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

INTRODUCTION: Mirogabalin, 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. METHODS: This 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. RESULTS: Of 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. CONCLUSIONS: Mirogabalin switching from pregabalin is well tolerated and effective in pain management for peripheral neuropathic pain using a step-wise titration. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs031190113).

The impact of endoscopic thoracic sympathectomy on sudomotor function in patients with palmar hyperhidrosis.

PURPOSE: When performing endoscopic thoracic sympathectomy (ETS) in palmar hyperhidrosis patients, a device can be used to measure sweat volume pre- and postoperatively in order to assess indications and treatment effects. In this study, we measured changes in the dynamics of sweating in hyperhidrosis patients pre- and postoperatively and compared the values with those in healthy subjects without hyperhidrosis. METHODS: The patient group comprised 25 persons with palmar hyperhidrosis who were scheduled for ETS. The dynamics of sweating was measured at 1 day prior to surgery and at 2 days postoperatively, in 18 patients at > 1 year postoperatively in another palmar hyperhidrosis group, and in 20 healthy subjects without hyperhidrosis. A device for measuring local sweat volume was applied at the thenar eminence of both palms. Indicators established were basal sweat rate (BSR; mg/min/cm2), peak sweat rate (PSR; mg/min/cm2) during mental stress (sympathetic sweating response), sweat volume (SV), and sweat time (ST; s). RESULTS: After surgery, all of the indicators were significantly reduced in hyperhidrosis patients and there was very little response to mental stress. The subgroup of these patients assessed at > 1 year after ETS showed a trend of increased BSR similar to that of healthy subjects. These changes did not correlate with the extent of the removal surgery. Preoperatively, hyperhidrosis patients had significantly greater BSR, PSR, and SV and longer ST than healthy subjects. CONCLUSION: All of the sweating parameters were increased in palmar hyperhidrosis patients prior to surgery. Immediately after ETS, all these parameters were significantly reduced. At > 1 year after ETS, the BSR had increased to a level similar to that of the healthy volunteers, although PSR did not respond to mental stress.

Development of an application for management of drug holidays in perioperative periods.

Before surgery and other invasive treatments, decisions must be made on whether to discontinue drugs and provide appropriate drug holidays especially for antithrombotic drugs, and this is made difficult by the large number of available drugs and associated guidelines. We have therefore developed an online application for perioperative drug discontinuation and resumption management, named Saga Application for Management of Drug Holidays in PeriOperative Periods (SAMPOP).Multidisciplinary medical staff at Saga University Hospital (SUH) worked together to build an evidence-based Perioperative Drug Discontinuation Management Database (PDDMD) and developed the user-friendly SAMPOP online application via preliminary verification at SUH. From September 2018 to February 2020, 420 medical staff at SUH, including physicians, nurses, and pharmacists, installed and tested SAMPOP.Rate per surgical procedure for forgetting to discontinue antithrombotic drugs preoperatively decreased from 0.18% to 0.09% as of August 2019, 12 months after the introduction of SAMPOP (P = .1359). In addition, six months later, it decreased further to 0.03% as of February 2020 (P = .0436). Forgetting to resume antithrombotic drugs postoperatively decreased from 0.20% to 0.02% as of August 2019, 12 months after the introduction of SAMPOP (P = .0008). There was no case of forgetting to resume the medication in the last 6 months.SAMPOP may be useful for management of drug holidays in the clinic and warrants further evaluation of its safety and efficacy.

Essential roles of C-type lectin Mincle in induction of neuropathic pain in mice.

