Efficacy and Safety of a New Sustained-release Pregabalin Formulation Compared With Immediate-release Pregabalin in Patients With Peripheral Neuropathic Pain: A Randomized Noninferiority Phase 3 Trial.

OBJECTIVE: This study investigated whether a new sustained-release (SR) pregabalin formulation is noninferior to immediate-release (IR) pregabalin in alleviating peripheral neuropathic pain in Korean patients. MATERIALS AND METHODS: This was a randomized, double-blind, active-controlled phase 3 study of patients with diabetic peripheral neuropathy or postherpetic neuralgia from 41 sites in South Korea in 2017-2018. Eligible patients were randomized (1:1) to receive once-daily SR pregabalin or twice-daily IR pregabalin (150 to 600 mg/d) in a double-dummy manner for 12 weeks according to a stratified permuted block randomization scheme. The primary endpoint was the Daily Pain Rating Scale score at the end of treatment, averaged from the last 7 available scores. RESULTS: A total of 319 of 371 (86.0%) randomized patients completed the 12-week treatment (SR pregabalin: n=154; IR pregabalin: n=165; per-protocol set: n=296). The least square mean difference between both groups for the primary endpoint was 0.06 (SE 0.19); (95% confidence interval -0.31 to 0.42), with the lower limit of the confidence interval above the pre-specified margin (-0.78; Pnoninferiority<0.0001). Drug-related treatment-emergent adverse events (TEAEs) were comparable between both groups. The incidence of drug-related TEAEs leading to treatment discontinuation was low (SR pregabalin: 2.7%; IR pregabalin: 1.1%). No serious drug-related TEAEs or deaths occurred. DISCUSSION: The results demonstrate that the new once-daily SR pregabalin formulation is noninferior to twice-daily IR pregabalin in reducing peripheral neuropathic pain and is well tolerated in Korean patients with diabetic peripheral neuropathy or postherpetic neuralgia after 12 weeks of treatment.

Regional analgesia techniques for video-assisted thoracic surgery: a frequentist network meta-analysis.

BACKGROUND: Various regional analgesia techniques are used to reduce postoperative pain in patients undergoing video-assisted thoracic surgery (VATS). This study aimed to determine the relative efficacy of regional analgesic interventions for VATS using a network meta-analysis (NMA). METHODS: We searched the Medline, EMBASE, Cochrane Controlled Trial Register, Web of Science, and Google Scholar databases to identify all randomized controlled trials (RCTs) that compared the analgesic effects of the following interventions: control, thoracic paravertebral block (TPVB), erector spinae plane block (ESPB), serratus plane block (SPB), and intercostal nerve block (INB). The primary outcome was opioid consumption during the first 24-h postoperative period. Pain scores were also collected during three different postoperative periods: the early (0-6 h), middle (6-18 h), and late (18-24 h) periods. RESULTS: A total of 21 RCTs (1391 patients) were included. TPVB showed the greatest effect on opioid consumption compared with the control (mean difference [MD] = -13.2 mg; 95% CI [-16.2, -10.1]). In terms of pain scores in the early period, ESPB had the greatest effect compared to control (MD = -1.6; 95% CI [-2.3, -0.9]). In the middle and late periods, pain scores showed that TPVB, ESPB and INB had superior analgesic effects compared to controls, while SPB did not. CONCLUSIONS: TPVB had the best analgesic efficacy following VATS, though the analgesic efficacy of ESPBs was comparable. However, further studies are needed to determine the optimal regional analgesia technique to improve postoperative pain control following VATS.

IKBKB siRNA-Encapsulated Poly (Lactic-co-Glycolic Acid) Nanoparticles Diminish Neuropathic Pain by Inhibiting Microglial Activation.

