hereafter mirogabalin) [Tarlige

Topics: Bridged Bicyclo Compounds; Calcium Channel Blockers; Calcium Channels; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Complications; Diabetes Mellitus; Drug Approval; Humans; Japan; Neuralgia; Neuralgia, Postherpetic; Pain; Randomized Controlled Trials as Topic

Patients with spinal cord injury (SCI) commonly experience central neuropathic pain (CNeP), which is challenging to treat. Mirogabalin is effective for peripheral neuropathic pain, but evidence for CNeP is lacking.. This randomized, double-blind, placebo-controlled, phase 3 study investigated mirogabalin efficacy and safety for the treatment of CNeP in patients with traumatic SCI. Adult patients from 120 sites throughout Japan, Korea, and Taiwan were randomized (1:1) to receive placebo or mirogabalin (5 mg twice daily [BID] for 1 week, 10 mg BID for 1 week, and 10 or 15 mg BID for 12 weeks). Patients with moderate renal impairment received half the dosage. The primary efficacy endpoint was change from baseline in the weekly average daily pain score (ADPS) at week 14. The secondary endpoints included ADPS responder rates, the Short-Form McGill Pain Questionnaire (SF-MPQ), average daily sleep interference score (ADSIS), and Neuropathic Pain Symptom Inventory (NPSI). Adverse events were monitored for safety.. Each treatment group comprised 150 patients. Mirogabalin elicited a statistical and clinically relevant improvement in change from baseline in the weekly ADPS at week 14 (least-squares mean difference [95% CI] vs placebo -0.71 [-1.08 to -0.34],. Mirogabalin elicited clinically relevant decreases in pain and was well tolerated, suggesting that mirogabalin is a promising treatment for patients with CNeP due to SCI.. ClinicalTrials.gov (NCT03901352); first submitted April 3, 2019; first patient enrolled March 14, 2019; available at clinicaltrials.gov/ct2/show/NCT03901352.. This study provides Class I evidence that in adult patients with CNeP due to traumatic SCI, mirogabalin, 10 or 15 mg BID, effectively improves weekly ADPS at week 14.

Topics: Adult; Analgesics; Asia; Double-Blind Method; Humans; Neuralgia; Spinal Cord Injuries; Treatment Outcome

Mirogabalin is a treatment option for patients with neuropathic pain; however, safety, tolerability, and pharmacokinetics (PK) data specifically for Chinese individuals are limited to a single-dose study. We aimed to assess these for both single- and multiple-dose mirogabalin in healthy Chinese participants.. In this randomized, double-blind, placebo-controlled, phase I study, 54 healthy Chinese men and women aged 18-45 years were randomly allocated to receive single- (5, 10, or 15 mg, daily) or multiple-dose (5 mg titrated to 15 mg, twice-daily, over 22 days) oral mirogabalin or placebo. In each of three single-dose groups, 10 participants received mirogabalin and 2 received placebo; in the multiple-dose group, 14 participants received mirogabalin and 4 received placebo. The primary endpoints were PK, safety, and tolerability variables, including treatment-emergent adverse events (TEAEs), laboratory tests, and vital signs. PK data were collected for both single- and multiple-dose cohorts and evaluated by non-compartmental analysis.. Single- and multiple-dose mirogabalin was generally well tolerated with no deaths, serious TEAEs, or TEAEs leading to treatment discontinuation. Frequently reported TEAEs included dizziness, nystagmus, increased blood triglycerides, headache, and increased blood uric acid and creatine phosphokinase. Single-dose mirogabalin was rapidly absorbed (median time to maximum plasma concentration, 1.00 h) and eliminated (mean terminal elimination half-life, 2.57-3.08 h). The exposure was approximately dose-proportional. In the multiple-dose cohort, the trough plasma concentration increased dose-proportionally, and exposure and clearance were comparable to that following a single 15-mg dose. The mean cumulative amount excreted into urine up to 48 h post-dose increased in a dose-proportional manner, the mean cumulative percentage excreted into urine was 61.9%-74.3%, and renal clearance remained relatively constant.. Consistent with previous phase I studies in other populations, mirogabalin was safe and well tolerated in healthy Chinese participants at single and multiple doses of up to 15 mg twice-daily.