Increasing evidence indicates that pattern recognition receptors (PRRs) are involved in neuropathic pain after peripheral nerve injury (PNI). While a significant number of studies support an association between neuropathic pain and the innate immune response mediated through Toll-like receptors, a family of PRRs, the roles of other types of PRRs are largely unknown. In this study, we have focused on the macrophage-inducible C-type lectin (Mincle), a PRR allocated to the C-type lectin receptor family. Here, we show that Mincle is involved in neuropathic pain after PNI. Mincle-deficient mice showed impaired PNI-induced mechanical allodynia. After PNI, expression of Mincle mRNA was rapidly increased in the injured spinal nerve. Most Mincle-expressing cells were identified as infiltrating leucocytes, although the migration of leucocytes was also observed in Mincle-deficient mice. Furthermore, Mincle-deficiency affected the induction of genes, which are reported to contribute to neuropathic pain after PNI in the dorsal root ganglia and spinal dorsal horn. These results suggest that Mincle is involved in triggering sequential processes that lead to the pathogenesis of neuropathic pain.

Interleukin-27 controls basal pain threshold in physiological and pathological conditions.

Numerous studies have shown that pain sensation is affected by various immune molecules, such as cytokines, in tissues comprising the sensory pathway. Specifically, it has been shown that interleukin (IL)-17 promotes pain behaviour, but IL-10 suppresses it. IL-27 has been reported to have an anti-inflammatory effect through regulation of T cell differentiation, resulting in reduced IL-17 and induction of IL-10. Thus, we hypothesised that IL-27 would have some regulatory role in pain sensation. Here, we provide evidence that endogenous IL-27 constitutively controls thresholds for thermal and mechanical sensation in physiological and pathological conditions. Mice lacking IL-27 or its receptor WSX-1 spontaneously showed chronic pain-like hypersensitivity. Reconstitution of IL-27 in IL-27-deficient mice reversed thermal and mechanical hypersensitive behaviours. Thus, unlike many other cytokines induced by inflammatory events, IL-27 appears to be constitutively produced and to control pain sensation. Furthermore, mice lacking IL-27/WSX-1 signalling showed additional hypersensitivity when subjected to inflammatory or neuropathic pain models. Our results suggest that the mechanisms underlying hypersensitive behaviours caused by the ablation of IL-27/WSX-1 signalling are different from those underlying established chronic pain models. This novel pain control mechanism mediated by IL-27 might indicate a new mechanism for the chronic pain hypersensitivity.

Lusutrombopag (Mulpleta®) treatment in a patient with thrombocytopenia complicated by cirrhosis prior to continuous epidural anesthesia during renal artery embolization: a case report.

BACKGROUND: The oral thrombopoietin (TPO) receptor agonist lusutrombopag (Mulpleta®) was developed to improve thrombocytopenia in patients with chronic liver disease prior to elective invasive medical procedures. Mulpleta® was first approved for use in Japan in 2015 and in the USA in 2018. In the present report, we discuss a case in which pain management was performed during left renal artery embolization via continuous epidural anesthesia following oral administration of lusutrombopag. To our knowledge, this is the first report to discuss the use of lusutrombopag prior to epidural anesthesia. CASE PRESENTATION: The patient was a 78-year-old woman scheduled to undergo renal artery embolization to address a 3-cm aneurysm of the left renal artery. Fourteen days prior to the scheduled embolization procedure, the urologist was asked to insert an epidural catheter for perioperative and postoperative analgesia. Type C chronic cirrhosis was observed, and platelet count was 5.6 × 104/µL. Eleven days prior to embolization, oral lusutrombopag was initiated at a dosage of 3 mg/day (day 1). Oral lusutrombopag therapy was continued for 5 days, and platelet count on day 11 (i.e., the day prior to surgery) was 12.6 × 104/µL. An epidural catheter was inserted on day 12, following which embolization was performed. Platelet count on day 13 was 11.0 × 104/µL, and the catheter was removed on day 14. No symptoms of epidural hematoma or thrombosis were observed during the patient's disease course. CONCLUSIONS: As lusutrombopag is a relatively safe platelet-increasing agent, we believe that this drug can serve as a potential treatment option when performing elective epidural anesthesia in patients with chronic liver disease complicated by thrombocytopenia.

Changes in uncuffed endotracheal tube leak during laparoscopic inguinal herniorrhaphy in children.

