Safety, tolerability, and efficacy of a selective gabapentinoid mirogabalin in neuropathic pain—a topical review

Gabapentin and pregabalin, known as gabapentinoids, have been used effectively as a monotherapy or in combination with other agents for managing chronic neuropathic pain due to various etiologies. These drugs act via α2δ-1 and α2δ-2 subunits of voltage-gated calcium channels (VGCCs) non-selectively. Due to its non-selective action, a certain group of patients reports central nervous system adverse effects like dizziness, drowsiness, somnolence, and cerebellar ataxia. Mirogabalin besylate is an orally administered next-generation gabapentinoid approved for use in diabetic neuropathy and post-herpetic neuralgia. It binds selectively and with greater affinity to the α2δ-1 and α2δ-2 subunits of human VGCCs and thus has lesser central nervous system adverse events making it more tolerable. We reviewed all articles in various categories, published in reputed databases since 2014 where mirogabalin was used to treat chronic neuropathic pain. Case series and open-label studies have demonstrated the safety and efficacy of mirogabalin in cancer pain and lumbar spine disease. Pharmacokinetic/pharmacodynamic studies have cautioned using full dose in patients with renal/hepatic impairment and along with drugs that could lead to adverse effects like sedatives and opioids. Dose up to 30 mg/day when administered as a twice-daily divided dose has been tolerated quite well with adequate pain relief in diabetic neuropathy and post-herpetic neuralgia. Mirogabalin appears to be a safe gabapentinoid in diabetic neuropathy and post-herpetic neuralgia. Further studies need to be conducted to explore the role of mirogabalin in cancer pain, postoperative pain, and neuropathic pain due to various other etiologies.


Background
Gabapentin and pregabalin are commonly used gabapentinoid anticonvulsants for managing neuropathic pain due to various etiologies including cancer pain (Derry et al., 2019;Wiffen et al., 2017;Bar, 2010). Several studies have shown that when gabapentinoids are used as monotherapy or as a part of a multimodal regimen, it has been successful in alleviating chronic neuropathic pain due to several etiologies (Moore et al., 2018).
Dizziness, drowsiness, somnolence, and cerebellar ataxia were frequently reported with gabapentinoids. Other issues like visual blurring, ataxia, and weight gain were noticed by researchers with the use of pregabalin only (Shaheen et al., 2019). This is because of the binding of gabapentin and pregabalin to the α2δ-1 and α2δ-2 subunits of VGCCs non-selectively. There has been a concern with the use of gabapentinoids in the form of serious neuropsychiatric adverse drug reactions which has been discussed in several articles recently (Tambon et al., 2021). A review of pharmacovigilance data from France has shown serious hepatic and hematological adverse events with the use of gabapentinoids (Deeks, 2019).

Introduction of mirogabalin besylate
Mirogabalin besylate is a new gabapentinoid that has been approved for use in diabetic neuropathic pain and post-herpetic neuralgia (Calandre et al., 2016). Mirogabalin selectively binds to and modulates the α2δ-1 subunits of VGCCs and also has a unique binding profile and long duration of action (Fig. 1). This topical review discusses the various chronic pain indications in various doses where mirogabalin was used in humans only and also the adverse effects encountered in the published articles.

Pharmacology and clinical uses of mirogabalin besylate
Mirogabalin is an orally administered gabapentinoid developed by Daiichi Sankyo, Japan, for the treatment of peripheral neuropathic pain like diabetic peripheral neuropathic pain, post-herpetic neuralgia, lumbar spine disease, and cancer pain. Mirogabalin tablets (Tarlige®; 2.5, 5, 10, and 15mg) were approved in Japan in January 2019 for the treatment of peripheral neuropathic pain based on the results of trials conducted in patients with diabetic peripheral neuropathic pain or post-herpetic neuralgia (Domon et al., 2018).
Mirogabalin binds selectively and with greater affinity to the α2δ-1 and α2δ-2 subunits of human VGCCs in vitro (Kd 13.5 and 22.7 nmol/L). Mirogabalin takes considerably longer to dissociate from α2δ-1 (dissociation half-life 11.1 h) than α2δ-2 in vitro (dissociation half-life 2.4 h) compared to pregabalin which required 1.4 h to dissociate from both α2δ-1 and α2δ-2 subunits of VGCCs. Mirogabalin has a tendency of greater affinity to and slow dissociation from the α2δ-1 subunits which leads to its longer duration of action. At the same time, it has demonstrated a low affinity to and fast dissociation from the α2δ-2 subunits in the cerebellum leading to lesser incidence of ataxia and other central nervous system adverse events. Mirogabalin is rapidly absorbed after when taken orally (median time to maximum plasma concentration (Tmax) of 0.5-1.5 h) single or multiple doses. With daily dosing, a steady-state plasma concentration gets achieved by day 3 (Brown et al., 2018). The adverse effects commonly encountered with the use of mirogabalin are dizziness (8-16%), somnolence (6-24%), and headache (6-14%). Issues like constipation, nausea, diarrhea, vomiting, edema, fatigue, and weight gain have rarely been encountered (Burgess et al., 2020).

