Α2δ Ligands Research Articles

Heme oxygenase-1 in the spinal cord plays crucial roles in the analgesic effects of pregabalin and gabapentin in a spared nerve-injury mouse model

IntroductionNeuropathic pain remains one of the most intractable types of pain; although calcium channel α2δ ligands, such as pregabalin and gabapentin, are classified as first-line drugs, they have only modest efficacy. Heme oxygenase-1 (HO-1) signaling attenuates glial activation during neuropathic pain. Thus, this study aimed to investigate the effects of the blood–brain barrier (BBB)-permeable HO-1 inhibitor, tin protoporphyrin IX (SnPP), or the BBB-impermeable HO-1 inhibitor, zinc (II) protoporphyrin IX (ZnPP), on the analgesic efficacy of pregabalin and gabapentin. Additionally, we examined the effects of co-administration of SnPP with pregabalin or gabapentin on the expression of glial markers or other genes. MethodsNeuropathic pain was induced by spared nerve injury (SNI) of the sciatic nerve. The mechanical threshold was tested using the von Frey filaments. The expression of spinal glial markers or other genes was examined using reverse transcription polymerase chain reaction. ResultsSystemic HO-1 inhibition reversed the mechanical antiallodynic effects of pregabalin and gabapentin, although peripheral HO-1 inhibition did not alter the mechanical antiallodynic effects of either pregabalin or gabapentin. Intrathecal injection of SnPP or ZnPP abolished the mechanical antiallodynic effects of pregabalin and gabapentin. Pregabalin and gabapentin increased HO-1, arginase-1, and endogenous opioid precursor preproenkephalin gene expression and decreased the expression of glial markers, interleukin-1β, and inducible nitric oxide synthase. ConclusionsThis study suggests that spinal HO-1 plays a crucial role in the analgesic effects of calcium channel α2δ ligands through the attenuation of glial activation and endogenous opioid release.

A review of a new voltage-gated Ca2+ channel α2δ ligand, mirogabalin, for the treatment of peripheral neuropathic pain

ABSTRACT Introduction Neuropathic pain (NeP) is a chronic and refractory condition in many patients, and its treatment is a challenge for physicians. A new voltage-gated Ca2+ channel α2δ ligand, mirogabalin, has a high specific binding affinity for the α2δ subunit, with a slower dissociation rate for α2δ-1 than α2δ-2 compared to that of pregabalin. Mirogabalin was shown to be effective in NeP animal models, with a margin of safety between central nervous system side effects and the analgesic effect of the dose. It exerted a favorable analgesic effect, was well tolerated in patients with peripheral NeP (P-NeP), and was first approved in Japan in 2019 and subsequently in Korea and Taiwan in 2020. Areas covered 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. Expert opinion 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.

Switching From Pregabalin to Mirogabalin in Patients with Peripheral Neuropathic Pain: A Multi-Center, Prospective, Single-Arm, Open-Label Study (MIROP Study).

IntroductionMirogabalin, which is a selective ligand of the α2δ subunit of voltage-gated Ca2+ channels, was recently approved in Japan for peripheral neuropathic pain. The α2δ ligands, including mirogabalin and pregabalin, are associated with significant risk of adverse events (AEs) such as somnolence or dizziness, leading to poor compliance and subsequent inefficacy. Safety and efficacy data for switching patients from pregabalin to mirogabalin are scarce.MethodsThis prospective, single-arm, open-label study involving ten participating centers in Japan recruited patients aged ≥ 20 years with peripheral neuropathic pain [visual analog scale (VAS) score ≥ 40 mm]. Where necessary, patients underwent a 1-week tapering period to reduce their pregabalin dose, after which pregabalin was stopped and mirogabalin dose was increased using a step-wise dose titration. Patients underwent dose increases after the first and second weeks if there were no tolerability issues, followed by the effective doses until the end of the study (4 weeks). The primary endpoint was the incidence of somnolence, dizziness, and peripheral edema; secondary endpoints included changes in VAS score. AEs were monitored for safety.ResultsOf 157 patients who provided informed consent, 152 patients were enrolled; 136 (89.5%) patients completed the study. The overall incidences of somnolence, dizziness, and peripheral edema were 41.4, 15.8, and 2.6%, respectively. Most patients (> 70%) experienced mild AEs, and one patient experienced a severe AE (dizziness). Most patients (> 70%) were able to achieve dose titration to an effective dose. Overall mean VAS score significantly decreased (Δ15.7 mm, p < 0.0001) by the end of the study.ConclusionsMirogabalin switching from pregabalin is well tolerated and effective in pain management for peripheral neuropathic pain using a step-wise titration.Trial RegistrationJapan Registry of Clinical Trials (jRCTs031190113).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40122-021-00255-y.