The present study was conducted to investigate changes in uncuffed endotracheal tube (ETT) leak during laparoscopic surgery. The study included 31 patients aged between 1 and 6 years scheduled for elective laparoscopic inguinal herniorrhaphy. Inspiratory and expiratory tidal volumes (TVi and TVe) were measured during mechanical ventilation, and ETT leak was calculated using the formula-ETT leak = (TVi - TVe)/TVi × 100 (%), assessed at the following time-points-5 min after the start of mechanical ventilation (T1, baseline), just before the start of surgery (T2), 5 min after the induction of pneumoperitoneum with 15° Trendelenburg tilt (T3), and at the end of surgery (T4). Additionally, leak pressure was assessed after successful tracheal intubation (T0, baseline) at T2, T3 and T4. Uncuffed ETT leak significantly decreased at T3 compared with T1 (baseline). Leak pressure significantly increased at T3 and T4 compared with T0 (baseline). Further studies are needed in order to determine whether the results are universal and associated with clinically significant outcomes.

Effects of various antiepileptics used to alleviate neuropathic pain on compound action potential in frog sciatic nerves: comparison with those of local anesthetics.

Antiepileptics used for treating neuropathic pain have various actions including voltage-gated Na(+) and Ca(2+) channels, glutamate-receptor inhibition, and GABA(A)-receptor activation, while local anesthetics are also used to alleviate the pain. It has not been fully examined yet how nerve conduction inhibitions by local anesthetics differ in extent from those by antiepileptics. Fast-conducting compound action potentials (CAPs) were recorded from frog sciatic nerve fibers by using the air-gap method. Antiepileptics (lamotrigine and carbamazepine) concentration dependently reduced the peak amplitude of the CAP (IC50 = 0.44 and 0.50 mM, resp.). Carbamazepine analog oxcarbazepine exhibited an inhibition smaller than that of carbamazepine. Antiepileptic phenytoin (0.1 mM) reduced CAP amplitude by 15%. On the other hand, other antiepileptics (gabapentin, sodium valproate, and topiramate) at 10 mM had no effect on CAPs. The CAPs were inhibited by local anesthetic levobupivacaine (IC50 = 0.23 mM). These results indicate that there is a difference in the extent of nerve conduction inhibition among antiepileptics and that some antiepileptics inhibit nerve conduction with an efficacy similar to that of levobupivacaine or to those of other local anesthetics (lidocaine, ropivacaine, and cocaine) as reported previously. This may serve to know a contribution of nerve conduction inhibition in the antinociception by antiepileptics.

[Management of opioid-induced nausea and vomiting].

Opioids are available for patients with chronic non-cancer pain. At the start of treatment, side effects such as nausea and vomiting may occur. As these symptoms appear at a dose lower than that at which analgesic actions are achieved, preventive strategies are important. CTZ stimulation, vestibular stimulation, and motor stagnation of the digestive tract may be involved in the mechanism of opioid-induced nausea and vomiting (OINV). To prevent these symptoms, it is recommended that each mechanism-matched antiemetic agent be administered. Anti-dopaminergic, antihistaminergic, and digestive tract movement-enhancing agents are used as first-choice drugs, respectively. However, it must be considered that the long-term administration of antiemetic agents may cause extrapyramidal symptoms. It is also effective to use opioid rotation or change the administration route from oral to continuous subcutaneous administration. However, concerning chronic, non-cancer pain, the opioid rotation regimen is limited to a combination of codeine preparations, morphine preparations, and fentanyl patches. For long-term administration, the continuous intravenous/subcutaneous injection of opioids is not indicated.

Microvascular decompression for glossopharyngeal neuralgia through the transcondylar fossa (supracondylar transjugular tubercle) approach.