Activation of nuclear factor-kappa B (NF-κB) in microglia plays a decisive role in the progress of neuropathic pain, and the inhibitor of kappa B (IκB) is a protein that blocks the activation of NF-κB and is degraded by the inhibitor of NF-κB kinase subunit beta (IKBKB). The role of IKBKB is to break down IκB, which blocks the activity of NF-kB. Therefore, it prevents the activity of NK-kB. This study investigated whether neuropathic pain can be reduced in spinal nerve ligation (SNL) rats by reducing the activity of microglia by delivering IKBKB small interfering RNA (siRNA)-encapsulated poly (lactic-co-glycolic acid) (PLGA) nanoparticles. PLGA nanoparticles, as a carrier for the delivery of IKBKB genes silencer, were used because they have shown potential to enhance microglial targeting. SNL rats were injected with IKBKB siRNA-encapsulated PLGA nanoparticles intrathecally for behavioral tests on pain response. IKBKB siRNA was delivered for suppressing the expression of IKBKB. In rats injected with IKBKB siRNA-encapsulated PLGA nanoparticles, allodynia caused by mechanical stimulation was reduced, and the secretion of pro-inflammatory mediators due to NF-κB was reduced. Delivering IKBKB siRNA through PLGA nanoparticles can effectively control the inflammatory response and is worth studying as a treatment for neuropathic pain.

CX3CR1-Targeted PLGA Nanoparticles Reduce Microglia Activation and Pain Behavior in Rats with Spinal Nerve Ligation.

Activation of CX3CR1 in microglia plays an important role in the development of neuropathic pain. Here, we investigated whether neuropathic pain could be attenuated in spinal nerve ligation (SNL)-induced rats by reducing microglial activation through the use of poly(D,L-lactic-co-glycolic acid) (PLGA)-encapsulated CX3CR1 small-interfering RNA (siRNA) nanoparticles. After confirming the efficacy and specificity of CX3CR1 siRNA, as evidenced by its anti-inflammatory effects in lipopolysaccharide-stimulated BV2 cells in vitro, PLGA-encapsulated CX3CR1 siRNA nanoparticles were synthesized by sonication using the conventional double emulsion (W/O/W) method and administered intrathecally into SNL rats. CX3CR1 siRNA-treated rats exhibited significant reductions in the activation of microglia in the spinal dorsal horn and a downregulation of proinflammatory mediators, as well as a significant attenuation of mechanical allodynia. These data indicate that the PLGA-encapsulated CX3CR1 siRNA nanoparticles effectively reduce neuropathic pain in SNL-induced rats by reducing microglial activity and the expression of proinflammatory mediators. Therefore, we believe that PLGA-encapsulated CX3CR1 siRNA nanoparticles represent a valuable new treatment option for neuropathic pain.

Implementation of the Obturator Nerve Block into a Supra-Inguinal Fascia Iliaca Compartment Block Based Analgesia Protocol for Hip Arthroscopy: Retrospective Pre-Post Study.

Background and Objectives: The effect of supra-inguinal fascia iliaca compartment block (SI-FICB) in hip arthroscopy is not apparent. It is also controversial whether SI-FICB can block the obturator nerve, which may affect postoperative analgesia after hip arthroscopy. We compared analgesic effects before and after the implementation of obturator nerve block into SI-FICB for hip arthroscopy. Materials and Methods: We retrospectively reviewed medical records of 90 consecutive patients who underwent hip arthroscopy from January 2017 to August 2019. Since August 2018, the analgesic protocol was changed from SI-FICB to SI-FICB with obturator nerve block. According to the analgesic regimen, patients were categorized as group N (no blockade), group F (SI-FICB only), and group FO (SI-FICB with obturator nerve block). Primary outcome was the cumulative opioid consumption at 24 hours after surgery. Additionally, cumulative opioid consumption at 6 and 12 hours after surgery, pain score, additional analgesic requests, intraoperative opioid consumption and hemodynamic stability, and postoperative nausea and vomiting were assessed. Results: Among 87 patients, there were 47 patients in group N, 21 in group F, and 19 in group FO. The cumulative opioid (fentanyl) consumption at 24 hours after surgery was significantly lower in the group FO compared with the group N (N: 678.5 (444.0-890.0) µg; FO: 482.8 (305.8-635.0) µg; p = 0.014), whereas the group F did not show a significant difference (F: 636.0 (426.8-803.0) µg). Conclusion: Our findings suggest that implementing obturator nerve block into SI-FICB can reduce postoperative opioid consumption in hip arthroscopy.

Effects of nicardipine on the onset time and intubation conditions of rocuronium-induced neuromuscular blockade.

