• Maxillofacial Plastic and Reconstructive Surgery
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• v.40
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• pp.21.1-21.5
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• 2018

Background: The purpose of this study was to evaluate the clinical outcomes of treatment of non-odontogenic atypical orofacial pain using botulinum toxin-A. Methods: This study involved seven patients (seven females, mean age 65.1 years) who had non-odontogenic orofacial pain (neuropathic pain and atypical orofacial pain) and visited the Seoul National University Bundang Hospital between 2015 and 2017. All medication therapies were preceded by botulinum toxin-A injections, followed by injections in the insignificant effects of medication therapies. Five of the seven patients received intraoral injections in the gingival vestibule or mucosa, while the remaining two received extraoral injections in the masseter and temporal muscle areas. Results: In five of the seven patients, pain after botulinum toxin-A injection was significantly reduced. Most of the patients who underwent surgery for dental implantation or facial nerve reconstruction recovered after injections. However, the pain did not disappear in two patients who reported experiencing persistent pain without any cause. Conclusions: The use of botulinum toxin-A for the treatment of non-odontogenic neuropathic orofacial pain is clinically useful. It is more effective to administer botulinum toxin-A in combination with other medications and physical therapy to improve pain.

• The Korean Journal of Pain
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• v.26 no.2
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• pp.135-141
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• 2013

Background: Although paclitaxel is a widely used chemotherapeutic agent for the treatment of solid cancers, side effects such as neuropathic pain lead to poor compliance and discontinuation of the therapy. Ethyl pyruvate (EP) is known to have analgesic effects in several pain models and may inhibit apoptosis. The present study was designed to investigate the analgesic effects of EP on mechanical allodynia and apoptosis in dorsal root ganglion (DRG) cells after paclitaxel administration. Methods: Rats were randomly divided into 3 groups: 1) a control group, which received only vehicle; 2) a paclitaxel group, which received paclitaxel; and 3) an EP group, which received EP after paclitaxel administration. Mechanical allodynia was tested before and at 7 and 14 days after final paclitaxel administration. Fourteen days after paclitaxel treatment, DRG apoptosis was determined by activated caspase-3 immunoreactivity (IR). Results: Post-treatment with EP did not significantly affect paclitaxel-induced allodynia, although it tended to slightly reduce sensitivities to mechanical stimuli after paclitaxel administration. After paclitaxel administration, an increase in caspase-3 IR in DRG cells was observed, which was co-localized with NF200-positive myelinated neurons. Post-treatment with EP decreased the paclitaxel-induced caspase-3 IR. Paclitaxel administration or post-treatment with EP did not alter the glial fibrillary acidic protein IRs in DRG cells. Conclusions: Inhibition of apoptosis in DRG neurons by EP may not be critical in paclitaxel-induced mechanical allodynia.

• The Korean Journal of Pain
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• v.33 no.1
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• pp.30-39
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• 2020

Background: This study examined the effects of gabexate mesilate on spinal nerve ligation (SNL)-induced neuropathic pain. To confirm the involvement of gabexate mesilate on neuroinflammation, we focused on the activation of nuclear factor-κB (NF-κB) and consequent the expression of proinflammatory cytokines and inducible nitric oxide synthase (iNOS). Methods: Male Sprague-Dawley rats were used for the study. After randomization into three groups: the sham-operation group, vehicle-treated group (administered normal saline as a control), and the gabexate group (administered gabexate mesilate 20 mg/kg), SNL was performed. At the 3rd day, mechanical allodynia was confirmed using von Frey filaments, and drugs were administered intraperitoneally daily according to the group. The paw withdrawal threshold (PWT) was examined on the 3rd, 7th, and 14th day. The expressions of p65 subunit of NF-κB, interleukin (IL)-1, IL-6, tumor necrosis factor-α, and iNOS were evaluated on the 7th and 14th day following SNL. Results: The PWT was significantly higher in the gabexate group compared with the vehicle-treated group (P < 0.05). The expressions of p65, proinflammatory cytokines, and iNOS significantly decreased in the gabexate group compared with the vehicle-treated group (P < 0.05) on the 7th day. On the 14th day, the expressions of p65 and iNOS showed lower levels, but those of the proinflammatory cytokines showed no significant differences. Conclusions: Gabexate mesilate increased PWT after SNL and attenuate the progress of mechanical allodynia. These results seem to be involved with the antiinflammatory effect of gabexate mesilate via inhibition of NF-κB, proinflammatory cytokines, and nitric oxide.