Topics: Area Under Curve; Bridged Bicyclo Compounds; Dose-Response Relationship, Drug; Double-Blind Method; East Asian People; Female; Healthy Volunteers; Humans; Male; Neuralgia

Mirogabalin besylate has been approved in several countries to treat peripheral neuropathic pain. This pooled analysis, using data from the two pivotal Phase III studies in Asian patients with diabetic peripheral neuropathic pain and post-herpetic neuralgia, aimed to provide clinicians with more detailed and precise information relating to mirogabalin's safety and efficacy.. Data were pooled from 2 multicenter, double-blind, placebo-controlled, parallel-group, 14-week treatment studies of mirogabalin conducted at ∼350 study sites (Japan, South Korea, Taiwan, Singapore, Malaysia, and Thailand). Eligible patients in both studies were randomized in a 2:1:1:1 ratio, stratified according to a baseline average daily pain score (ADPS) of <6 or ≥6, to placebo, mirogabalin 15-mg once daily (QD), mirogabalin 10-mg twice daily (BID), or mirogabalin 15-mg BID treatment groups. Safety was assessed based on treatment-emergent adverse events identified from the adverse events collected throughout both studies. The primary efficacy end point of both studies was the change from baseline in ADPS at week 14.. In total, 1587 patients (824 with diabetic peripheral neuropathic pain; 763 with post-herpetic neuralgia) who received at least 1 dose of study drug were analyzed (633 received placebo, 954 treated with mirogabalin). Treatment-emergent adverse events included somnolence (3.8%, 10.8%, 14.5%, and 19.1%) and dizziness (2.7%, 5.7%, 9.1%, and 13.1%) in patients receiving placebo, mirogabalin 15 mg QD, mirogabalin 10 mg BID, and mirogabalin 15 mg BID, respectively. In patients treated with mirogabalin 15 mg QD, 2 (0.6%) of 316 patients discontinued due to somnolence. In the mirogabalin 10-mg BID group, somnolence, edema, and peripheral edema each resulted in 3 (0.9%) of 318 patient discontinuations. In the mirogabalin 15-mg BID group, 6 (1.9%) of 320 patients discontinued due to dizziness and 3 (0.9%) due to somnolence. At week 14, mirogabalin 10 mg BID and 15 mg BID statistically significantly improved ADPS versus placebo, with least squares mean changes (95% CI) of -0.31 (-0.55, -0.08) and -0.63 (-0.86, -0.40). Post hoc analysis showed a statistically significant difference 2 days after administration in the mirogabalin 10-mg and 15-mg BID groups compared with placebo. Female sex, age ≥65 years, and baseline weight <60 kg may influence the safety of mirogabalin, particularly regarding the incidence of somnolence and dizziness, but had no notable impact on efficacy. ClinicalTrials.gov identifiers: NCT02318706 and NCT02318719.. This pooled analysis showed that mirogabalin was efficacious and well-tolerated by Asian patients with peripheral neuropathic pain.

Topics: Aged; Analgesics; Bridged Bicyclo Compounds; Diabetic Neuropathies; Double-Blind Method; Female; Humans; Neuralgia; Pharmaceutical Preparations; Treatment Outcome

Diabetic peripheral neuropathic pain (DPNP) affects the functionality, mood and sleep patterns of patients with diabetes. Mirogabalin, an α. This 52-week open-label extension study was carried out in Japan, Korea and Taiwan in patients with DPNP. Patients received mirogabalin, initiated at 5 mg twice daily and increased to a flexible maintenance dosage of 10 or 15 mg twice daily. Adverse events were monitored throughout the study. Patients provided a self-assessment of pain using the Short-Form McGill Pain Questionnaire.. Of the 214 patients who entered the study, 172 (80.4%) completed the extension study. Of 172 patients who completed the study, 149 received the highest dosage of mirogabalin (15 mg twice daily). The most common treatment-emergent adverse events were nasopharyngitis, diabetic retinopathy, peripheral edema, somnolence, diarrhea, increased weight and dizziness. Most treatment-emergent adverse events were mild or moderate in severity. The incidence of treatment-emergent adverse events leading to treatment discontinuation was 13.1%. The visual analog scale and all other Short-Form McGill Pain Questionnaire subscales (sensory score, affective score, total score and present pain intensity) generally decreased over time from baseline until week 52.. This extension study showed the safety and efficacy of a long-term flexible dosing regimen of mirogabalin 10 or 15 mg twice daily in patients with DPNP.