Materials and methods
We used the keywords mirogabalin, chronic pain, neuropathic pain, cancer pain, and neuropathy to search MEDLINE, Embase, Web of Science, and Google Scholar databases. We included only those articles in the review where mirogabalin was used in human patients and volunteers. The full text of all articles was reviewed, and details like type of study, indication for which mirogabalin was used, number of patients, the dose of mirogabalin used, and key points of the articles were summarized in a tabular form. Animal studies, experimental studies like induced neuropathic pain, and review articles were excluded. However, those articles were used in the discussion for citing wherever necessary.

Study selection
Starting from the year 2014 till date, we retrieved 20 full-text articles in which mirogabalin was used by researchers for various indications like diabetic neuropathy, post-herpetic neuropathic pain, lumbar spine disease, fibromyalgia, and cancer pain (Fig. 2). The dose of mirogabalin ranged from 10 to 30 mg/day. Table 1 depicts various studies published starting from 2014 till 2020 where mirogabalin was used in various doses for several chronic pain indications. The results of the first study were by Vinik et al. published in 2014 which was a randomized, double-blind, placebo-and active comparator-controlled, adaptive proof-of-concept phase 2 study (Vinik et al., 2014). The authors enrolled 452 patients in seven groups; patients in 5 groups received different doses of mirogabalin (5-30 mg/day), the 6th group received pregabalin 300 mg/day, and the 7th Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Mirogabalin) group was placebo, for 5 weeks. In 20-mg and 30-mg arms, patients received mirogabalin twice daily in divided doses. At doses from 15 to 30 mg/day, mirogabalin provided statistically significant pain relief when compared to pregabalin, placebo, and fewer doses of mirogabalin and was well tolerated. Later, Hutmacher et al. analyzed central nervous system adverse events of single-dose versus twice-daily divided dosing of mirogabalin (in the group where the dose was 20 mg/day or more) from the article by Vinik et al. (Hutmacher et al., 2016). After analysis, the authors suggested that for a dose of 20 mg or more, a divided dosing results in lesser adverse effects thereby increasing tolerability.