STUDY OBJECTIVE: The objective of this study was to identify the effects of nicardipine on neuromuscular blockade of rocuronium, such as the onset time and intubation conditions, using a nicardipine dose that attenuates cardiovascular responses during endotracheal intubation. DESIGN: Randomized, double-blinded, placebo-controlled clinical comparison was used as the design of this study SETTING: The study was conducted at the operating room of a university hospital. PATIENTS: Participants of this study comprise 78 American Society of Anesthesiologists physical status 1 and 2 patients, aged 18 to 60 years who were undergoing elective surgery under general anesthesia. INTERVENTIONS: The nicardipine group was given an intravenous bolus of 20 µg/kg nicardipine before tracheal intubation: the control group was given an intravenous bolus of a comparable volume of normal saline before tracheal intubation. MEASUREMENTS: Using a TOF-Watch SX monitor, the time from the end of the injection of rocuronium to maximum depression of T1 (onset time) was measured. Intubation was performed 1 minute after rocuronium administration, and the status of the intubation conditions was assessed. The mean blood pressure and heart rate were each measured after endotracheal intubation. Rate pressure product values were also calculated. MAIN RESULTS: Intubation conditions were clinically acceptable in 37 (94.9%) of 39 patients in group N compared with 29 (74.4%) of 39 in group C (P < .05). The onset time of rocuronium was significantly faster in group N than in group C (P < .05). The mean blood pressure was significantly lower in group N than in group C (P < .05). The heart rate was significantly higher in group N than in group C (P < .05). Rate pressure product values showed no significant difference between the two groups (P > .05). CONCLUSIONS: Pretreatment with 20 µg/kg nicardipine improves intubation conditions, shortens the onset time of rocuronium, and attenuates cardiovascular responses to tracheal intubation.

A comparison of regional and general anesthesia effects on 5 year survival and cancer recurrence after transurethral resection of the bladder tumor: a retrospective analysis.

BACKGROUND: Recent studies have reported that cancer surgeries involving regional anesthesia have better outcomes than those under general anesthesia. However, the effects of anesthetic technique have not been investigated in patients with bladder cancer. Therefore, this retrospective study was conducted to investigate which anesthetic technique results in a better bladder cancer prognosis. METHODS: Sixty-one of 531 patients underwent transurethral resection of a bladder tumor under general anesthesia from 2001 to 2008 in our hospital. Patients who attended five years of follow-up and who had pathological findings of urothelial carcinoma grades I-II were enrolled. Finally, 24 patients (G group) who underwent general anesthesia and 137 (R group) who underwent regional (spinal or epidural) anesthesia were compared. Five-year survival and recurrence-free time were compared using the chi-square and t-tests, respectively. A logistic regression and partial correlation analysis were performed to evaluate other factors affecting survival. RESULTS: Five-year survival was 87.5% for general anesthesia and 96.3% for regional (P = 0.099). The regression analysis showed that older age contributed to reduced survival (odds ratio = 0.85, P = 0.001). Regional anesthesia showed higher 5-year survival (coefficient = -0.167, P = 0.044) more than general anesthesia through the partial correlation analysis. CONCLUSIONS: Though partial correlation analysis show that five-year survival is higher in patients whose surgery is under regional than general anesthesia, the association was not significant in the chi-square test and logistic regression analysis. Large prospective studies are needed to determine whether the association between regional anesthesia and survival is causative.

Anesthesia and sedation outside of the operating room.

Due to rapid evolution and technological advancements, medical personnel now require special training outside of their safe zones. Anesthesiologists face challenges in practicing in locations beyond the operating room. New locations, inadequate monitoring devices, poor assisting staff, unfamiliarity of procedures, insufficient knowledge of basic standards, and lack of experience compromise the quality of patient care. Therefore, anesthesiologists must recognize possible risk factors during anesthesia in nonoperating rooms and familiarize themselves with standards to improve safe practice. This review article emphasizes the need for standardizing hospitals and facilities requiring nonoperating room anesthesia, and encourages anesthesiologists to take the lead in applying these practice guidelines to improve patient outcomes and reduce adverse events.