Pharmacologic Treatment of Restless Legs Syndrome.

Restless legs syndrome (RLS)/Willis-Ekbom disease is a neurologic disorder characterized by a strong desire to move when at rest (usually in the evening) and paraesthesia in their lower legs. The most widely used therapies for first-line treatment of RLS are dopaminergic drugs; however, their long-term use can lead to augmentation. α2δ Ligands, opioids, iron, glutamatergic drugs, adenosine, and sleep aids have been investigated as alternatives. The pathogenesis of RLS is not well understood. Despite the efficacy of dopaminergic drugs in the treatment of this disorder, unlike in Parkinson’s disease dopaminergic cell loss in the substantia nigra has not been observed in RLS. The etiology of RLS is likely complex, involving multiple neural pathways. RLS-related genes identified in genome-wide association studies can provide insight into the mechanistic basis and pathophysiology of RLS. Here we review the current treatments and knowledge of the mechanisms underlying RLS.

Cost-Effectiveness of Mirogabalin for the Treatment of Diabetic Peripheral Neuropathic Pain in Taiwan

ObjectivesTo 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. MethodsA 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. ResultsA 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. ConclusionEconomic 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.

Metabolism, excretion, and pharmacokinetics of [14C]mirogabalin, a novel α2δ ligand, in healthy volunteers following oral administration

The metabolism, excretion, and pharmacokinetics of mirogabalin were investigated following a single oral administration of [14C]mirogabalin at 30 mg/5.55 MBq to six healthy male subjects. The mean recovery values of radioactivity in urine and faeces were 96.85 and 1.21%, respectively. The main component of radioactivity in the plasma, urine, and faeces was mirogabalin. A204-4455 (lactam form), mirogabalin N-glucuronide, and glucuronide of oxidized A204-4455 were detected as minor components in the specimens. Renal clearance of mirogabalin was higher than the glomerular filtration rate of the human kidneys, indicating renal secretion is involved in the clearance. In vitro studies revealed that UDP-glucuronosyltransferase produced two metabolites: A204-4455, formed via mirogabalin acylglucuronide, and a ring-opened form of mirogabalin N-glucuronide. Mirogabalin was absorbed almost completely, and was eliminated via urine. A part of the orally administered dose of mirogabalin was metabolized through glucuronidation at the amine and carboxylic acid moiety, which represents the primary metabolic pathway.

Analgesic characteristics of a newly developed α2δ ligand, mirogabalin, on inflammatory pain.

Mirogabalin is a novel α2δ ligand approved in Japan for the treatment of peripheral neuropathic pain. However, the sites of action of α2δ ligands to produce analgesic effects on inflammatory pain remain unclear. In this study, we investigated the analgesic effect and site of action of mirogabalin using the rat formalin test, an acute inflammatory pain model. Mirogabalin was administered orally, intrathecally, and intracerebroventricularly. Open field tests were performed to evaluate the effect of oral-, intrathecally, and intracerebroventricularly administered mirogabalin on locomotor activity and orientation ability. Oral mirogabalin produced an analgesic effect when the formalin test was performed 4 h, but not 1 or 2 h, after oral administration. Intrathecal, but not intracerebroventricular, administration of mirogabalin produced analgesic effects when mirogabalin was administered 10 min before formalin injection. These analgesic effects were not antagonized by idazoxan, an α2 adrenergic antagonist; WAY100135, a 5-HT1A antagonist; or naloxone, an opioid receptor antagonist. Mirogabalin attenuated moving distances 1 and 2 h after oral administration and 10 min after intracerebroventricular administration, but not 10 min after intrathecal administration. In the oral administration group, the time course of the analgesic effect was different from that of moving distance. In the intracerebroventricular group, mirogabalin attenuated moving distances but did not produce an analgesic effect. In the intrathecal group, mirogabalin produced an analgesic effect but did not affect moving distances. These findings suggest that the analgesic effect of mirogabalin on the rat formalin test is mediated by spinal action and not by the activation of α2, 5-HT1A, or opioid receptors, and that the inhibitory effect of mirogabalin on moving distances is mediated by the supraspinal brain.