Topics: Analgesics; Asian People; Bridged Bicyclo Compounds; Diabetic Neuropathies; Double-Blind Method; Female; Humans; Male; Middle Aged; Neuralgia; Pain Measurement; Treatment Outcome

This study evaluated the efficacy and safety of mirogabalin, a novel, potent, selective ligand of the α. During this double-blind, multisite, placebo-controlled phase III study, Asian patients aged ≥20 years with type 1 or 2 diabetes and DPNP were randomized 2:1:1:1 to a placebo, mirogabalin 15, 20 or 30 mg/day for up to 14 weeks, with a 1- to 2-week titration (NCT02318706). The primary endpoint was the change from baseline in average daily pain score (ADPS) at week 14, defined as a weekly average of daily pain (0 = no pain to 10 = worst possible pain, for the past 24 h).. Of 834 randomized patients, 330, 164, 165 and 165 received placebo, mirogabalin 15, 20 or 30 mg/day, respectively, and were included in analyses (modified intention-to-treat population, n = 824); 755 (90.5%) completed the study. At week 14, the least squares mean average daily pain score change from baseline was -1.31, -1.34, -1.47 and -1.81, respectively, showing statistical significance for mirogabalin 30 mg/day versus placebo (P = 0.0027). The treatment-emergent adverse events observed were mostly mild-to-moderate in all mirogabalin doses, and the most frequent treatment-emergent adverse events were nasopharyngitis, somnolence, dizziness, peripheral edema and weight increase.. Mirogabalin relieved DPNP in a dose-dependent manner; mirogabalin 30 mg/day showed statistically significant pain relief (vs placebo) in Asian DPNP patients. All doses of mirogabalin tested were well tolerated.

Topics: Adolescent; Adult; Aged; Asian People; Bridged Bicyclo Compounds; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neuralgia; Treatment Outcome; Young Adult

Mirogabalin is a novel, preferentially selective α

Topics: Adult; Area Under Curve; Asian People; Bridged Bicyclo Compounds; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Healthy Volunteers; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neuralgia; Tissue Distribution; Young Adult

The primary aim of this study was to assess the individual effects of probenecid and cimetidine on mirogabalin exposure.. This phase 1, open-label, crossover study randomized healthy adults to receive three treatment regimens, each separated by ≥5-day washout: a single oral dose of mirogabalin 15 mg on day 2, mirogabalin 15 mg on day 2 plus probenecid 500 mg every 6 h from days 1 to 4, and mirogabalin 15 mg on day 2 plus cimetidine 400 mg every 6 h from days 1 to 4.. Coadministration of mirogabalin with probenecid or cimetidine increased the maximum and total mirogabalin exposure. The geometric mean ratios of C. A greater magnitude of change in mirogabalin exposure was observed when coadministered with a drug that inhibits both renal and metabolic clearance (probenecid) vs. a drug that only affects renal clearance (cimetidine). However, as the increase in exposure is not clinically significant (>2-fold), no a priori dose adjustment is recommended.

Topics: Administration, Oral; Adult; Area Under Curve; Bridged Bicyclo Compounds; Cimetidine; Cross-Over Studies; Diabetic Neuropathies; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Female; Healthy Volunteers; Herpes Zoster; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neuralgia; Probenecid; Renal Elimination

Three phase 1 pharmacokinetic (PK)/pharmacodynamics (PD) studies were conducted in healthy men and women to further characterize the safety, tolerability, and PK/PD of mirogabalin administration with or without food and to guide the dose selection and regimen for phase 2 and 3 clinical development. The 3 studies included 2 randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose studies, and 1 open-label, crossover study to evaluate the PK of mirogabalin administered under fasting and fed (high-fat meal) conditions. Forty-eight and 47 healthy volunteers completed the single- and multiple-dose studies, respectively. Thirty subjects were enrolled and completed the food effect study. Mirogabalin was well tolerated in the fed and fasted states. The most frequent treatment-emergent adverse events (TEAEs)-dizziness and somnolence-were expected based on mirogabalin's mechanism of action. Subjects receiving the highest mirogabalin doses (50 and 75 mg single dose) showed greater dizziness and sedation and higher rates of TEAEs than subjects receiving 3-30 mg. After oral administration, mirogabalin was rapidly absorbed (time to maximum concentration, ∼1 hour) and eliminated through urine unchanged (61%-72% urinary excretion). Exposure increased in a dose-proportional manner after single or multiple mirogabalin doses. No significant accumulation occurred with multiple doses over 14 days. After single doses of mirogabalin (15 mg), the bioavailability was considered equivalent in the fed and fasted states, indicating that mirogabalin can be taken without food restrictions. Based on these data, mirogabalin 15 mg twice daily was selected as the highest target dose for further clinical development.