• The Korean Journal of Physiology and Pharmacology
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• v.25 no.3
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• pp.217-225
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• 2021

Neuropathic pain (NP) that contributes to the comorbidity between pain and depression is a clinical dilemma. Neuroinflammatory responses are known to have potentially important roles in the initiation of NP and depressive mood. In this study, we aimed to investigate the effects of paeoniflorin (PF) on NP-induced depression-like behaviors by targeting the hippocampal neuroinflammation through the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. We used a murine model of NP caused by unilateral sciatic nerve cuffing (Cuff). PF was injected intraperitoneally once a day for a total of 14 days. Pain and depression-like behavior changes were evaluated via behavioral tests. Pathological changes in the hippocampus of mice were observed by H&E staining. The levels of proinflammatory cytokines in the hippocampus were detected using ELISA. Activated microglia were measured by immunohistochemical staining. The TLR4/NF-κB signaling pathway-associated protein expression in the hippocampus was detected by western blotting. We found that the PF could significantly alleviate Cuff-induced hyperalgesia and depressive behaviors, lessen the pathological damage to the hippocampal cell, reduce proinflammatory cytokines levels, and inhibit microglial over-activation. Furthermore, PF downregulated the expression levels of TLR4/NF-κB signaling pathway-related proteins in the hippocampus. These results indicate that PF is an effective drug for improving the comorbidity between NP and depression.

• The Korean Journal of Pain
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• v.32 no.1
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• pp.47-50
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• 2019

Background: It is uncommon for patients who have received a permanent implant to remove the spinal cord stimulator (SCS) after discontinuation of medication in complex regional pain syndrome (CRPS) due to their completely painless state. This study evaluated CRPS patients who successfully removed their SCSs. Methods: This 10-year retrospective study was performed on patients who had received the permanent implantation of an SCS and had removed it 6 months after discontinuation of stimulation, while halting all medications for neuropathic pain. Age, sex, duration of implantation, site and type of CRPS, and their return to work were compared between the removal and non-removal groups. Results: Five (12.5%, M/F = 4/1) of 40 patients (M/F = 33/7) successfully removed the permanent implant. The mean age was younger in the removal group ($27.2{\pm}6.4$ vs. $43.5{\pm}10.7$ years, P < 0.01). The mean duration of implantation in the removal group was $34.4{\pm}18.2$ months. Two of 15 patients (13.3%) and 3 of 25 patients (12%) who had upper and lower extremity pain, respectively, had removed the implant. The implants could be removed in 5 of 27 patients (18.5%) with CRPS type 1 (P < 0.01). All 5 patients (100%) who removed their SCS returned to work, while only 5 of 35 (14.3%) in the non-removal group did (P < 0.01). Conclusions: Even though this study had limited data, younger patients with CRPS type 1 could remove their SCSs within a 5-year period and return to work with complete pain relief.

• The Korean Journal of Pain
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• v.34 no.1
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• pp.4-18
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• 2021

Except for carbamazepine for trigeminal neuralgia, gabapentinoid anticonvulsants have been the standard for the treatment of neuropathic pain. Pregabalin, which followed gabapentin, was developed with the benefit of rapid peak blood concentration and better bioavailability. Mirogabalin besylate (DS-5565, Tarlige®) shows greater sustained analgesia due to a high affinity to, and slow dissociation from, the α2δ-1 subunits in the dorsal root ganglion (DRG). Additionally, it produces a lower level of central nervous system-specific adverse drug reactions (ADRs), due to a low affinity to, and rapid dissociation from, the α2δ-2 subunits in the cerebellum. Maximum plasma concentration is achieved in less than 1 hour, compared to 1 hour for pregabalin and 3 hours for gabapentin. The plasma protein binding is relatively low, at less than 25%. As with all gabapentinoids, it is also largely excreted via the kidneys in an unchanged form, and so the administration dose should also be adjusted according to renal function. The equianalgesic daily dose for 30 mg of mirogabalin is 600 mg of pregabalin and over 1,200 mg of gabapentin. The initial adult dose starts at 5 mg, given orally twice a day, and is gradually increased by 5 mg at an interval of at least a week, to 15 mg. In conclusion, mirogabalin is anticipated to be a novel, safe gabapentinoid anticonvulsant with a greater therapeutic effect for neuropathic pain in the DRG and lower ADRs in the cerebellum.

• The Korean Journal of Pain
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• v.34 no.2
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• pp.156-164
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• 2021

Several types of pain occur following spinal cord injury (SCI); however, neuropathic pain (NP) is one of the most intractable. Invasive and non-invasive brain stimulation techniques have been studied in clinical trials to treat chronic NP following SCI. The evidence for invasive stimulation including motor cortex and deep brain stimulation via the use of implanted electrodes to reduce SCI-related NP remains limited, due to the small scale of existing studies. The lower risk of complications associated with non-invasive stimulation, including transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), provide potentially attractive alternative central neuromodulation techniques. Compared to rTMS, tDCS is technically easier to apply, more affordable, available, and potentially feasible for home use. Accordingly, several new studies have investigated the efficacy of tDCS to treat NP after SCI. In this review, articles relating to the mechanisms, clinical efficacy and safety of tDCS on SCI-related NP were searched from inception to December 2019. Six clinical trials, including five randomized placebo-controlled trials and one prospective controlled trial, were included for evidence specific to the efficacy of tDCS for treating SCI-related NP. The mechanisms of action of tDCS are complex and not fully understood. Several factors including stimulation parameters and individual patient characteristics may affect the efficacy of tDCS intervention. Current evidence to support the efficacy of utilizing tDCS for relieving chronic NP after SCI remains limited. Further strong evidence is needed to confirm the efficacy of tDCS intervention for treating SCI-related NP.