OBJECTIVE: Our surgical results were reviewed to clarify the cause of glossopharyngeal neuralgia (GPN) and the effects of the microvascular decompression (MVD) procedure. METHODS: Fourteen cases of idiopathic GPN were operated on through the transcondylar fossa (supracondylar transjugular tubercle) approach. Their clinical data and operative records were retrospectively reviewed. RESULTS: In every case, vascular compression on the glossopharyngeal nerve was found and MVD was performed without any major complications. In 13 of the 14 cases the neuralgia completely disappeared postoperatively. Recurrence of pain was found in 1 case. Offending vessels were the posterior inferior cerebellar artery (PICA) in 10 cases, the anterior inferior cerebellar artery (AICA) in 2 cases, and both arteries in 2 cases. In 10 of the 14 cases, the high-origin PICA formed an upward loop between the glossopharyngeal and vagus nerves, compressing the glossopharyngeal nerve upward. In those cases, the PICA was transposed and fixed to the dura mater by the stitched sling retraction technique, and MVD was very effective. CONCLUSION: The offending artery was the PICA in most cases. MVD is expected to be very effective, especially when the radiological images show the following 3 findings: 1) high-origin PICA, 2) the PICA making an upward loop, and 3) the PICA coursing the supraolivary fossette. The transcondylar fossa approach is suitable for transposing the PICA by the stitched sling retraction technique, and provides sufficient surgical results.

Endoscopic thoracic sympathectomy as a novel strategy for vasospastic angina refractory to medical treatments.

Although vasospastic angina (VSA) is usually controlled by medications, refractory or lethal cases are occasionally encountered. We performed bilateral endoscopic thoracic sympathectomy (ETS) in 5 male patients with refractory VSA. Prior to ETS, stellate ganglion blockade was performed in 4 patients to reduce VSA attacks and to confirm the effect of sympathetic blockade. Under endoscopic guidance, the second to fourth thoracic sympathetic ganglia were ablated with a YAG-laser. No patient had complications after ETS, including major sweating abnormalities. In 4 of 5 patients, ETS relieved all VSA symptoms. ST-segment elevation often detected before ETS was absent on repeated ambulatory 24-h Holter monitoring after ETS. ETS is an effective strategy for the treatment of refractory VSA.

Iodoform intoxication; a case report of prolonged consciousness disturbance in a patient with a high plasma iodine level.

This report describes a case in which a consciousness disturbance was associated with a high plasma iodine level and which improved after the removal of iodoform gauze that had been applied to infected wounds. A 71-year-old male with poorly controlled diabetes underwent a laminectomy for an epidural abscess. On the 6th and 8th postoperative days, he underwent debridement for fasciitis in the both arms and iodoform gauze was applied to the wounds (both arms and lumbar region) at the end of the first debridement and then changed every day. His consciousness then gradually deteriorated after the debridement. His plasma iodine level was measured and was shown to be remarkably high (6,280 microg/dl) 19 days after the laminectomy (13 days after the beginning of iodoform application). His consciousness recovered gradually with a concomitant decrease in the plasma iodine level. Three months after the removal of the iodoform he became almost alert. Caution should be exercised in using iodoform gauze because of the possibility that it could affect consciousness.

Primary palmar hyperhidrosis locus maps to 14q11.2-q13.

Primary palmar hyperhidrosis (PPH) is a unique disorder of unknown cause. It is characterized by excessive perspiration of the eccrine sweat gland in the palm, sole, and the axilla. It is presumed that PPH results from overactivation of the cholinergic sympathetic nerve or dysfunction of the autonomic nervous system. There have been no genetic studies on the disease. We performed a linkage analysis of 11 families including 42 affected and 40 unaffected members using genome-wide DNA polymorphic markers to identify the disease locus. Diagnosis of their PPH was made by direct inspection, interviewing and measurement of the sweating rate with perspirometer. Consequently, from data of three of the 11 families examined, the combined maximum two-point LOD scores of 3.08 and 3.16 (recombination fraction = 0) were obtained at the D14S283 and D14S264 loci, respectively, on chromosome 14q11.2-q13, under an assumption that two liability conditions depend on age. These regions were ruled out in eight other families. Haplotype analysis of the three families supported that one of the PPH locus is assigned at minimum to about a 6-cM interval between D14S1070 and D14S990 and at maximum to about a 30-cM interval between D14S1070 and D14S70. This is the first report of systemic mapping of the PPH locus.