Protease-Activated Receptor-2 Is Associated with Terminal Differentiation of Epidermis and Eccrine Sweat Glands.

BACKGROUND: Protease-activated receptor 2 (PAR-2) participates in various biological activities, including the regulation of epidermal barrier homeostasis, inflammation, pain perception, and melanosome transfer in the skin. OBJECTIVE: To evaluate the basic physiological role of PAR-2 in skin. METHODS: We investigated PAR-2 expression in human epidermis, skin tumors, and cultured epidermal cells using western blot and immunohistochemical analysis. Additionally, we examined the effect of the PAR-2 agonist, SLIGRL-NH2, on cultured keratinocytes. RESULTS: Strong PAR-2 immunoreactivity was observed in the granular layer of normal human skin and the acrosyringium of the eccrine sweat glands. In contrast, weak PAR-2 immunoreactivity was seen in the granular layer of callused skin and in the duct and gland cells of the eccrine sweat glands. Interestingly, PAR-2 immunoreactivity was very weak or absent in the tumor cells of squamous cell carcinoma (SCC) and syringoma. PAR-2 was detected in primary keratinocytes and SV-40T-transformed human epidermal keratinocytes (SV-HEKs), an immortalized keratinocyte cell line, but not in SCC12 cells. SV-HEKs that were fully differentiated following calcium treatment displayed higher PAR-2 expression than undifferentiated SV-HEKs. Treatment of cultured SV-HEKs with PAR-2 agonist increased loricrin and filaggrin expression, a terminal differentiation marker. CONCLUSION: Our data suggest that PAR-2 is associated with terminal differentiation of epidermis and eccrine sweat glands.

Successful Treatment of Occipital Radiating Headache Using Pulsed Radiofrequency Therapy.

Rheumatoid arthritis (RA) is a chronic inflammatory disease involving multiple joints. The cervical spine is often affected, and cases involving atlantoaxial joint can lead to instability. Anterior atlantoaxial subluxation in RA patients can lead to posterior neck pain or occipital headache because of compression of the C2 ganglion or nerve. Here, we report the successful treatment of a RA patient with occipital radiating headache using pulsed radiofrequency therapy at the C2 dorsal root ganglion.

Comparison of etomidate and propofol on intubating conditions and the onset time associated with cisatracurium administration.

BACKGROUND: This study compared intubating conditions and the onset time associated with administration of cisatracurium, a nondepolarizing neuromuscular blocker with a relatively slow onset, according to prior injection of one of two intravenous anesthetic agents: propofol or etomidate. METHODS: Forty-six female patients, undergoing general anesthesia and endotracheal intubation for elective surgery, were randomized to two groups; group P were administered propofol (2 mg/kg) prior to cisatracurium (0.2 mg/kg); group E were administered etomidate (0.3 mg/kg) prior to cisatracurium (0.2 mg/kg). We measured intubating conditions and the onset time according to the types of intravenous anesthetic administered. Measurements of heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were taken immediately prior to induction; immediately and 1 min after IV anesthetic administration; and immediately and 1, 2, 3, 4, 5, 7, and 15 min after endotracheal intubation. RESULTS: Intubating conditions were superior in group E compared with group P (P = 0.009). The average onset time of cisatracurium was more rapid in group E (155.74 ± 32.92 s vs. 185.26 ± 38.57 s in group P; P = 0.008). There were no group differences in SBP, DBP, and HR following intravenous anesthetic drug injection and endotracheal intubation. However, SBP and DBP were substantially higher in group E after endotracheal intubation. CONCLUSIONS: Etomidate improves intubating conditions and provide a more rapid onset time of cisatracurium during anesthetic induction compared to propofol.

Analysis of anesthesia-related medical disputes in the 2009-2014 period using the Korean Society of Anesthesiologists database.