Review of literature and discussion
Arnold et al. investigated the efficacy of mirogabalin in three 13-week, multicenter, double-blind, phase 3 studies in patients with fibromyalgia. Patients were randomized to receive placebo, pregabalin 150 mg twice daily, mirogabalin 15 mg once daily, or mirogabalin 15 mg twice daily. On analysis, authors concluded that although well tolerated the primary endpoint of significant pain reduction in patients on mirogabalin compared with placebo was not achieved in any of the three randomized controlled studies (Arnold et al., 2019). Later, Merante et al., (2017) published a commentary in which the author discussed the lessons learned from the negative outcome of the mirogabalin ALDAY phase 3 clinical program in pain associated with fibromyalgia, i.e., the paper by Arnold et al. (Merante, 2020). The author emphasized the need for a comprehensive patient-focused strategy to identify the challenges of fibromyalgia based on the patient perspective and study complexity; the need for a harmonized, patient-centric, global regulatory guidance accepted by regulatory agencies; and the importance of a phase 2 proof-of-concept, dose-ranging study before starting any phase 3 program in fibromyalgia.
Kanbayashi et al. enrolled 159 patients with various chronic neuropathic etiologies and eventually analyzed retrospective data of 133 patients who received less than 20 mg/day of mirogabalin for 2 weeks. The authors found that mirogabalin was effective in 85 of 133 patients. The authors suggested avoiding mirogabalin with concomitant opioids but found that it can be safely used with neurotrophin (NTP) which is a non-protein extract isolated from the inflamed skin of rabbits inoculated with vaccinia virus and used for the treatment of neuropathic pain (Kanbayashi et al., 2020). Caution needs to be exercised when using other drugs like opioids, benzodiazepines with mirogabalin. In a pharmacokinetic/pharmacodynamic study, Jansen et al. enrolled healthy  Mirogabalin was well tolerated in the doses with good pain relief. (Baba et al., 2020a) 16 60 Retrospective Lumbar spine disease 10-30 mg/ Mirogabalin was useful for the (Kim et al., volunteers on 30 mg/day mirogabalin and coadministered ethanol, lorazepam, zolpidem, and tramadol. Although there were no major adverse events as they were all healthy volunteers, patients should be warned and monitored if drugs with sedative effects are co-administered (Jansen et al., 2018a). In a pharmacokinetic study designed to understand dosing in patients with renal impairment, Yin et al. concluded that although no dose adjustment is required in mild renal impairment, reduction by 50% or 75% in subjects is necessary for patients with moderate or severe renal impairment (Yin et al., 2016). Dose adjustment in moderate to severe renal impairment was further established by Kato et al. in their study involving 30 Japanese patients with mild, moderate, and severe renal impairment who received a 5-mg dose of mirogabalin (Kato et al., 2018). However, mild to moderate hepatic dysfunction did not interfere with the dosing of mirogabalin. A dose of 15 mg once daily was well tolerated without any adverse events (Duchin et al., 2018). Nakanishi et al. prescribed mirogabalin in 34 patients who were not having cancer pain under effective control despite opioid titration (Nakanishi et al., 2020). The rate of effectiveness of this addition as per the authors was 88.2%. Two patients experienced mild central nervous system adverse effects but the medication was not discontinued. Except for this article, to date, mirogabalin has not been explored in managing cancer neuropathic pain in the form of randomized studies.
In a critical appraisal of gabapentinoids for managing neuropathic pain in cancer patients performed by Jordan et al., authors felt that studies were not designed appropriately, had a small sample size, lacked blinding, and had an inadequate follow-up. Moreover, high doses although offered better pain relief, the use was associated with neurological adverse events due to which therapy was discontinued or dosing changed. Well-designed, prospective, multicentric studies need to be planned to explore the unique properties of mirogabalin in managing cancer pain (Jordan et al., 2018). Alyoubi et al. performed a systematic review and meta-analysis of randomized controlled trials to investigate the analgesic efficacy of mirogabalin in diabetic peripheral neuropathic pain (Alyoubi et al., 2020). The authors concluded that mirogabalin treatment was superior to placebo and pregabalin in decreasing the average daily pain score over time and that mirogabalin was safe and associated with some adverse events that could be managed conservatively.
Current evidence suggests starting mirogabalin at a dose of 10 mg/day (preferably in divided doses, i.e., 5 mg twice daily and weekly increase by 10 mg/day every week to a maximum of 30 mg/day). The adverse effect profile and safety in renal and hepatic impairment makes it a viable option as an adjuvant in various chronic neuropathic pain conditions. From existing data, the neurological adverse effects appear mild and can be managed conservatively.

Limitations
This is a topical review and not a systematic review due to the type of data available, i.e., case series and a limited number of randomized controlled studies. Mirogabalin is not yet approved by the Food and Drug Administration (US-FDA) of the USA. This could be the reason behind limited data across other countries due to nonavailability.

Conclusions
Mirogabalin appears to be a selective, well-tolerated, next-generation gabapentinoid which appears to be effective in managing chronic neuropathic pain due to Mirogabalin was well tolerated and significantly reduced pain levels when used at a fixed dose of 7.5 mg once or twice daily in patients with renal impairment. (Baba et al., 2020c) diabetes, post-herpetic neuralgia, lumbar spine disease, and to some extent cancer in combination with other drugs. Further research is warranted to establish its safety and efficacy in managing postoperative pain, cancer pain, and fibromyalgia.