Topics: Administration, Oral; Adult; Analgesics; Bridged Bicyclo Compounds; Calcium Channel Blockers; Calcium Channels; Cross-Over Studies; Dizziness; Dose-Response Relationship, Drug; Fasting; Female; Food-Drug Interactions; Healthy Volunteers; Humans; Male; Metabolic Clearance Rate; Neuralgia; Sleepiness; Young Adult

To evaluate the effects of mirogabalin on patient-reported pain and sleep interference in diabetic peripheral neuropathic pain (DPNP).. Adults (≥18 years) with type 1 or 2 diabetes, glycosylated hemoglobin of 10% or less at screening, and DPNP for six months or more were eligible for participation.. Subjects (N = 452) were randomly assigned (2:1:1:1:1:1:1) to receive placebo, dose-ranging mirogabalin (5, 10, 15, 20, 30 mg/day), or pregabalin (300 mg/day) for five weeks. Secondary efficacy end points studied here included patient global impression of change (PGIC), modified brief pain inventory (BPI), and average daily sleep interference score (ADSIS). Correlation plots were generated to examine the relationship between ADSIS and average daily pain score (ADPS).. At week 5, significant reductions in ADSIS were observed in the mirogabalin 15, 20, and 30 mg/day groups, compared with placebo (P < 0.05). Baseline ADSIS and ADPS were strongly correlated (R2 = 0.4407), as were mean changes from baseline in ADSIS and ADPS at week 5 (R2 = 0.6694). The mirogabalin 30 mg/day group showed significant improvement compared with placebo in four of six BPI subscales at end point; the mirogabalin 15 mg/day group showed significant improvement in three of six BPI subscales (P < 0.05). At end of treatment, the percentage of subject with PGIC status of "much improved or better" was greater in all mirogabalin dose groups than in the placebo group (P < 0.05). A low incidence of treatment-related adverse events was reported for mirogabalin.. Results support the effectiveness of mirogabalin in improving patient-reported pain and sleep interference in DPNP.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Bridged Bicyclo Compounds; Diabetic Neuropathies; Female; gamma-Aminobutyric Acid; Humans; Male; Middle Aged; Neuralgia; Pain Measurement; Pregabalin; Sleep; Treatment Outcome

Mirogabalin (DS-5565) is an α2δ-1 ligand being developed for pain associated with diabetic peripheral neuropathy, fibromyalgia, and postherpetic neuralgia. Nonlinear mixed-effects analyses were performed on average daily pain and on the incidence of the adverse events dizziness and somnolence. These models were used to predict the dose of mirogabalin equivalent to pregabalin and the probability of meaningful reduction in pain compared with placebo and pregabalin. In addition, regimen effects were evaluated for reductions of adverse events. Mirogabalin was estimated to be 17-fold more potent than pregabalin. The effectiveness of 150 mg pregabalin, dosed twice daily, attenuated by week 5. Therefore, the estimated mechanism-based equivalent dose (ED) of 17.7 mg mirogabalin was higher than that predicted to achieve comparable pain reduction. If attenuation of the pregabalin effect is real, mirogabalin doses lower than the ED could yield comparable pain reduction, albeit with less differentiation in pain from placebo. The incidence rate of dizziness and somnolence decreased over time. Twice-daily dosing of mirogabalin was predicted to yield a lower incidence rate of dizziness than once-daily dosing; thus, titration of dosages should reduce adverse event rates. These model results were used to influence phase 3 dosing selection.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Bridged Bicyclo Compounds; Diabetes Mellitus; Disorders of Excessive Somnolence; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Models, Biological; Neuralgia; Pain Measurement

