Rs11726196 Single-Nucleotide Polymorphism of the Transient Receptor Potential Canonical 3 (TRPC3) Gene Is Associated with Chronic Pain.

Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the TRPC3 gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the TRPC3 gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain.

Single-Nucleotide Polymorphisms of the PAR2 and IL-17A Genes Are Significantly Associated with Chronic Pain.

Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case-control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine.

Heparan sulfate 3-O-sulfotransferase 4 is genetically associated with herpes zoster and enhances varicella-zoster virus-mediated fusogenic activity.

Acute pain that is associated with herpes zoster (HZ) can become long-lasting neuropathic pain, known as chronic post-herpetic neuralgia (PHN), especially in the elderly. HZ is caused by the reactivation of latent varicella-zoster virus (VZV), whereas PHN is not attributed to ongoing viral replication. Although VZV infection reportedly induces neuronal cell fusion in humans, the pathogenesis of PHN is not fully understood. A genome-wide association study (GWAS) revealed significant associations between PHN and the rs12596324 single-nucleotide polymorphism (SNP) of the heparan sulfate 3-O-sulfotransferase 4 (HS3ST4) gene in a previous study. To further examine whether this SNP is associated with both PHN and VZV reactivation, associations between rs12596324 and a history of HZ were statistically analyzed using GWAS data. HZ was significantly associated with the rs12596324 SNP of HS3ST4, indicating that HS3ST4 is related to viral replication. We investigated the influence of HS3ST4 expression on VZV infection in cultured cells. Fusogenic activity after VZV infection was enhanced in cells with HS3ST4 expression by microscopy. To quantitatively evaluate the fusogenic activity, we applied cytotoxicity assay and revealed that HS3ST4 expression enhanced cytotoxicity after VZV infection. Expression of the VZV glycoproteins gB, gH, and gL significantly increased cytotoxicity in cells with HS3ST4 expression by cytotoxicity assay, consistent with the fusogenic activity as visualized by fluorescence microscopy. HS3ST4 had little influence on viral genome replication, revealed by quantitative real-time polymerase chain reaction. These results suggest that HS3ST4 enhances cytotoxicity including fusogenic activity in the presence of VZV glycoproteins without enhancing viral genome replication.

Genome-wide association study identifies candidate loci associated with chronic pain and postherpetic neuralgia.

BACKGROUND: Human twin studies and other studies have indicated that chronic pain has heritability that ranges from 30% to 70%. We aimed to identify potential genetic variants that contribute to the susceptibility to chronic pain and efficacy of administered drugs. We conducted genome-wide association studies (GWASs) using whole-genome genotyping arrays with more than 700,000 markers in 191 chronic pain patients and a subgroup of 89 patients with postherpetic neuralgia (PHN) in addition to 282 healthy control subjects in several genetic models, followed by additional gene-based and gene-set analyses of the same phenotypes. We also performed a GWAS for the efficacy of drugs for the treatment of pain. RESULTS: Although none of the single-nucleotide polymorphisms (SNPs) were found to be genome-wide significantly associated with chronic pain (p ≥ 1.858 × 10-7), the GWAS of PHN patients revealed that the rs4773840 SNP within the ABCC4 gene region was significantly associated with PHN in the trend model (nominal p = 1.638 × 10-7). In the additional gene-based analysis, one gene, PRKCQ, was significantly associated with chronic pain in the trend model (adjusted p = 0.03722). In the gene-set analysis, several gene sets were significantly associated with chronic pain and PHN. No SNPs were significantly associated with the efficacy of any of types of drugs in any of the genetic models. CONCLUSIONS: These results suggest that the PRKCQ gene and rs4773840 SNP within the ABCC4 gene region may be related to the susceptibility to chronic pain conditions and PHN, respectively.

Comparison of dermatomal sensory block following ultrasound-guided transversus abdominis plane block by the lateral and posterior approaches: A randomized controlled trial.

