Analgesic Effects of Ketamine Infusion Therapy in Korean Patients With Neuropathic Pain: A 2-Week, Open-Label, Uncontrolled Study

BACKGROUND: The overexcitation of the N-methyl-D-aspartate receptor complex appears to play a critical role in the development of neuropathic pain, and ketamine acts as an antagonist to that receptor. Some publications have reported on the prominent relief of neuropathic pain with intravenous or subcutaneous ketamine infusions or a single-dose intravenous ketamine injection, despite adverse effects. OBJECTIVES: The primary objective of this study was to determine the analgesic effect of intravenous ketamine infusion therapy for neuropathic pain refractory to conventional treatments. Secondary objectives included identifying the variables related to the analgesic effect and the pain descriptors susceptible to ketamine infusion. METHODS: This 2-week, open-label, uncontrolled study was conducted in Korean patients with neuropathic pain recruited from the Samsung Seoul Hospital (Seoul, Republic of Korea) outpatient pain management unit. Patients were required to have a pain severity score >5 (visual analog scale [VAS), where 0 = no pain and 10 = worst pain imaginable) over a period of month while on standard treatment. The patients were required to have shown no benefit from standard treatment and no pain relief lasting over 1 month. The ketamine infusion therapy was composed of 3 sessions performed consecutively every other day. Midazolam was administered concomitantly to reduce the occurrence of central nervous system related adverse events (AEs) secondary to ketamine. Each session was as follows: ketamine 0.2 mg/kg and midazolam 0.1 mg/kg were administered intravenously for 5 minutes as a loading close, followed by a continuous infusion of ketamine 0.5 mg/kg/h and midazolam 0.025 mg/kg/h for 2 hours. AEs were assessed in the following ways: close monitoring of ECG, blood pressure, oxygen saturation, and evaluating the need for treatment of AEs during infusion and until discharge by an attending anesthesiologist; an open question about discomfort at the end of each session; spontaneous reports about AEs during each session; and the patients` and caregivers` checklist of AEs occurring at home for 2 weeks after discharge. All the descriptors of pain expressed by the patients in Korean were recorded and translated into appropriate English terminology on the basis of the literature on Korean verbal descriptors of pain. Each of the translated pain descriptors was then classified into 1 of 18 sensory items. RESULTS: The overall VAS score for pain decreased from a baseline mean (SD) of 7.20 (1.77) to 5.46 (2.29) (P < 0.001) 2 weeks after treatment in 103 patients (53 males and 50 females; mean age, 52.56 [17.33] years) who completed the study. Variables such as age, sex, and the duration and diagnosis of pain were not found to be associated with analgesic effect. Seven of the 18 pain descriptors were found to have a significant response to ketamine infusion treatment between baseline and 2 weeks follow-up: burning pain (P = 0.008); dull, aching pain (P < 0.001); overly sensitive to touch (P = 0.002); stabbing pain (P = 0.008); electric pain (P = 0.031); tingling pain (P < 0.001); and squeezing pain (P < 0.001). A total of 52 patients reported AEs: 33 during infusion and 44 during recovery and up to 2 weeks follow up. The most commonly reported AEs were snoring (15 [15%]) during infusion and dizziness (43 [42%]) during recovery. CONCLUSIONS: Ketamine infusion therapy was associated with reduced severity of neuropathic pain and generally well tolerated for up to 2 weeks in these patients with neuropathic pain refractory to standard treatment. Variables such as sex, age, and the diagnosis and duration of pain had no association with the analgesic effect of this treatment. Randomized controlled trials are needed to evaluate the efficacy and tolerability of treatment with ketamine infusion. 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<i>Transthyretin</i> Is a Key Regulator of Myoblast Differentiation

<div><p><i>Transthyretin</i> (<i>TTR</i>) is a known carrier protein for thyroxine (T₄) and retinol-binding protein in the blood that is primarily synthesized in the liver and choroid plexus of the brain. Herein, we report that the <i>TTR</i> gene is expressed in skeletal muscle tissue and up-regulated during myotube formation in C2C12 cells. <i>TTR</i> silencing (TTR_kd) significantly reduced myogenin expression and myotube formation, whereas myogenin silencing (MYOG_kd) did not have any effect on <i>TTR</i> gene expression. Both TTR_kd and MYOG_kd led to a decrease in calcium channel related genes including <i>Cav1.1</i>, <i>STIM1</i> and <i>Orai1</i>. A significant decrease in intracellular T₄ uptake during myogenesis was observed in <i>TTR_kd</i> cells. Taken together, the results of this study suggest that <i>TTR</i> initiates myoblast differentiation via affecting expression of the genes involved during early stage of myogenesis and the genes related to calcium channel.</p></div