We aimed to identify doses of mirogabalin (DS-5565) providing clinically meaningful efficacy with manageable side effects for treatment of diabetic peripheral neuropathic pain (DPNP).. Adults (≥18 years) with type 1 or 2 diabetes, HbA₁c ≤10% at screening, and DPNP for ≥6 months were eligible for study participation. Subjects (n = 452) were randomized (2:1:1:1:1:1:1 ratio) to placebo, dose-ranging mirogabalin (5, 10, 15, 20, and 30 mg/day), or pregabalin (300 mg/day) for 5 weeks. The primary end point was weekly change in average daily pain score (ADPS; 0 to 10 numeric rating scale) from baseline to week 5 (minimally meaningful effect, ≥1.0-point decrease versus placebo). ANCOVA was conducted using last observation carried forward, and treatment effect least squares (LS) means were provided for each contrast. Safety assessments included adverse events (AEs), clinical laboratory tests, and electrocardiograms.. LS mean differences in change in ADPS from baseline to week 5 versus placebo were -0.22, -0.53, -0.94, -0.88, and -1.01 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively, and -0.05 in the pregabalin group (P < 0.05 versus placebo for mirogabalin 15, 20, and 30 mg/day). Most frequent AEs (n = 277) were primarily mild to moderate dizziness (9.4%), somnolence (6.1%), and headache (6.1%); otherwise, mirogabalin was well tolerated.. Mirogabalin 15, 20, and 30 mg/day had statistically significant reductions in ADPS versus placebo, and mirogabalin 30 mg/day also met the criteria of minimally meaningful effect. Mirogabalin may be a promising new treatment option for patients with DPNP.

Topics: Adult; Aged; Analgesics; Bridged Bicyclo Compounds; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Dose-Response Relationship, Drug; Double-Blind Method; Female; gamma-Aminobutyric Acid; Humans; Male; Middle Aged; Neuralgia; Placebos; Pregabalin; Treatment Outcome

Inhibitory interneurons in the spinal dorsal horn (DH) play a major role in regulating innocuous and noxious information. Reduction in inhibitory synaptic transmission is thought to contribute to the development of touch-evoked pain (allodynia), a common symptom of neuropathic pain. However, it is not fully understood how inhibitory neurons in the DH regulate sensory responses in surrounding neurons and modulate sensory transmission. In this study, we established a novel experimental method to analyze temporal activity of DH neurons during the optogenetically induced disinhibition state by combining extracellular recording and optogenetics. We investigated how specific and temporally restricted dysfunction of DH inhibitory neurons affected spinal neuronal activities evoked by cutaneous mechanical stimulation. In behavioral experiments, the specific and temporally restricted spinal optogenetic suppression of DH inhibitory neurons induced mechanical hypersensitivity. Furthermore, this manipulation enhanced the mechanical responses of wide dynamic range (WDR) neurons, which are important for pain transmission, in response to brush and von Frey stimulation but not in response to nociceptive pinch stimulation. In addition, we examined whether a neuropathic pain medication, mirogabalin, suppressed these optogenetically induced abnormal pain responses. We found that mirogabalin treatment attenuated the abnormal firing responses of WDR neurons and mechanical hypersensitivity. These results suggest that temporally restricted and specific reduction of spinal inhibitory neuronal activity facilitates the mechanical responses of WDR neurons, resulting in neuropathic-like mechanical allodynia which can be suppressed by mirogabalin. Our optogenetic methods could be useful for developing novel therapeutics for neuropathic pain.

Topics: Humans; Hyperalgesia; Neuralgia; Neurons; Optogenetics; Spinal Cord; Spinal Cord Dorsal Horn

Mirogabalin has been attracting attention for treating peripheral neuropathic pain. The package insert recommends that mirogabalin should be titrated depending on renal function. Here, we investigated the relationship between dose titration patterns and adherence, and persistence of mirogabalin treatment.. Peripheral neuropathic pain patients who initiated mirogabalin between March 2020 and May 2021 were identified using an electronic medical record database. The dose titration pattern was described according to degrees of renal function. Regression analyses were performed to compare adherence and persistence between the patients with and without titration.. Of the 4,138 identified patients, 1,696 (41.0%) titrated the dose within 45 days and were more adherent than those without titration (Adjusted odds ratio: 1.75, 95% CI 1.21, 2.54). Of the total 952 patients with renal function parameters, 229 (24.1%) titrated to the effective dose within 45 days and were less likely to discontinue than those without titration (Adjusted hazard ratio: 0.57, 95% CI 0.40, 0.81).. Mirogabalin dose titration was associated with better adherence and persistence. It is important for mirogabalin treatment to determine the initial prescription dose based on renal function and subsequent dose titration according to the package insert.. UMIN000047313.

