Evaluation of the antinociceptive activities of natural propolis extract derived from stingless bee Trigona thoracica in mice.

Background: : Stingless bee propolis is a popular traditional folk medicine and has been employed since ancient times. This study aimed to evaluate the antinociceptive activities of the chemical constituents of aqueous propolis extract (APE) collected by Trigona thoracica in a nociceptive model in mice. Methods: : The identification of chemical constituents of APE was performed using high-performance liquid chromatography (HPLC). Ninety-six male Swiss mice were administered APE (400 mg/kg, 1,000 mg/kg, and 2,000 mg/kg) before developing nociceptive pain models. Then, the antinociceptive properties of each APE dose were evaluated in acetic acid-induced abdominal constriction, hot plate test, and formalin-induced paw licking test. Administration of normal saline, acetylsalicylic acid (ASA, 100 mg/kg, orally), and morphine (5 mg/kg, intraperitoneally) were used for the experiments. Results: : HPLC revealed that the APE from Trigona thoracica contained p-coumaric acid (R2 = 0.999) and caffeic acid (R2 = 0.998). Although all APE dosages showed inhibition of acetic acid-induced abdominal constriction, only 2,000 mg/kg was comparable to the result of ASA (68.7% vs. 73.3%, respectively). In the hot plate test, only 2,000 mg/kg of APE increased the latency time significantly compared to the control. In the formalin test, the durations of paw licking were significantly reduced at early and late phases in all APE groups with a decrease from 45.1% to 53.3%. Conclusions: : APE from Trigona thoracica, containing p-coumaric acid and caffeic acid, exhibited antinociceptive effects, which supports its potential use in targeting the prevention or reversal of central and peripheral sensitization that may produce clinical pain conditions.

Neuromodulation for chronic pain.

Neuromodulation is an expanding area of pain medicine that incorporates an array of non-invasive, minimally invasive, and surgical electrical therapies. In this Series paper, we focus on spinal cord stimulation (SCS) therapies discussed within the framework of other invasive, minimally invasive, and non-invasive neuromodulation therapies. These therapies include deep brain and motor cortex stimulation, peripheral nerve stimulation, and the non-invasive treatments of repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and transcutaneous electrical nerve stimulation. SCS methods with electrical variables that differ from traditional SCS have been approved. Although methods devoid of paraesthesias (eg, high frequency) should theoretically allow for placebo-controlled trials, few have been done. There is low-to-moderate quality evidence that SCS is superior to reoperation or conventional medical management for failed back surgery syndrome, and conflicting evidence as to the superiority of traditional SCS over sham stimulation or between different SCS modalities. Peripheral nerve stimulation technologies have also undergone rapid development and become less invasive, including many that are placed percutaneously. There is low-to-moderate quality evidence that peripheral nerve stimulation is effective for neuropathic pain in an extremity, low quality evidence that it is effective for back pain with or without leg pain, and conflicting evidence that it can prevent migraines. In the USA and many areas in Europe, deep brain and motor cortex stimulation are not approved for chronic pain, but are used off-label for refractory cases. Overall, there is mixed evidence supporting brain stimulation, with most sham-controlled trials yielding negative findings. Regarding non-invasive modalities, there is moderate quality evidence that repetitive transcranial magnetic stimulation does not provide meaningful benefit for chronic pain in general, but conflicting evidence regarding pain relief for neuropathic pain and headaches. For transcranial direct current stimulation, there is low-quality evidence supporting its benefit for chronic pain, but conflicting evidence regarding a small treatment effect for neuropathic pain and headaches. For transcutaneous electrical nerve stimulation, there is low-quality evidence that it is superior to sham or no treatment for neuropathic pain, but conflicting evidence for non-neuropathic pain. Future research should focus on better evaluating the short-term and long-term effectiveness of all neuromodulation modalities and whether they decrease health-care use, and on refining selection criteria and treatment variables.

Dysfunctional energy metabolisms in fibromyalgia compared with healthy subjects.

This study aimed to investigate the levels of creatine (Cr) metabolites in the anterior cingulate cortex (ACC), thalamus, and insula of patients with fibromyalgia (FM) using proton magnetic resonance spectroscopy (MRS). The levels of Cr and phosphocreatine (PCr) relative to total Cr (tCr), which includes Cr and PCr, in the ACC, thalamus, and insula were determined using MRS in 12 patients with FM and in 13 healthy controls. The FM group had lower levels of PCr/tCr in the ACC and right insula compared to healthy controls. There was a negative correlation between Cr/tCr in the ACC and total pain levels (McGill Pain Questionnaire-Total; r = -0.579, p = 0.049) and between Cr/tCr in the left insula and affective pain levels (McGill Pain Questionnaire-Affective; r = -0.638, p = 0.047) in patients with FM. In addition, there were negative correlations between stress levels (Stress Response Inventory) and Cr/tCr in the right (r = -0.780, p = 0.005) and left thalamus (r = -0.740, p = 0.006), as well as in the right insula (r = -0.631, p = 0.028) in patients with FM. There were negative correlations between symptom levels of post-traumatic stress disorder (PTSD; PTSD checklist) and Cr/tCr in the right (r = -0.783, p = 0.004) and left thalamus (r = -0.642, p = 0.024) of patients with FM. These findings are paramount to understanding the decisive pathologies related to brain energy metabolism in patients with FM.