A Clinical Study of Nine Cases with the Novel α2δ Ligand Mirogabalin for Orofacial Pain

A Clinical Study of Nine Cases with the Novel α2δ Ligand Mirogabalin for Orofacial Pain

Long-term safety and efficacy of mirogabalin in Asian patients with postherpetic neuralgia: Results from an open-label extension of a multicenter randomized, double-blind, placebo-controlled trial.

Postherpetic neuralgia (PHN) is a condition that results from nerve dysfunction following an episode of acute herpes zoster (shingles). Mirogabalin is a novel, selective oral α2δ ligand that demonstrated safety and efficacy in a multicenter, randomized, double-blind, placebo-controlled 14-week study in Asian patients with PHN. This 52-week, open-label extension study investigated the long-term safety and efficacy of flexible-dosage mirogabalin in Asian patients with PHN. This open-label extension study enrolled patients who completed the placebo-controlled study. Patients started with a dose of 5 mg mirogabalin twice daily (BID), which was followed by a flexible dose of 10 or 15 mg BID. During the study, patients assessed their pain using the Short-Form McGill Pain Questionnaire (SF-MPQ). Adverse events were monitored throughout the study. Of 239 enrolled patients, 184 (77.0%) completed the study and 185 patients (77.4%) received the 15 mg BID dose most during the treatment duration. Most treatment-emergent adverse events (TEAEs) were mild or moderate. The most common TEAEs were nasopharyngitis, somnolence, dizziness, weight increased, and edema. All SF-MPQ scales decreased from baseline to week 52. This study showed the safety and stable pain management of a long-term flexible dosing regimen of mirogabalin 10 or 15 mg twice daily for 52 weeks in patients with PHN. CLINICAL TRIAL REGISTERED AT CLINICALTRIALS.GOV:: NCT02318719. Mirogabalin-a novel α2δ oral ligand-was shown to be effective and well tolerated for treating postherpetic neuralgia (PHN) in an Asian multicenter, randomized, double-blind, placebo-controlled, 14-week study. This open-label, 52-week study was conducted as an extension of the double-blind study to demonstrate long-term safety and efficacy of mirogabalin.

Pharmacologic and Nonpharmacologic Treatment of Restless Legs Syndrome.

This article provides an updated practical guide for the treatment of primary restless legs syndrome (RLS). Articles that appeared after the American Academy of Neurology guideline search were reviewed according to the same evidence rating schedule. We found limited evidence for nonpharmacologic treatment options. In moderate to severe primary RLS, pharmacologic options may be considered, including iron suppletion, an α2δ ligand, a dopamine agonist, a combination of an α2δ ligand and a dopamine agonist, or oxycodone/naloxone. This article includes treatment options in case of augmentation.

Anxiolytic-like effects of mirogabalin, a novel ligand for α2δ ligand of voltage-gated calcium channels, in rats repeatedly injected with acidic saline intramuscularly, as an experimental model of fibromyalgia.

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 α2δ-subunit of voltage-gated calcium channels, shows analgesic effects in fibromyalgia and neuropathic pain models. To provide additional information regarding its potential utility for treating chronic pain, we examined its anxiolytic-like effects in rats repeatedly injected with acidic saline intramuscularly (Sluka model), as an experimental fibromyalgia model. 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 10mg/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.