Topics: Bridged Bicyclo Compounds; Electronic Health Records; Humans; Kidney; Neuralgia

Patients with dry eye disease (DED) sometimes complain of ocular pain. DED-related ocular pain has many similarities with neuropathic pain. Mirogabalin, a novel ligand for the α2δ subunit of voltage-gated calcium channels, is approved for treating neuropathic pain in Japan. This study aimed to investigate the effect of mirogabalin on hyperalgesia and chronic ocular pain in a rat DED model.. DED was induced in female Sprague Dawley rats by unilaterally excising the external lacrimal gland (ELG) and Harderian gland (HG). After 4 weeks of ELG and HG removal, tear production (pH threads) and corneal epithelial damage (fluorescein staining) were evaluated. Corneal hyperalgesia and chronic pain were analyzed, respectively, by measuring capsaicin-induced eye-wiping behavior and c-Fos expression in the trigeminal nucleus. Mirogabalin (10 or 3 mg/kg) was evaluated for effects on DED-induced hyperalgesia and chronic ocular pain.. Tear production was significantly lower in DED-induced eyes than in control eyes. Corneal damage was significantly higher in DED eyes than in control eyes. Hyperalgesia and chronic ocular pain were detected 4 weeks after ELG and HG removal. Five days of mirogabalin administration significantly suppressed capsaicin-induced eye-wiping behavior, which indicated the suppression of ocular hyperalgesia. Administration of 10 mg/kg mirogabalin significantly reduced c-Fos expression in the trigeminal nucleus, which indicated the amelioration of chronic ocular pain.. Mirogabalin suppressed DED-induced hyperalgesia and chronic ocular pain in a rat DED model. Our findings suggested that mirogabalin might effectively alleviate chronic ocular pain in patients with DED.

Topics: Animals; Capsaicin; Chronic Pain; Dry Eye Syndromes; Eye Pain; Female; Hyperalgesia; Neuralgia; Rats; Rats, Sprague-Dawley; Tears

Psychiatric disorders such as anxiety and depression are frequently observed in neuropathic pain patients, and negatively impact their quality of life. Mirogabalin is a novel ligand for the α. To provide further information on the pharmacological profile of mirogabalin and its utility for chronic pain therapy, we investigated its anxiolytic effects in an experimental animal model for neuropathic pain.. In chronic constriction injury (CCI) model rats, mechanical hypersensitivity was determined by the von Frey test. Anxiety- and depression-related behaviours were evaluated using the elevated plus maze test and forced swimming test, respectively.. CCI model rats showed sustained tactile allodynia followed by anxiety-related behaviours, not depression-related behaviours. The tactile allodynia (significant decreases in paw withdrawal threshold) developed within 2 weeks after model preparation, whereas the anxiety-related behaviours (significant decreases in the number of entries and time spent in open arms and significant increases in time spent in closed arms) were observed at 5 weeks but not 4 weeks after model preparation. Single oral administration of mirogabalin (3 or 10 mg/kg) dose-dependently alleviated the above-mentioned anxiety-related behaviours and tactile allodynia.. CCI model rats showed anxiety-related behaviours in a time-dependent manner in the elevated plus maze test. Mirogabalin alleviated both the anxiety-related behaviours and tactile allodynia in CCI model rats. Mirogabalin may provide effective anxiety relief as well as pain relief in patients with neuropathic pain.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Bridged Bicyclo Compounds; Calcium Channel Agonists; Disease Models, Animal; Hyperalgesia; Male; Neuralgia; Rats

