Background
The International Association for the Study of Pain defined neuropathic pain as “pain caused by a lesion or disease of the somatosensory nervous system” [
1]. Neuropathic pain results in multiple symptoms, including spontaneous neurological pain, allodynia, hyperalgesia, and numbness, and results in decreases in quality of life (QOL) [
2]. In addition, neuropathic pain may become intractable [
2]. Chronic low back pain is known to be due to neuropathic as well as nociceptive pain mechanisms [
3,
4]. Patients with neuropathic pain show higher ratings for pain intensity with more comorbidities, such as depression panic/anxiety disorder, and sleep disorders than those with nociceptive pain [
4]. It is thus important to determine which factors contribute to neuropathic pain at an early stage and start appropriate drug therapy [
5]. Unfortunately, current treatment methods are not always satisfactory [
5].
Pregabalin is a ligand for the α2δ subunit of voltage-sensitive calcium channels and is recommended as the first-line drug for neuropathic pain in guidelines around the world [
6]. It decreases the release of neurotransmitters such as glutamate, noradrenalin, and substance P, which leads to pain relief [
7]. Pregabalin has been used in patients with neuropathic pain and shown to be a cost-effective treatment [
8,
9] that has a positive impact on QOL [
10,
11]. It is generally well tolerated [
12], and most adverse events are mild to moderate [
13]. Pregabalin binds to the α2δ-1 and α2δ-2 subunits of presynaptic, voltage-dependent calcium channels, which are widely distributed throughout the central and peripheral nervous systems [
14]. The most frequently reported side effects of pregabalin include dizziness and somnolence, which are related to the central nervous system (CNS) [
14]. Therefore, the clinical utility of pregabalin may be limited by CNS adverse events [
14].
Mirogabalin, which is a potent and specific ligand for the α2δ subunit of voltage-gated calcium channels, is an orally administered gabapentinoid developed for the treatment of peripheral neuropathic pain in Japan [
15,
16]. This agent has the distinguishing feature of persistently binding to the α2δ-1 subunit, which plays an important role in neuropathic pain [
16]. This new drug is reportedly well tolerated and well absorbed following oral administration and was first approved for peripheral neuropathic pain in 2019.
Although there are many positive reports associated with pregabalin, some patients have moderate adverse events [
14]. Tetsunaga et al. reported that somnolence (46.9%), dizziness (18.8%), weight gain (9.4%), and rash (4.7%) were noted as side effects of pregabalin [
17]. No reports regarding the treatment outcomes with mirogabalin in patients who experienced moderate adverse events with pregabalin treatment have been published. In the present study, we examined the outcomes with mirogabalin as a rescue drug in patients with peripheral neuropathic pain who developed moderate side effects from pregabalin treatment.
Discussion
In this study, we used mirogabalin to treat patients with peripheral neuropathic pain who switched from pregabalin treatment to mirogabalin treatment due to lack of efficacy or adverse events. Mirogabalin is a new drug for the treatment of peripheral neuropathic pain, and to our knowledge, there have been no reports of its clinical outcomes for patients who were previously treated with pregabalin. Mirogabalin exerted a significant analgesic effect within 1 week and was associated with mild CNS adverse effects.
Guidelines for the pharmacologic management of neuropathic pain recommend drugs acting at α2δ subunits of voltage-gated calcium channels, serotonin–norepinephrine reuptake inhibitors, and tricyclic antidepressants as first-line agents, neurotropin and tramadol as second-line agents, and opioids as third-line agents [
25]. Several other scientific associations and guidelines recommend gabapentinoids as first-line drugs for the treatment of neuropathic pain [
26‐
29]. Mirogabalin, a ligand for the α2δ subunits (α2δ-1 and α2δ-2) of voltage-sensitive calcium channels in the CNS, was approved as a medication for pain relief in patients with peripheral neuropathic pain in 2019 in Japan. Mirogabalin reportedly relieved diabetic peripheral neuropathic pain in a dose-dependent manner in Asian patients with diabetic peripheral neuropathic pain and was associated with only mild adverse events [
30]. It was also shown to be effective and well tolerated in the management of postherpetic neuralgia in Asian patients [
31]. In the present study, which included only patients who withdrew from pregabalin treatment due to adverse events or lack of efficacy, we found that mirogabalin was an effective analgesic and that few patients stopped treatment due to adverse events.