Using the Korean Society of Anesthesiologists database of anesthesia-related medical disputes (July 2009-June 2014), causative mechanisms and injury patterns were analyzed. In total, 105 cases were analyzed. Most patients were aged < 60 yr (82.9%) and were classified as American Society of Anesthesiologists physical status ≤ II (90.5%). In 42.9% of all cases, the injuries were determined to be 'avoidable' if the appropriate standard of care had been applied. Sedation was the sec most common type of anesthesia (37.1% of all cases), following by general anesthesia. Most sedation cases (27/39, 69.2%) showed a common lack of vigilance: no pre-procedural testing (82.1%), absence of anesthesia record (89.7%), and non-use of intra-procedural monitoring (15.4%). Most sedation (92.3%) was provided simultaneously by the non-anesthesiologists who performed the procedures. After the resulting injuries were grouped into four categories (temporary, permanent/minor, permanent/major, and death), their causative mechanisms were analyzed in cases with permanent injuries (n=20) and death (n=82). A 'respiratory events' was the leading causative mechanism (56/102, 54.9%). Of these, the most common specific mechanism was hypoxia secondary to airway obstruction or respiratory depression (n=31). The sec most common damaging event was a 'cardiovascular events' (26/102, 25.5%), in which myocardial infarction was the most common specific mechanism (n=12). Our database analysis demonstrated several typical injury profiles (a lack of vigilance in seemingly safe procedures or sedation, non-compliance with the airway management guidelines, and the prevalence of myocardial infarction) and can be helpful to improve patient safety.

Intrathecal administration of mesenchymal stem cells reduces the reactive oxygen species and pain behavior in neuropathic rats.

BACKGROUND: Neuropathic pain induced by spinal or peripheral nerve injury is very resistant to common pain killers, nerve block, and other pain management approaches. Recently, several studies using stem cells suggested a new way to control the neuropatic pain. In this study, we used the spinal nerve L5 ligation (SNL) model to investigate whether intrathecal rat mesenchymal stem cells (rMSCs) were able to decrease pain behavior, as well as the relationship between rMSCs and reactive oxygen species (ROS). METHODS: Neuropathic pain of the left hind paw was induced by unilateral SNL in Sprague-Dawley rats (n = 10 in each group). Mechanical sensitivity was assessed using Von Frey filaments at 3, 7, 10, 12, 14, 17, and 24 days post-ligation. rMSCs (10 µl, 1 × 10(5)) or phosphate buffer saline (PBS, 10 µl) was injected intrathecally at 7 days post-ligation. Dihydroethidium (DHE), an oxidative fluorescent dye, was used to detect ROS at 24 days post-ligation. RESULTS: Tight ligation of the L5 spinal nerve induced allodynia in the left hind paw after 3 days post-ligation. ROS expression was increased significantly (P < 0.05) in spinal dorsal horn of L5. Intrathecal rMSCs significantly (P < 0.01) alleviated the allodynia at 10 days after intrathecal injection (17 days post-ligation). Intrathecal rMSCs administration significantly (P < 0.05) reduced ROS expression in the spinal dorsal horn. CONCLUSIONS: These results suggest that rMSCs may modulate neuropathic pain generation through ROS expression after spinal nerve ligation.

Glomus tumor causing anterior thigh pain: a case report.

Glomus tumors are a rare, benign neoplasm and 75% exist in the subungual region. Extradigital glomus tumors are much more difficult to diagnose because of their atypical location and symptoms. Furthermore, if their symptoms are similar to neuropathic pain, the patient can suffer from misdirected treatment due to misdiagnosis. It is essential to perform careful evaluation of the lesion itself in order to reduce misdiagnosis. Ultrasonography is a useful, non-invasive method that can be easily performed in the pain clinic for local evaluation and diagnosis. We report a case of misdiagnosed glomus tumor in the thigh which was properly diagnosed after ultrasonography.

Efficacy of the oral neurokinin-1 receptor antagonist aprepitant administered with ondansetron for the prevention of postoperative nausea and vomiting.