Deep Spinal Infection after Outpatient Epidural Injections for Pain: A Retrospective Sample Cohort Study Using a Claims Database in South Korea.

BACKGROUND: Deep spinal infection is a devastating complication after epidural injection. This study aimed to investigate the incidence of deep spinal infection primarily after outpatient single-shot epidural injection for pain. Secondarily, this study assessed the national trends of the procedure and risk factors for said infection. METHODS: Using South Korea's National Health Insurance Service sample cohort database, the 10-yr national trend of single-shot epidural injections for pain and the incidence rate of deep spinal infection after the procedure with its risk factors were determined. New-onset deep spinal infections were defined as those occurring within 90 days of the most recent outpatient single-shot epidural injection for pain, needing hospitalization for at least 1 night, and receiving at least a 4-week course of antibiotics. RESULTS: The number of outpatient single-shot epidural injections per 1,000 persons in pain practice doubled from 40.8 in 2006 to 84.4 in 2015 in South Korea. Among the 501,509 injections performed between 2007 and 2015, 52 cases of deep spinal infections were detected within 90 days postprocedurally (0.01% per injection). In multivariable analysis, age of 65 yr or more (odds ratio, 2.91; 95% CI, 1.62 to 5.5; P = 0.001), living in a rural area (odds ratio, 2.85; 95% CI, 1.57 to 5.0; P < 0.001), complicated diabetes (odds ratio, 3.18; 95% CI, 1.30 to 6.7; P = 0.005), multiple epidural injections (three times or more) within the previous 90 days (odds ratio, 2.34; 95% CI, 1.22 to 4.2; P = 0.007), and recent use of immunosuppressants (odds ratio, 2.90; 95% CI, 1.00 to 6.7; P = 0.025) were significant risk factors of the infection postprocedurally. CONCLUSIONS: The incidence of deep spinal infection after outpatient single-shot epidural injections for pain is very rare within 90 days of the procedure (0.01%). The data identify high-risk patients and procedure characteristics that may inform healthcare provider decision-making.

Evaluation of an effectiveness and safety of the electroacupuncture in the management of intractable neuropathic pain: A prospective, open-labeled, randomized, cross-over clinical trial.

BACKGROUND: There is no sufficient evidence on the effectiveness of acupuncture for neuropathic pain. This protocol describes a study that aims to evaluate the effectiveness and safety of electroacupuncture combined with conventional medicine for patients with intractable neuropathic pain, when compared with conventional medicine alone. METHODS/DESIGN: This study is a prospective, open-labeled, randomized, cross-over clinical trial. A total of 40 patients with neuropathic pain who had a numeric rating scale (NRS) score of over 4 despite receiving conventional treatment for more than 3 months will be enrolled. Participants will receive conventional treatment for neuropathic pain (treatment C) or treatment C combined with 12 additional sessions of electroacupuncture treatment (treatment A) for 6 weeks. Participants will be randomly assigned to 1 of the 2 sequence groups (AC and CA group) with a 1:1 allocation. The differences of responder in the composite efficacy outcomes, which consist of the NRS, Brief Pain Inventory-Short Form (BPI-SF) pain subscale, and global assessment at 6 weeks after randomization will be examined as the primary outcome. Secondary outcomes include differences in the NRS, the Short-Form McGill Pain Questionnaire, BPI-SF, Fatigue Severity Scale, Hospital Anxiety and Depression Scale, Medical Outcomes Study Sleep Scale, global assessment, EQ-5D, and incremental cost-effective ratio at 6 and 15 weeks after randomization. Adverse events, vital signs, and physical examinations will be recorded to evaluate safety. DISCUSSION: The study protocol for this trial will provide up-to-date evidence on the effectiveness and safety of electroacupuncture for patients with intractable neuropathic pain. The results will be disseminated through a peer-reviewed journal and conference presentations. TRIAL REGISTRATION: Clinical Research Information Service, ID: KCT0003615. Registered on March 12, 2019. https://cris.nih.go.kr/cris/search/search_result_st01_kren.jsp?seq=13410& ltype=&rtype=.

Electroacupuncture May Improve Burning and Electric Shock-Like Neuropathic Pain: A Prospective Exploratory Pilot Study.