• Journal of Korean Foot and Ankle Society
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• v.26 no.4
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• pp.177-182
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• 2022

Purpose: The efficacy and safety of low-dose pregabalin and alpha lipoic acid in diabetic neuropathy were evaluated and analyzed. Materials and Methods: This study designed a retrospective study that included patients with diabetic neuropathic pain. From 2009 to 2022, 100 patients who suffered from diabetic neuropathic pain were included in this study. The patients were divided into group I (pregabalin 150 mg/day with alpha lipoic acid 600 mg/day) and group II (pregabalin 300 mg/day with alpha lipoic acid 600 mg/day). The visual analogue scale (VAS), medication side effects, and neurometer results were compared. Results: The mean follow-up period of the above patients was 120.23 weeks in group I and 149.05 weeks in group II. The average VAS score in group I decreased by 3.23 points, and the average VAS score in group II decreased by 2.86 points. Approximately 24.3% of group I had side effects, such as dizziness, sleepiness, and gastrointestinal trouble, while 76.7% of patients in group II had side effects. Sixtyseven patients had a neurometer examination before and after the medication, and there is no statistical difference between the two groups. Conclusion: The combination of low-dose pregabalin (pregabalin 150 mg/day) and alpha lipoic acid in diabetic neuropathy had a similar clinical effect and less frequent medication side effects than regular dose pregabalin (pregabalin 300 mg/day) and alpha lipoic acid. Therefore, low-dose pregabalin (pregabalin 150 mg/day) and alpha lipoic acid should be considered in treating diabetic neuropathy.

• The Korean Journal of Pain
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• v.36 no.4
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• pp.425-440
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• 2023

Background: Muscimol's quick onset and GABAergic properties make it a promising candidate for the treatment of pain. This systematic review and meta-analysis of preclinical studies aimed at summarizing the evidence regarding the efficacy of muscimol administration in the amelioration of nerve injury-related neuropathic pain. Methods: Two independent researchers performed the screening process in Medline, Embase, Scopus and Web of Science extracting data were extracted into a checklist designed according to the PRISMA guideline. A standardized mean difference (SMD [95% confidence interval]) was calculated for each. To assess the heterogeneity between studies, ² and chi-square tests were utilized. In the case of heterogeneity, meta-regression and subgroup analyses were performed to identify the potential source. Results: Twenty-two articles met the inclusion criteria. Pooled data analysis showed that the administration of muscimol during the peak effect causes a significant reduction in mechanical allodynia (SMD = 1.78 [1.45-2.11]; P < 0.0001; I² = 72.70%), mechanical hyperalgesia (SMD = 1.62 [1.28-1.96]; P < 0.0001; I² = 40.66%), and thermal hyperalgesia (SMD = 2.59 [1.79-3.39]; P < 0.0001; I² = 80.33%). This significant amendment of pain was observed at a declining rate from 15 minutes to at least 180 minutes post-treatment in mechanical allodynia and mechanical hyperalgesia, and up to 30 minutes in thermal hyperalgesia (P < 0 .0001). Conclusions: Muscimol is effective in the amelioration of mechanical allodynia, mechanical hyperalgesia, and thermal hyperalgesia, exerting its analgesic effects 15 minutes after administration for up to at least 3 hours.

• The Korean Journal of Pain
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• v.36 no.4
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• pp.441-449
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• 2023

Background: Hypertonic saline is used for treating chronic pain; however, clinical studies that aid in optimizing therapeutic protocols are lacking. We aimed to determine the concentration of intrathecally injected hypertonic saline at which the effect reaches its peak as well as the underlying γ-aminobutyric acid (GABA) receptor-related antinociceptive mechanism. Methods: Spinal nerve ligation (SNL; left L5 and L6) was performed to induce neuropathic pain in rats weighing 250-300 g. Experiment 1: one week after implanting the intrathecal catheter, 60 rats were assigned randomly to intrathecal injection with 0.45%, 0.9%, 2.5%, 5%, 10%, and 20% NaCl, followed by behavioral testing at baseline and after 30 minutes, 2 hours, 1 day, and 1 week to determine the minimal concentration which produced maximal analgesia. Experiment 2: after determining the optimal intrathecal hypertonic saline concentration, 60 rats were randomly divided into four groups: Sham, hypertonic saline without pretreatment, and hypertonic saline after pretreatment with one of two GABA receptor antagonists (GABA_A [bicuculline], or GABA_B [phaclofen]). Behavioral tests were performed at weeks 1 and 3 following each treatment. Results: Hypertonic saline at concentrations greater than 5% alleviated SNL-induced mechanical allodynia and had a significant therapeutic effect, while showing a partial time- and dose-dependent antinociceptive effect on thermal and cold hyperalgesia. However, pretreatment with GABA receptor antagonists inhibited the antinociceptive effect of 5% NaCl. Conclusions: This study indicates that the optimal concentration of hypertonic saline for controlling mechanical allodynia in neuropathic pain is 5%, and that its analgesic effect is related to GABA_A and GABA_B receptors.