BACKGROUND: 5-HT3 receptor antagonist, dexamethasone and droperidol were used for the prevention of postoperative nausea and vomiting (PONV). Recently, neurokinin-1 (NK1) antagonist has been used for PONV. We evaluated the effect of oral aprepitant premedication in addition to ondansetron. METHODS: A total 90 patients scheduled for elective rhinolaryngological surgery were allocated to three groups (Control, Ap80, Ap125), each of 30 at random. Ondansetron 4 mg was injected intravenously to all patients just before the end of surgery. On the morning of surgery, 80 mg and 125 mg aprepitant were additionally administered into the Ap80 group and Ap125 group, respectively. The rhodes index of nausea, vomiting and retching (RINVR) was checked at 6 hr and 24 hr after surgery. RESULTS: Twelve patients who used steroids unexpectedly were excluded. Finally 78 patients (control : Ap80 : Ap125 = 24 : 28 : 26) were enrolled. Overall PONV occurrence rate of Ap125 group (1/26, 3.9%) was lower (P = 0.015) than the control group (7/24, 29.2%) at 6 hr after surgery. The nausea distress score of Ap125 group (0.04 ± 0.20) was lower (P = 0.032) than the control group (0.67 ± 1.24) at 6 hr after surgery. No evident side effect of aprepitant was observed. CONCLUSIONS: Oral aprepitant 125 mg can be used as combination therapy for the prevention of PONV.

Effect of lidocaine (40 mg) mixed to prevent injection pain of propofol on the intubating conditions and onset time of rocuronium.

BACKGROUND: To analyze how lidocaine 40 mg mixed prevents injection pain of propofol affects the onset time of rocuronium, tracheal intubating conditions and intubation related hemodynamic changes. METHODS: This study consisted of 70 patients with an American Society of Anesthesiologists (ASA) physical status class 1 or 2 for general anesthesia. All the patients were randomly allocated into two groups: propofol 2 mg/kg plus normal saline 2 ml (Group C) and propofol 2 mg/kg plus 2% lidocaine 40 mg (Group L). Each group was administrated intravenously during induction and the patient was intubated 1 minute after an injection of 0.6 mg/kg of rocuronium. The time at disappearance of the first twitch and intubation scores were recorded. Also, blood pressure and heart rate were measured at the baseline, after intravenous injection of propofol, before intubation, and at 0, 1, 2, 3 and 5 minutes after intubation. RESULTS: There were no significant differences between group C and L (P > 0.05). CONCLUSIONS: 40 mg of lidocaine mixed with propofol to prevent injection pain did not affect the onset time of rocuronium, intubating conditions and intubation related hemodynamic changes.

Intrathecal ketamine and pregabalin at sub-effective doses synergistically reduces neuropathic pain without motor dysfunction in mice.

Peripheral or central nerve injury often leads to neuropathic pain. Although ketamine and pregabalin are first line options for the treatment of neuropathic pain, their clinical application is limited due to side effects such as sedation, dizziness and somnolence. We designed this study to determine whether the intrathecal (i.t.) co-treatment with ketamine and pregabalin at sub-effective low doses would elicit a sufficient pain relief without producing side effect in a neuropathic pain mouse model. At day 7 after chronic constriction injury (CCI) of sciatic nerve, dose dependent effects of i.t. ketamine (3, 10, 30, 100 µg) or i.t. pregabalin (10, 30, 100 µg) on mechanical allodynia and thermal hyperalgesia were measured. For combination treatment, 3 or 10 µg of ketamine and 30 µg of pregabalin were selected because these doses of drugs were not effective on neuropathic pain. Interestingly, combined i.t. treatment groups (ketamine 3 µg+pregabalin 30 µg and ketamine 10 µg+pregabalin 30 µg) produced strong analgesia on neuropathic pain although these doses of ketamine and pregabalin alone are not effective. Moreover, rota rod test revealed that normal motor function was not affected by combined treatment while i.t. ketamine at doses above 10 µg showed a significant motor dysfunction. Results of this study suggested that i.t. co-treatment with ketamine and pregabalin at sub-effect low doses may be a useful therapeutic method for the treatment of neuropathic pain patients.

Clinical experiences on the effect of scrambler therapy for patients with postherpetic neuralgia.

Postherpetic neuralgia (PHN) is a debilitating complication of herpes zoster, especially in elderly and comorbid patients. Unfortunately, the currently available treatments have shown limited efficacy and some adverse events that are poorly tolerated in elderly patients. Scrambler Therapy, proposed as an alternative treatment for chronic neuropathic pain recently, is a noninvasive approach to relieve pain by changing pain perception at the brain level. Here, we report our clinical experiences on the effect of Scrambler Therapy for three patients with PHN refractory to conventional treatment.