BACKGROUND AND AIMS: Ultrasound (US)-guided transversus abdominis plane (TAP) block is used as a part of a multimodal analgesic regimen in the postoperative period. Lateral approach TAP block (LTAP) has been widely used for postoperative analgesia after lower abdominal surgeries. Posterior approach TAP block (PTAP), which is achieved by more posterior blockade of the anterior ramus of the spinal nerve, also provides profound postoperative analgesia after transverse lower abdominal incision. We investigated the dermatomal sensory block following LTAP and PTAP under US guidance. MATERIAL AND METHODS: Twenty-seven adult female patients undergoing the laparoscopic resection of ovarian tumors under general anesthesia were randomly divided into two groups, those receiving LTAP (Group L, n = 14) and those receiving PTAP (Group P, n = 13). Before induction of general anesthesia, all patients were given bilateral TAP blocks with 15 ml of 0.25% levobupivacaine on each side under US guidance, and the sensory blockade was evaluated. RESULTS: The data are expressed as median (interquartile range [IQR]). PTAP produced a median sensory blockade to sharp touch of three dermatomal segments (IQR 3-4), the most cephalad being T-10 (IQR T-9-T-10), whereas LTAP produced blockade of a median of two segments (IQR 2-2, P = 0.002), the most cephalad being T-10 (IQR T-10-T-10, P = 0.005). CONCLUSIONS: PTAP produced a sensory block that involved a greater number of dermatomes and involvement of more cephalad dermatome blocked to sharp touch, compared with LTAP under US guidance.

[Device for quantitative analysis of perception and pain sensation].

The article describes an analysing device that measures the perception and intensity of pain quantitatively. While it is not necessarily true that psychological aspect is totally irrelevant to pain measurement, this device is remarkable in that it is capable of measuring the intensity of pain felt by the patient more objectively by using electric stimuli. The feature of this device is that it uses a non-pain heteresthesia for measuring the intensity of pain. The device is compact, light-weight, and portable. Unlike VAS that requires only a scale, the device requires a person to carry out the measurement. Nevertheless, as the National Health Insurance (NHI) coverage has been approved, introduction of the device may be facilitated in terms of budget for the purchase and labor. The device is useful to better understand not only the intensity of pain but also the pathological conditions, resulting in more appropriate treatment, by (1) comparing degree of pain or VAS values taken by a multicenter study with those of a patient; (2) using both degree of pain and VAS; and (3) multiple measurements of degree of pain and VAS in one case.

Appearance of burning abdominal pain during cesarean section under spinal anesthesia in a patient with complex regional pain syndrome: a case report.

INTRODUCTION: The mechanism of complex regional pain syndrome (CRPS) was reported as being related to both the central and peripheral nervous systems. Recurrence of CRPS was, reportedly, induced by hand surgery in a patient with upper limb CRPS. However, there is no documentation of mechanical allodynia and burning abdominal pain induced by Cesarean section under spinal anesthesia in patients with upper limb CRPS. CASE: We report the case of a patient who suffered from burning abdominal pain during Cesarean section under spinal anesthesia 13 years after the occurrence of venipuncture-induced CRPS of the upper arm. The patient's pain characteristics were similar to the pain characteristics of her right arm during her previous CRPS episode 13 years earlier. In addition, mechanical allodynia around the incision area was confirmed after surgery. We provided ultrasound-guided rectus sheath block using 20 mL of 0.4% ropivacaine under ultrasound guidance twice, which resulted in the disappearance of the spontaneous pain and allodynia. DISCUSSION: The pain relief was probably related to blockade of the peripheral input by this block, which in turn would have improved her central sensitization. CONCLUSION: Our report shows that attention should be paid to the appearance of neuropathic pain of the abdomen during Cesarean section under spinal anesthesia in patients with a history of CRPS.

Effect of spinal anesthesia for elective cesarean section on cerebral blood oxygenation changes: comparison of hyperbaric and isobaric bupivacaine.

We used near-infrared spectroscopy (NIRS) to evaluate cerebral blood oxygenation changes in subjects undergoing cesarean section under spinal anesthesia (SP) with hyperbaric bupivacaine (group H, 27 subjects) or isobaric bupivacaine (group I, 15 subjects). In group H, total-Hb, oxy-Hb, and mean blood pressure (MBP) within 20 min after SP were significantly lower than the baseline values. In contrast, there was no significant change from baseline in total-Hb, oxy-Hb, or MBP in group I after SP. Total-Hb and MBP in group H were significantly lower than those in group I within 10 min after SP. There was no significant change of deoxy-Hb, tissue oxygen index, or heart rate from baseline in either of the groups. These results suggest that isobaric bupivacaine may be superior to hyperbaric bupivacaine for preventing a decrease of maternal cerebral blood flow after SP for cesarean section.

