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.

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.

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.

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).

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.

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.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SUMMARY FOR TABLE OF CONTENTS: 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.

Hospital-pharmacy cooperative training and drug-taking compliance in outpatients with chronic pain: a case-control study.

Purpose: Chronic pain is a common symptom that is suffered by 20% of the overall population in Japan. Although pharmacotherapy is critical for the treatment of chronic pain, there are no reports on the pharmacies. In the present study, we examined the effect of hospital-community pharmacy cooperative training on improving drug-taking compliance, pain relief, anxiety, insomnia, and motor function in patients with chronic pain. Patients and methods: The subject sample included 87 patients with chronic pain who were examined for the first time at the outpatient services department of Nihon University Itabashi Hospital. Patients were interviewed to obtain information regarding drugs used before and after the treatment, habitually used community pharmacies, presence of cooperative training with Itabashi Hospital, drug-taking compliance, and side effects. We compared treatment outcomes before and after consultation using the Brief Pain Inventory (BPI), Hospital Anxiety and Depression Scale (HADS), EuroQol Group measure (EQ-5D) for quality of life, Athens Insomnia Scale, and Locomo 25 scale for motor function. Results: In patients who used community pharmacies that perform training, drug-taking compliance was significantly better, and a significant improvement was observed in the scores of BPI, HADS Anxiety, Athens Insomnia, and Locomo 25. Conclusion: Pharmacotherapy is essential for the treatment of chronic pain. To this end, appropriate drugs with proper drug management guidance are indispensable. In this study, the use of community pharmacies that have undergone cooperative training with hospitals improves pain and anxiety. This is achieved through proper drug management guidance, shared awareness of drug information, and achievement of better drug-taking compliance. To improve the quality of treatment for chronic pain, involvement of community pharmacies such as by providing accurate information is essential. In the future, expanding cooperative training with hospitals may further help reassure patients, facilitate drug-taking, and improve the quality of treatment for chronic pain.

Mirogabalin for the management of postherpetic neuralgia: a randomized, double-blind, placebo-controlled phase 3 study in Asian patients.

This study investigated the safety and efficacy of mirogabalin, a novel, potent, selective ligand of the α2δ subunit of voltage-dependent Ca channels, for the treatment of postherpetic neuralgia (PHN). In this multicenter, double-blind, placebo-controlled phase 3 study, Asian patients ≥20 years with PHN were randomized 2:1:1:1 to placebo or mirogabalin 15, 20, or 30 mg/day for up to 14 weeks (NCT02318719). The primary efficacy endpoint was the change from baseline in average daily pain score at week 14, defined as a weekly average of daily pain (0 = "no pain" to 10 = "worst possible pain," for the last 24 hours). Of 765 patients randomized, 763 received ≥ 1 dose of the study drug and were included in the analysis; 303, 152, 153, and 155 received placebo, mirogabalin 15, 20, or 30 mg/day, respectively. A total of 671 (87.7%) patients completed the study. At week 14, the difference in average daily pain score least squares mean vs placebo was -0.41, -0.47, and -0.77, respectively; all mirogabalin groups showed statistical significance. The most common treatment-emergent adverse events were somnolence, nasopharyngitis, dizziness, weight increase, and edema, and all of them were mild or moderate in severity. Mirogabalin was superior to placebo in all groups for relieving PHN and appeared well tolerated.

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.

Anesthesia for cesarean section in a patient with isolated unilateral absence of a pulmonary artery / Anestesia para cesariana em paciente com ausência unilateral isolada de artéria pulmonar

Abstract Background and objectives: Congenital unilateral absence of a pulmonary artery (UAPA) is a rare anomaly. Although there are several reports regarding pregnancy in patients with unilateral absence of a pulmonary artery, there are no case reports describing anesthesia for Cesarean section in a patient with unilateral absence of a pulmonary artery. Case report: We present a patient with unilateral absence of a pulmonary artery who underwent Cesarean sections twice at the ages of 24 and 26 years under spinal anesthesia for surgery and epidural analgesia for postoperative pain relief. Both times, spinal anesthesia and epidural analgesia enabled successful anesthesia management without the development of either pulmonary hypertension or right heart failure. Conclusion: Spinal anesthesia combined with epidural analgesia is a useful anesthetic method for a Cesarean section in patients with unilateral absence of a pulmonary artery.

Resumo Justificativa e objetivos: A ausência congênita unilateral de uma artéria pulmonar (ACAP) é uma anomalia rara. Embora existam vários relatos sobre pacientes grávidas com ACAP, não há relatos de casos que descrevam anestesia para cesariana em pacientes com ACAP. Relato de caso: Apresentamos uma paciente com ACAP que foi submetida a duas cesarianas, aos 24 e 26 anos, sob raquianestesia para a cirurgia e analgesia epidural para a dor no pós-operatório. Nas duas cesarianas, a raquianestesia e a analgesia epidural possibilitaram o manejo bem-sucedido da anestesia, sem a ocorrência de qualquer hipertensão pulmonar ou insuficiência cardíaca direita. Conclusão: Raquianestesia combinada com analgesia epidural é um método anestésico útil para cesarianas em pacientes com ACAP.

[Anesthesia for cesarean section in a patient with isolated unilateral absence of a pulmonary artery]. / Anestesia para cesariana em paciente com ausência unilateral isolada de artéria pulmonar.