Mental disorders including anxiety and depression are common comorbidities in fibromyalgia patients, and exert a profound impact on their quality of life. Mirogabalin, a novel ligand for the α. Male Sprague-Dawley rats received two intramuscular injections of acidic saline (pH 4.0) into the gastrocnemius muscle. After the development of tactile allodynia demonstrated by decreased paw withdrawal threshold to von Frey filaments, anxiety-like behaviours were evaluated using the open field test and the elevated plus maze test.. Sluka model rats exhibited anxiety-like behaviours in the open field test (significant decreases in distance travelled and time spent in the central area, and significant increases in time spent in the wall area) and the elevated plus maze test (significant decreases in time spent in the open arms and significant increases in time spent in the closed arms). A single oral dose of mirogabalin (3 or 10 mg/kg) significantly alleviated and normalised these anxiety-like behaviours.. Sluka model rats exhibited anxiety-like behaviours in the open field test and the elevated plus maze test, but mirogabalin alleviated these behaviours. Mirogabalin might thus have the potential to relieve anxiety in fibromyalgia patients.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Bridged Bicyclo Compounds; Calcium Channels, L-Type; Elevated Plus Maze Test; Fibromyalgia; Male; Neuralgia; Open Field Test; Pain Threshold; Rats; Rats, Sprague-Dawley

Mirogabalin, which is approved for the treatment of peripheral neuropathic pain in Japan, is a ligand for the α2δ subunit of voltage-gated calcium channels. Both pregabalin and mirogabalin act as nonselective ligands at the α2δ-1 and α2δ-2 subunits. Mirogabalin has a unique binding profile and long duration of action. Pregabalin has been reported to produce intolerable adverse effects in some patients. This study investigated outcomes associated with mirogabalin administration in patients with peripheral neuropathic pain who ceased treatment with pregabalin.. We retrospectively assessed peripheral neuropathic pain using the neuropathic pain screening questionnaire (NeP score) in 187 patients (58 men, 129 women) who were treated with mirogabalin. All patients had switched from pregabalin to mirogabalin due to lack of efficacy or adverse events. Differences in the treatment course (i.e., numeric rating scale (NRS) scores) were compared using one-way analysis of variance with Bonferroni post hoc tests.. The mean age of the patients was 72.3 years (range, 30-94 years), and the mean duration of disease was 37 months (range, 3-252 months). After treatment with mirogabalin for 1 week, NRS scores significantly decreased compared with baseline and continued to decrease over time. After 8 weeks, NRS scores improved by ≥ 30% from baseline in 113 patients (69.3%). Twenty-four patients (12.8%) stopped mirogabalin treatment due to adverse events. Somnolence (26.7%), dizziness (12.3%), edema (5.9%), and weight gain (0.5%) were noted as adverse events of mirogabalin.. The results of this investigation indicate that mirogabalin is safe and effective for reducing peripheral neuropathic pain.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Bridged Bicyclo Compounds; Female; Humans; Male; Middle Aged; Neuralgia; Pain Measurement; Pregabalin; Retrospective Studies; Surveys and Questionnaires; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Analgesics, Opioid; Area Under Curve; Bridged Bicyclo Compounds; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neuralgia; Retrospective Studies; Treatment Outcome; Young Adult

Mirogabalin, which is a novel ligand for the α₂δ subunit of voltage-gated calcium channels, is under development for the treatment of pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Mirogabalin possesses unique binding characteristics to α₂δ subunits and potent and long-lasting analgesic effects in peripheral neuropathic pain models. In the present study, we investigated the analgesic effects of mirogabalin in a rat model of spinal cord injury as an experimental animal model for central neuropathic pain. The spinal cord injury model was established by acute compression of the spinal cord at the T6/7 level with a microvascular clip in male rats. Twenty-eight days after spinal cord injury, the animals received the test compound orally, and the paw withdrawal threshold to mechanical stimulation was determined using the von Frey test at 0 (before administration), 2, 4, 6, 8, and 24 h after administration. The area under the curve of the paw withdrawal threshold (paw withdrawal threshold AUC) was also calculated. In rats subjected to spinal cord injury, mechanical allodynia was demonstrated by a decreased paw withdrawal threshold. A single oral administration of mirogabalin (2.5, 5, or 10 mg/kg) significantly increased the paw withdrawal threshold. The effects of mirogabalin were still significant 6 or 8 h after administration. The paw withdrawal threshold AUC was significantly higher in the treated animals than in the control group. In conclusion, mirogabalin showed potent and long-lasting analgesic effects in a rat model of spinal cord injury and may therefore provide effective pain relief for patients with central neuropathic pain.

Topics: Analgesics; Animals; Bridged Bicyclo Compounds; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperalgesia; Male; Neuralgia; Pain Threshold; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Time Factors