[Tramadol/acetaminophen combination tablets].

Tramadol/acetaminophen fixed-dose combination tablets (Tramse) combine tramadol, a centrally acting week opioid analgesic, with low-dose acetaminophen. The action of tramadol may be described as a weak agonist at the mu-opioid receptor, inhibition of serotonin reuptake, and inhibition of noradrenaline reuptake. The second component in these tablets, acetaminophen mainly appears to act through central mechanism. Chronic pain may be broadly classified into nociceptive, neuropathic and mixed. Tramset may exert additive or synergic benefits in treating the multiple mechanism of pain. Clinical studies have revealed its efficacy and safety for a variety of pain condition such as chronic low back pain, rheumatoid arthritis, fibromyalgia and painful diabetic peripheral neuropathy. It is expected that Tramset is going to induce pain relief and to improve disturbance of daily life in patients with intractable chronic pain. However overuse of Tramset may induce severe adverse effects such as addiction, abuse and hepatotoxicity. Therefore clinician should continuously assess pain intensity, activity of daily life, mode of its consumption, and adverse effects after prescription.

Incidence and prognosis of persistent pain induced by venipuncture for blood sampling: an observational study over a 5-year period.

OBJECTIVE: The purpose of this study was to determine the incidence and prognosis of persistent and neuropathic pain induced by venipuncture for blood sampling in clinical practice. DESIGN & SETTING: We investigated the incidence of persistent and neuropathic pain after venipuncture for blood sampling and evaluated the prognosis of patients with neuropathic pain at Nihon University Itabashi Hospital, Japan, based on an observational study. SUBJECTS: Outpatients who required venipuncture for blood sampling at the laboratory room of Nihon University Itabashi Hospital between 2004 and 2008 were included as study subjects. RESULTS: In the present study, of the 587,551 venipunctures performed at our hospital between 2004 and 2008, the incidences of persistent and neuropathic pain after venipuncture were 1 in every 4,418 venipunctures (133/587,551) and 1 in every 30,923 venipunctures (19/587,551), respectively. All the 19 patients who were identified as having neuropathic pain recovered completely. CONCLUSIONS: We demonstrated that the incidence of persistent pain after venipuncture for blood sampling is low and that its prognosis is good.

The effect of dexmedetomidine on arterial-cardiac baroreflex function assessed by spectral and transfer function analysis.

PURPOSE: The α(2)-adrenergic receptor agonist dexmedetomidine reportedly weakens heart rate (HR) responses to 'rapid' (during a few seconds) reduction in arterial pressure, but does not affect HR responses to 'gradual' (during 60 s) reduction in arterial pressure. As the speed of neurotransmission along the parasympathetic nerve is relatively rapid, alteration of parasympathetic-mediated arterial-cardiac baroreflex function plays a more important role in HR responses to 'rapid' changes in arterial pressure. We therefore hypothesized that dexmedetomidine attenuates parasympathetic-mediated arterial-cardiac baroreflex function. METHODS: Twelve healthy men received placebo, low-dose (loading, 3 µg/kg/h for 10 min; maintenance, 0.2 µg/kg/h for 60 min) (low-DEX), or moderate-dose (loading, 6 µg/kg/h for 10 min; maintenance, 0.4 µg/kg/h for 60 min) (moderate-DEX) dexmedetomidine infusions in a randomized, double-blind, crossover study. Before and after 70 min of infusion, arterial-cardiac baroreflex function was assessed by spectral and transfer function analysis between arterial pressure variability and HR variability. RESULTS: The high-frequency power of systolic arterial pressure (SAP) variability increased significantly with low-DEX and moderate-DEX infusions (significant interaction effects, P = 0.005), whereas the high-frequency power of R-wave-R-wave interval (RRI) variability (as an index of cardiac parasympathetic activity) did not change significantly at any dose infusions. Then, transfer function gain in the high-frequency range (as an index of parasympathetic arterial-cardiac baroreflex) decreased significantly with low-DEX and moderate-DEX infusions (significant interaction effects, P = 0.007). CONCLUSIONS: The present results suggest that dexmedetomidine attenuates parasympathetic-mediated arterial-cardiac baroreflex function, implying weakened HR response to 'rapid' reduction in arterial pressure.