Cost-effectiveness of mirogabalin for the treatment of post-herpetic neuralgia in Taiwan

Objectives: To assess the cost-effectiveness of mirogabalin versus no treatment or pregabalin in patients with post-herpetic neuralgia (PHN) from a third-party perspective in Taiwan.Methods: A Markov model, which was developed with 2-week cycles and 1-year time horizon from the Taiwanese National Health Insurance Administration perspective, consisted of three health states: “mild,” “moderate,” and “severe” pain. Average daily pain score (ADPS) was assessed at the end of each cycle. Patients either remained in, or transitioned from, their assigned health state to a different state according to their pain score changes. All patients entered the model in “moderate” (4 ≤ ADPS <7) or “severe” (7 ≤ ADPS ≤ 10) pain health states. Efficacy data was informed by the pivotal Phase III trial, or by a network meta-analysis (NMA). Utility values were obtained from published literature and cost data from Taiwanese clinical experts and the Taiwan National Health Insurance Administration, using 2018 New Taiwan dollar (NT$). Probabilistic analysis was conducted to test the robustness of base case results.Results: Head-to-head analysis showed mirogabalin 30 mg to be cost-effective versus placebo in PHN. The deterministic analysis estimated a quality-adjusted life years gain of 0.041 at an ICER of NT$11,231 (US$365) versus no treatment (ICER: NT$274,567 [US$8,900]). In the NMAs, mirogabalin was cost-effective compared to pregabalin 150 mg (ICER: NT$515,881 [US$16,720]) and 300 mg (ICER: NT$201,671 [US$6,535]). Mirogabalin 30 mg dominated pregabalin 600 mg. Results from sensitivity and scenario analyses confirmed these results.Conclusion: Mirogabalin 30 mg, a potent and selective α2δ ligand, is a cost-effective treatment option for PHN in Taiwan, with ICERs below the willingness-to-pay threshold.

Treating Pain in Diabetic Neuropathy: Current and Developmental Drugs.

There is a high prevalence of painful diabetic polyneuropathy (pDPN) with around one-third of all patients with diabetes suffering from pDPN. pDPN has debilitating consequences, with a major impact on morbidity and quality of life. Unfortunately, there is no globally licenced pharmacotherapy that modulates the underlying disease mechanisms to prevent or halt the progression of diabetic neuropathy. The cornerstone of treatment therefore remains optimising glycaemic control and cardiovascular risk factors, and symptom control. Evidence from placebo-controlled studies has shown that antidepressants and anticonvulsants are effective for alleviating pDPN. Current clinical guidelines recommend the treatment of pDPN through the use of amitriptyline (tricyclic antidepressant), duloxetine (serotonin norepinephrine reuptake inhibitor), gabapentin and pregabalin (α2-δ ligands), tramadol and tapentadol (μ receptor agonists and norepinephrine reuptake inhibitors) and topical agents such as capsaicin (transient receptor potential V1 receptor desensitizer), although the latter is known to cause degeneration of small nerve fibers. pDPN can be difficult to treat, which frustrates healthcare providers, patients and caregivers. There is an additional need for clinical trials of novel therapeutic agents and optimal combinations for the management of pDPN. This article reviews the pharmacological management of pDPN, emerging therapies, the difficulties of placebo response in clinical trials and novel proposed biomarkers of treatment response.

Anxiolytic effects of the novel α2δ ligand mirogabalin in a rat model of chronic constriction injury, an experimental model of neuropathic pain.

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 α2δ subunit of voltage-gated calcium channels and has unique binding characteristics to α2δ subunits and potent and long-lasting analgesic effects in neuropathic pain models. 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 2weeks 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 5weeks but not 4weeks after model preparation. Single oral administration of mirogabalin (3 or 10mg/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.

Efficacy and safety of mirogabalin for the treatment of fibromyalgia: results from three 13-week randomized, double-blind, placebo- and active-controlled, parallel-group studies and a 52-week open-label extension study