In vitro studies of its pharmacologic action have demonstrated that mirogabalin had a higher binding affinity for the human and rat α2δ subunit than pregabalin [
16]. In a dissociation rate analysis, the dissociation half-lives of mirogabalin from the α2δ-1 and α2δ-2 subunits were 11.1 h and 2.4 h, respectively, compared with 1.4 h for pregabalin at both subunits [
16]. These reports indicated that mirogabalin has potent and selective binding affinities for the human and rat α2δ subunit and a slower dissociation rate for the α2δ-1 subunit than the α2δ-2 subunit compared with pregabalin [
16]. These findings support our results that even patients who discontinued pregabalin because of its CNS effects experienced fewer adverse events when they were treated with mirogabalin. In this study, the initial dose was reduced to 5 mg/day in patients with impaired renal function or in the elderly patients. In patients with impaired renal function, we consider that the initial dose of 10 mg/day was too high, which may cause adverse events. However, in this study, the incidence of adverse events was nearly the same in the patients with impaired renal function as in the patients with normal renal function, and there was no significant difference in the magnitude of NRS improvement after 8 weeks of treatment. Therefore, we consider that administering a reduced dose is useful in patients with impaired renal function. It has also been reported that continued oral mirogabalin treatment increases the pain threshold over time [
16]. In animal models of fibromyalgia, mirogabalin treatment has been shown to significantly decrease pain scores due to chronic allodynia [
32]. Neuropathic pain results in higher pain scores than nociceptive pain [
4]. In this study, the dose of mirogabalin was increased in response to pain over an 8-week treatment period. The magnitude of NRS improvement was 40% or more at the 10 mg/day, 20 mg/day, and 30 mg/day doses, and the analgesic effect of mirogabalin was evident after only 1 week, suggesting a good analgesic effect of mirogabalin.
The α2δ-1 subunit plays an important role in the onset and pathological persistence of neuropathic pain. Α2δ-1 expression levels correlated with tactile allodynia development were significantly increased in rats with spinal cord injury [
33]. Knockdown of the α2δ-1 subunit by antisense oligodeoxynucleotides reportedly inhibited tactile allodynia in rat models [
33,
34]. Overexpression of the α2δ-1 subunit resulted in enhanced currents, altered kinetics, and voltage-dependence of voltage-gated calcium channel activation in sensory neurons; exaggerated and prolonged dorsal horn neuronal responses to mechanical and thermal stimulations in the periphery; and enhanced pain-related behavior [
35]. To the best of our knowledge, no study has addressed the association between the α2δ-2 subunit and pain. Edvardson et al. reported the importance of the α2δ-2 subunit, which is dominantly expressed in cerebellar Purkinje cells, in the normal physiology of the human brain [
36]. Binding to the α2δ-1 subunit contributes to analgesic effects, whereas binding to the α2δ-2 subunit appears to contribute to undesirable CNS effects, such as somnolence [
37‐
39]. These studies indicated that gabapentinoids exert their analgesic effects via the α2δ-1 subunit, and the α2δ-1 subunit thus plays a major role in neuropathic pain. These findings suggested that the α2δ-2 subunit may be implicated in the CNS adverse events commonly seen with pregabalin treatment. These findings also suggested that the selective actions of mirogabalin on the α2δ-1 and α2δ-2 subunits may maximize its analgesic effects while minimizing CNS adverse events. The potent binding affinity of mirogabalin with the α2δ-1 subunit and its long dissociation half-life from the α2δ-2 subunit may thus make mirogabalin an attractive agent for the treatment of peripheral neuropathic pain. Although 12.8% of patients in the present study discontinued treatment because of adverse events, mirogabalin was generally well tolerated.
Although the results of the present study suggest that mirogabalin might be an alternative treatment option for the treatment of peripheral neuropathic pain, the present study has some limitations. First, both pregabalin and mirogabalin are ligands for the α2δ subunit of voltage-sensitive calcium channels. However, this study had no pretrial protocol and is a case series without a comparison or placebo group. We did not compare these two drugs in this study. Thus, the results cannot be clearly attributed to mirogabalin administration. Second, this study had a short observation period. Although most patients treated with mirogabalin for 8 weeks maintained their weight within ± 5% of their baseline weight, weight gain can be an issue with mirogabalin when used for a longer period. A third limitation was a lack of determination of the best screening questionnaire for neuropathic pain. Neuropathic pain screening questionnaires include painDETECT [
4], the spine painDETECT questionnaire, which is a screening tool for neuropathic pain caused by spinal disorders [
40], and the NeP score used in this study. We considered that if the NeP scores were high, there would be little decrease in NRS scores after mirogabalin treatment, making it suitable as a baseline index. However, the use of other neuropathic pain screening questionnaires might have led to different results. We consider that the assessment and diagnosis of neuropathic pain should follow an identical algorithm that is widely used as a current international standard for the diagnosis of neuropathic pain, and it should specifically include (1) an assessment of the range of pain that is neuroanatomically plausible, (2) the suggestion of a lesion or disease of the somatosensory system, and (3) objective findings of sensory damage that are observed in the neuroanatomically innervated region of the damaged nerve or tests that are performed to provide a diagnosis of a neurological lesion or disease that accounts for the neuropathic pain. Despite these limitations, mirogabalin, a recently developed agent, showed promising results in patients with peripheral neuropathic pain.
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