BACKGROUND AND OBJECTIVES: Congenital unilateral absence of a pulmonary artery (UAPA) is a rare anomaly. Although there are several reports regarding pregnancy in patients with unilateral absence of a pulmonary artery, there are no case reports describing anesthesia for Cesarean section in a patient with unilateral absence of a pulmonary artery. CASE REPORT: We present a patient with unilateral absence of a pulmonary artery who underwent Cesarean sections twice at the ages of 24 and 26 years under spinal anesthesia for surgery and epidural analgesia for postoperative pain relief. Both times, spinal anesthesia and epidural analgesia enabled successful anesthesia management without the development of either pulmonary hypertension or right heart failure. CONCLUSION: Spinal anesthesia combined with epidural analgesia is a useful anesthetic method for a Cesarean section in patients with unilateral absence of a pulmonary artery.

Anesthesia for cesarean section in a patient with isolated unilateral absence of a pulmonary artery.

BACKGROUND AND OBJECTIVES: Congenital unilateral absence of a pulmonary artery (UAPA) is a rare anomaly. Although there are several reports regarding pregnancy in patients with unilateral absence of a pulmonary artery, there are no case reports describing anesthesia for Cesarean section in a patient with unilateral absence of a pulmonary artery. CASE REPORT: We present a patient with unilateral absence of a pulmonary artery who underwent Cesarean sections twice at the ages of 24 and 26 years under spinal anesthesia for surgery and epidural analgesia for postoperative pain relief. Both times, spinal anesthesia and epidural analgesia enabled successful anesthesia management without the development of either pulmonary hypertension or right heart failure. CONCLUSION: Spinal anesthesia combined with epidural analgesia is a useful anesthetic method for a Cesarean section in patients with unilateral absence of a pulmonary artery.

The Effects of Flumazenil After Midazolam Sedation on Cerebral Blood Flow and Dynamic Cerebral Autoregulation in Healthy Young Males.

BACKGROUND: It is unknown whether flumazenil antagonizes the decrease in cerebral blood flow or the alteration in dynamic cerebral autoregulation induced by midazolam. We, therefore, investigated the effects on cerebral circulation of flumazenil administered after midazolam, to test our hypothesis that, along with complete reversal of sedation, flumazenil antagonizes the alterations in cerebral circulation induced by midazolam. METHODS: Sixteen healthy young male subjects received midazolam followed by flumazenil. The modified Observer's Assessment of Alertness/Sedation (OAA/S) scale and bispectral index (BIS) were used to assess levels of sedation/awareness. For evaluation of cerebral circulation, steady-state mean cerebral blood flow velocity (MCBFV) was measured by transcranial Doppler ultrasonography. In addition, dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between mean arterial pressure (MAP) variability and MCBFV variability. RESULTS: During midazolam sedation, defined by an OAA/S score of 3 (responds only after name is called loudly and/or repeatedly), BIS, steady-state MAP, steady-state CBFV, and transfer function gain decreased significantly compared with baseline. After flumazenil administration, an OAA/S score of 5 (responds readily to name spoken in a normal tone) was confirmed. Then, BIS and MAP returned to the same level as baseline. However, steady-state MCBFV showed a further significant decrease compared with that under midazolam sedation, and the decreased transfer function gain persisted. CONCLUSIONS: Contrary to our hypothesis, the present results suggest that despite complete antagonism of the sedative effects of midazolam, flumazenil would not reverse the alterations in cerebral circulation induced by midazolam.

[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.

[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.

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.

Differential effects of mild central hypovolemia with furosemide administration vs. lower body suction on dynamic cerebral autoregulation.

Diuretic-induced mild hypovolemia with hemoconcentration reportedly improves dynamic cerebral autoregulation, whereas central hypovolemia without hemoconcentration induced by lower body negative pressure (LBNP) has no effect or impairs dynamic cerebral autoregulation. This discrepancy may be explained by different blood properties, by degrees of central hypovolemia, or both. We investigated the effects of equivalent central hypovolemia induced by furosemide administration or LBNP application on dynamic cerebral autoregulation to test our hypothesis that mild central hypovolemia due to furosemide administration enhances dynamic cerebral autoregulation in contrast to LBNP. Seven healthy male subjects received 0.4 mg/kg furosemide and LBNP, with equivalent decreases in central venous pressure (CVP). Dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between beat-to-beat mean arterial blood pressure (MAP) and mean cerebral blood flow velocity (MCBFV). CVP decreased by ∼3-4 mmHg with both furosemide administration (∼26 mg) and LBNP (approximately -20 mmHg). Steady state MCBFV remained unchanged with both techniques, whereas MAP increased significantly with furosemide administration. Coherence and transfer function gain in the low and high frequency ranges with hypovolemia due to furosemide administration were significantly lower than those due to LBNP (ANOVA interaction effects, P < 0.05), although transfer function gain in the very low frequency range did not change. Our results suggest that although the decreases in CVP were equivalent between furosemide administration and LBNP, the resultant central hypovolemia differentially affected dynamic cerebral autoregulation. Mild central hypovolemia with hemoconcentration resulting from furosemide administration may enhance dynamic cerebral autoregulation compared with LBNP.