Objective: To investigate the efficacy and safety of mirogabalin, an α2δ ligand, in patients with fibromyalgia (FM).Methods: In three 13-week, multicenter, double-blind, phase 3 studies (studies A, B, and C), patients with FM (n = 1293, 1270, and 1301, respectively) were randomized (1:1:1:1) to placebo, pregabalin 150 mg twice daily, mirogabalin 15 mg once daily or mirogabalin 15 mg twice daily. The primary endpoint was the change in weekly average daily worst pain score (ADPS) at week 13. Key secondary endpoints included Patient Global Impression of Change and change in the Fibromyalgia Impact Questionnaire total score. Long-term safety of mirogabalin was assessed in a 52-week extension study.Results: Neither mirogabalin dose demonstrated a significant ADPS reduction from baseline vs. placebo at week 13 in any of the three studies. Pregabalin significantly reduced ADPS from baseline vs. placebo in studies B and C (p = .0008 and .0001, respectively). The effect of mirogabalin compared with placebo on key secondary endpoints was variable across the studies. Mirogabalin was well tolerated by most patients in the phase 3 studies; no unexpected adverse events occurring during the 52-week extension study.Conclusion: While both mirogabalin doses were well tolerated by most patients and showed potential for reducing pain associated with FM, 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.Clinical trial registration: NCT02146430; NCT02187159; NCT02187471; and NCT02234583 (extension study).

Update on Restless Legs Syndrome: from Mechanisms to Treatment.

To provide an overview of the molecular pathways and recent genetic risk loci associated with restless legs syndrome/Willis-Ekbom disease (RLS/WED) and describe the most recent treatment guidelines. Diagnostic criteria for RLS/WED now include a fifth criterion to differentiate from RLS/WED mimics. Our understanding of disease pathophysiology has improved, specifically regarding iron regulation in the brain and the role of other pathways such as opioid signaling and brain and spinal cord circuitry may play. Finally, several genetic risk loci have been described, including MEIS1 which is currently considered to be the strongest genetic risk factor for RLS/WED. Treatment guidelines now suggest α2δ ligands such as gabapentin enacarbil should be used as first-line treatment. The current literature focuses on disease pathways as well as the development of animal models based on genetic risk factors for RLS/WED. Updated treatment guidelines expand on first-line treatment options.

Blocking α2δ-1 Subunit Reduces Bladder Hypersensitivity and Inflammation in a Cystitis Mouse Model by Decreasing NF-kB Pathway Activation.

Bladder pain is frequently associated with bladder inflammation, as in conditions like interstitial cystitis (IC), for which current analgesic therapies have limited efficacy. The antinociceptive effect of alpha-2-delta (α2δ) ligands on inflammation-associated visceral pain like that experienced in cystitis has been poorly investigated. To investigate the effect of pregabalin (PGB), an α2δ ligand, we evaluated its impact on mechanical hyperalgesia in a mouse model of cystitis induced by cyclophosphamide (CYP). We further studied its effect on inflammation and NF-kB pathway activation. Acute cystitis was induced by intraperitoneal injection of 150 mg kg-1 of CYP in C57Bl/6J male mice. PGB was subcutaneously injected (30 mg kg-1) 3 h after CYP injection. The effect of PGB on CYP-induced mechanical referred hyperalgesia (abdominal Von Frey test), inflammation (organ weight, cytokine production, α2δ subunit level, NF-kB pathway activation) were assessed 1 h after its injection. In parallel, its effect on cytokine production, α2δ subunit level and NF-kB pathway activation was assessed in vitro on peritoneal exudate cells (PECs) stimulated with LPS. PGB treatment decreased mechanical referred hyperalgesia. Interestingly, it had an anti-inflammatory effect in the cystitis model by reducing pro-inflammatory cytokine production. PGB also inhibited NF-kB pathway activation in the cystitis model and in macrophages stimulated with LPS, in which it blocked the increase in intracellular calcium. This study shows the efficacy of PGB in hypersensitivity and inflammation associated with cystitis. It is therefore of great interest in assessing the benefit of α2δ ligands in patients suffering from cystitis.

Analgesic effects of mirogabalin, a novel ligand for α2δ subunit of voltage-gated calcium channels, in experimental animal models of fibromyalgia.