Cauda equina syndrome following combined spinal and epidural anesthesia: a case report.

PURPOSE: To describe a case of complete neurological recovery from cauda equina syndrome lasting ten months following spinal anesthesia with 0.5% hyperbaric bupivacaine and epidural anesthesia with ropivacaine, and to discuss the possible mechanisms involved. CLINICAL FINDINGS: A 79-yr-old man with Paget's disease was scheduled for surgery to remove a skin tumour below his scrotum. He had no history of radicular pain or back pain and no pre-existing neurologic disorder. Surgery was performed with the patient in the supine position. He received 0.5% hyperbaric bupivacaine intrathecally for the procedure and ropivacaine through an epidural catheter for postoperative pain management. After catheter removal, the patient developed urinary retention, fecal incontinence, and perianal hypoesthesia. A lumbosacral magnetic resonance imaging (MRI) revealed no tumour, infarction, degeneration, spinal stenosis, or compression on the cauda equina nerve roots. A diagnosis of cauda equina syndrome was made, and the etiology was thought to be toxicity of bupivacaine either alone or in combination with ropivacaine. After three months, the patient reported some return of sensation at the perianal area, with complete resolution at four months. At the ten-month follow-up visit, the patient had recovered from his urinary retention and fecal incontinence. CONCLUSION: This case suggests that spinal anesthesia, even with an ordinary dose of hyperbaric 0.5% bupivacaine, might induce cauda equina syndrome in older patients.

[PainVision].

Visual analogue pain scale (VAS) is believed to be a gold standard to evaluate pain intensity. However in practice it is not so easy to evaluate pain intensity by conventional assessment tool including VAS. Especially VAS is considered to be affected by a patient's mental state. Recently a newly developed device PainVision PS-2100 (Nipro Co., Osaka, Japan) for the quantitative analysis of perception and pain sensation was used to obtain pain intensity as "degree of pain". A new device PainVision calculating a "degree of pain" in addition to VAS may be a helpful tool to assess pain in cancer pain.

[Comprehensive evaluation of the effect of triazolam on amnesia during the preoperative period].

BACKGROUND: Triazolam reportedly has greater amnesic potential than other benzodiazepines. The present study was designed to investigate whether this amnesic potential can be applied to surgical patients as premedication, thus relieving them from postoperatively remembering preoperative fears of anesthesia and surgery. METHODS: We prospectively evaluated the effect on amnesia of triazolam administered during the preoperative period in 80 patients between 20-64 years of age (mean, 43.1 +/- 14.3 years) who underwent surgeries for non-malignant diseases under general anesthesia maintained with sevoflurane and nitrous oxide in oxygen throughout the operation, or general anesthesia maintained with the same anesthetics combined with epidural or spinal anesthesia. Patients with diseases or factors influencing the effect of triazolam, such as a history of mental diseases, recent sedative or antihistamine usage, or current sleep disturbances, were excluded from this study. Triazolam was administered to the 80 patients orally at a dose of 0.375 mg 60 minutes prior to entering the operating room. During structured interviews on postoperative day 1, the patients were asked to state what they remembered of the preoperative period. Amnesia was classified based on the patients' last memory before the anesthetic induction as follows: loss of memory from immediately after taking triazolam, loss of memory at departure from the ward, loss of memory at the entrance to the operating room, loss of memory at the operating table and some recall of events at the operating table. RESULTS: Interviews revealed that 26.3% of the patients experienced loss of memory immediately after taking triazolam, this number increasing to 28.8% of the patients at departure from the ward, 35.0% at the entrance to the operating room and 67.5% on the operating table. The remaining patients (32.5%) had some memory of the operating room and table. Triazolam caused no respiratory depression at the operating table, although 2 of the patients experienced dizziness, 1 patient had nausea and 1 patient felt heavy-headed during the period between taking triazolam and the induction of anesthesia. Although 13 patients had delayed emergence from general anesthesia, these patients remaining anesthetized even 5 minutes after the concentration of sevoflurane in the expired gas decreased and remained below 0.1 percent, all these patients emerged immediately after intravenous administration of flumazenil. CONCLUSIONS: The use of triazolam as premedication produced a high incidence of amnesia for preoperative events without causing respiratory depression. Triazolam appears to be a useful premedicant for surgical patients who wish to have no memory at the operating room.