Mirogabalin, a novel ligand for the α2δ subunit of voltage-gated calcium channels, is under the development for the treatment of neuropathic pain. Mirogabalin specifically and potently binds to α2δ subunits, and it shows analgesic effects in both peripheral and central neuropathic pain models in rats. To expand pharmacological findings on mirogabalin and provide additional information of its potential for chronic pain therapy, we examined the effects of mirogabalin in 2 experimental models of fibromyalgia, namely, the intermittent cold stress model (ICS model) and the unilateral intramuscular acidic saline injection model (Sluka model). To induce chronic mechanical hypersensitivity, mice were placed under ICS conditions for 3days, whereas rats were injected twice with acidic saline (pH4) into the gastrocnemius muscle in a 4-day interval. The pain sensitivity was evaluated by the von Frey test. Long-lasting increases in pain response score or decreases in pain threshold to the von Frey stimulation were observed in both the ICS and Sluka models. Mirogabalin (1, 3, or 10mg/kg, p.o.) dose-dependently alleviated the mechanical hypersensitivity, with significant effects persisting at 6 or 8h following administration. The standard α2δ ligand, pregabalin (30mg/kg, p.o.), also significantly reduced the mechanical hypersensitivity. In summary, mirogabalin showed analgesic effects in the ICS model mice and in the Sluka model rats. Therefore, mirogabalin may have the potential to provide effective pain relief in patients with fibromyalgia.

Randomised clinical trial: pregabalin vs placebo for irritable bowel syndrome.

Pregabalin is a calcium channel α2δ ligand that modifies visceral hypersensitivity in IBS patients. Clinical data for pregabalin in IBS are lacking. To test the efficacy of pregabalin on gastrointestinal symptoms in IBS patients. A double-blind, placebo-controlled trial was performed. Adults meeting IBS Rome III criteria with ≥3 pain attacks per month were randomised to pregabalin 225mg vs placebo twice daily for 12weeks. Questionnaires were completed weekly. The primary endpoint was average pain Bowel Symptom Scale (BSS) scores weeks 9-12. An intention-to-treat analysis of covariance evaluated treatment effects on quantitative endpoints, adjusting for age and gender. Adequate relief and change in pain score were assessed using a chi-squared test. Eighty-five patients were recruited and randomised. Sample characteristics include: mean age 39.4 (SD=14.6); 73 (86%) female; 37 (44%) IBS-D, 29 (35%) IBS-M, 18 (21%) IBS-C. The pregabalin arm had lower average pain-BSS scores weeks 9-12 (25 vs 42, P=0.008). Compared with placebo, the overall IBS BSS severity score was lower in the pregabalin arm (26 vs 42, P=0.009). Differences were observed for the diarrhoea-BSS and bloating-BSS scores (P=0.049 and 0.016, respectively). No differences between groups were seen for constipation-BSS scores. Adequate relief was not different between the two arms (46% vs 36%, P=0.35). 63% pregabalin vs 45% placebo had a change in pain score ≥30 at week 12 from baseline (P=0.10). Post-treatment IBS-QoL scores did not differ between groups. This trial suggests that pregabalin may be beneficial for IBS abdominal pain, bloating and diarrhoea.

Non-dopaminergic vs. dopaminergic treatment options in restless legs syndrome.

Two types of drugs have been extensively investigated for the treatment of restless legs syndrome (RLS)/Willis-Ekbom disease (WED): dopamine agonists and α2δ ligands to the α2δ subunit of calcium channels. Comparative studies show that both classes of drugs are similarly effective in treating RLS symptoms over the short- and long-term. While dopamine agonists are more effective in treating periodic limb movements (PLMs), α2δ ligands are more effective in consolidating sleep. However, given the fact that dopamine agonists cause high rates of augmentation of symptoms, recent international guidelines recommend that whenever possible the initial treatment of choice should be an α2δ ligand. In fact, the most effective preventive strategy involves not using dopaminergic agents unless absolutely necessary. Indeed, should dopaminergic treatment be needed to handle the symptoms effectively, then it is recommended that the dopaminergic load be reduced by using the lowest effective dose for the shortest possible period of time. However, it must be taken into account that the only α2δ ligand approved for RLS/WED is gabapentin enacarbil, which is not yet available in Europe. Furthermore, recent studies have also reported on the efficacy of opioids as a second-line treatment of RLS/WED, following treatment failure with dopamine agonists. Recent guidelines have taken these new data into account and highlight that a low dose of an opioid (prolonged-release oxycodone or methadone) may be considered in patients with very severe augmentation of symptoms. Alternative non-dopaminergic treatment concepts based on glutamatergic and adenosinergic mechanisms are currently in development, and are likely to provide encouraging therapeutic alternatives.