[Effects of the induction of anesthesia with propofol on hemodynamics in patients with Parkinson's disease].

BACKGROUND: Patients with Parkinson's disease frequently suffer from impaired autonomic nervous function. To elucidate the effects of the induction of anesthesia with propofol on cardiovascular hemodynamics has become important, since the number of patients with Parkinson's disease undergoing deep brain stimulation under general anesthesia has increased recently. METHODS: Effects of induction with propofol in patients with Parkinson's disease on cardiovascular hemodynamics and autonomic nervous activity were compared with those of the control patients. Moreover, possible different effect on hemodynamics between the propofol alone and the combination of propofol and fentanyl for the induction were examined in patients with Parkinson's disease. RESULTS: Although heart rate or blood pressure was not different between patients with Parkinson's disease and the control patients before the induction, sympathetic vasomotor activity was lower in patients with Parkinson's disease than the control patients. The induction of anesthesia significantly decreased blood pressure in patients with Parkinson's disease. However the decreasing systolic blood pressure after the induction of anesthesia was more marked in patients with Parkinson's disease than the control patients. We did not find differences in the changes of blood pressure between the propofol alone and the combination of propofol and fentanyl in patients with Parkinson's disease. CONCLUSIONS: No abnormal responses to the induction of anesthesia with propofol were found in the patients with Parkinson's disease.

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

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.

Safety and Efficacy of Mirogabalin for Peripheral Neuropathic Pain: Pooled Analysis of Two Pivotal Phase III Studies.

PURPOSE: 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. METHODS: 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. FINDINGS: 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. IMPLICATIONS: This pooled analysis showed that mirogabalin was efficacious and well-tolerated by Asian patients with peripheral neuropathic pain.

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 different effects of midazolam and propofol sedation on dynamic cerebral autoregulation.

BACKGROUND: Although midazolam and propofol reduce cerebral blood flow (CBF) similarly, they generate different effects on the autonomic nervous system and endothelium-induced relaxation. Midazolam induces sympathetic dominance, whereas propofol induces parasympathetic dominance. Midazolam has no effect on endothelium-dependent relaxation, whereas propofol suppresses endothelium-dependent relaxation. Moreover, midazolam apparently constricts cerebral arterioles. We therefore hypothesized that midazolam and propofol have different effects on dynamic cerebral autoregulation. METHODS: Ten healthy male subjects received midazolam, propofol, and placebo administrations in a randomized, single-blind, crossover study. The modified Observer's Assessment of Alertness/Sedation scale was used to assess sedation depth. After reaching a target depth of sedation (Observer's Assessment of Alertness/Sedation scale score 3, responds only after name is called loudly and/or repeatedly) or after 15 minutes of normal saline administration as placebo, dynamic cerebral autoregulation was evaluated by spectral and transfer function analyses between mean arterial blood pressure variability in the radial artery measured by tonometry, and CBF velocity variability in the middle cerebral artery measured by transcranial Doppler ultrasonography. RESULTS: Steady-state CBF velocity decreased significantly with midazolam and propofol administration (significant interaction effects, P = 0.024). However, transfer function gain in the low-frequency range decreased significantly only with midazolam administration (significant interaction effects, P = 0.015), suggesting a reduced magnitude of transfer from mean arterial blood pressure oscillations to CBF fluctuations during midazolam sedation. CONCLUSION: Our results suggest that midazolam and propofol sedation have different effects on dynamic cerebral autoregulation despite causing equivalent decreases in steady-state CBF velocity. Only midazolam sedation is likely to improve dynamic cerebral autoregulation.

[Peripheral nerve injury in venipuncture].

To prevent peripheral nerve injury and neuropathic pain resulting from venipuncture, medical students and medical workers should be educated about the following points in clinical practice. First, the medial aspect of the antecubital fossa should not be punctured, to prevent injury to the median and medial anterobrachial cutaneous nerves. Second, the symptoms and signs of neuropathic pain resulting from venipuncture should be taught, to recognize the onset of neuropathic pain. Third, pharmacotherapy for the management of neuropathic pain should be taught to treat neuropathic pain resulting from venipuncture.