Objective: To test the effectiveness of electroacupuncture (EA) for managing intractable neuropathic pain (NeP) and assess the protocol for a larger confirmatory trial. Design: A prospective, multicenter, single-armed, add-on, pilot study. Settings/location: At two tertiary university-based hospitals in Seoul, Republic of Korea. Subjects: Patients with chronic peripheral NeP, who have received conventional oral medications but complained of moderate to severe pain. Interventions: Two Korean medicine doctors conducted 12 sessions of EA (2 sessions per week for 4 weeks, followed by 1 session per week for the second month) in addition to conventional treatment. Outcome measures: During the 8-week treatment period, pain intensity, pain natures such as burning, electric shock-like, temperature or mechanical hyperalgesia, and numbness, Short Form of the McGill Pain Questionnaire (SF-MPQ) and the Brief Pain Inventory (BPI-SF), the EuroQol five dimensions questionnaire, patients' satisfaction, and adverse events were evaluated. The primary endpoint was a change in pain intensity (%) at 4 weeks from the baseline. Results: Among 22 patients, 19 finished the protocol. The eight EA sessions over a month reduced pain intensity from 6.0 ± 1.6 at baseline to 3.2 ± 0.9 at 4 weeks, which was a 46.7% reduction (p < 0.001). The incidences of severe burning, electric shock-like pain, and mechanical hyperalgesia reduced at 8 weeks [36%-16% (p = 0.04), 53%-21% (p = 0.009), and 53%-26% (p = 0.03), respectively]. The affective dimensions in the SF-MPQ (p = 0.007) and the pain interference parameters, including mood (p = 0.02), relations with other people (p = 0.03), and enjoyment of life (p = 0.002) in the BPI-SF, were improved at 4 and 8 weeks. The majority of patients (68%) responded that their pain was "much or somewhat improved." Overall, 84.2% expressed "satisfaction" with their multidisciplinary management. Conclusions: EA might decrease the intensity of NeP, in particular, such as burning, electric shock-like pain, and mechanical hyperalgesia, which was accompanied by psychosocial and functional improvement. A larger study is warranted to prove the effectiveness of EA for managing refractory NeP. Trial registration: ClinicalTrials.gov: NCT03315598. Retrospectively registered on October 20, 2017.

Disruption of Homeostasis Based on the Right and Left Hemisphere in Patients with Complex Regional Pain Syndrome.

OBJECTIVE: Although the clinical features and pathophysiology of complex regional pain syndrome (CRPS) have been studied in the peripheral and central nervous systems, few plausible pathological interactions are known among the metabolites in these systems. Thus, the purpose of this study was to investigate abnormal relationships and interactions between peripheral metabolites and central neurometabolites in patients with CRPS. METHODS: Various metabolites and molecules were measured in the peripheral blood, and central neurometabolites in the right and left thalamus using proton magnetic resonance spectroscopy in 12 patients with CRPS and 11 healthy controls. Interactions between peripheral metabolites in blood and central neurometabolites in the right and left thalamus were also investigated. RESULTS: The interactions between peripheral and central metabolites were different in the right and left hemispheres of healthy subjects, suggesting the presence of right hemisphere-dependent energy homeostasis and left hemisphere-dependent acid-base homeostasis that enables effective functioning. The interactions between central and peripheral metabolites in CRPS patients were distinct from those in healthy individuals, supporting the possibility of abnormal interactions and disrupted homeostasis between peripheral and central metabolites, which may result from neuroinflammation and immune system dysfunction. CONCLUSION: To the authors' knowledge, this is the first report describing abnormal metabolic dysfunction and disrupted homeostasis in interactions between metabolites of the peripheral and central nervous systems in CRPS. The approach used to uncover hidden pathophysiologies will improve understanding of how chronic pain can disrupt homeostasis in interactions between two systems and how alternative metabolites can be activated to recover and compensate for pathological dysfunctions in patients with CRPS.

The minimal effective dose of cis-9-cetylmyristoleate (CMO) in persons presenting with knee joint pain: A double-blind, randomized, placebo-controlled trial.

BACKGROUND: Nutraceuticals containing cis-9-cetylmyristoleate (CMO) are used to improve knee pain despite the lack of placebo-controlled studies in humans. The aim of the study was to explore the minimal effective dose of CMO for relieving knee joint pain. METHODS: Twenty-eight subjects with mild degree arthritic knee joint pain were randomized into 4 groups; groups A, B, and C that contained 100%, 80%, and 62.4% of fatty acid component with 12.5% of CMO, and control group D (starch 100%). The pain intensity, functional disability, and the Patient Global Impression of Change (PGIC) were assessed for a 12-week ingestion period. RESULTS: Compared to group D (n = 6), there were significant differences in pain score in group A (n = 7, P = 0.005) and group C (n = 7, P = 0.012), but not significant in group B (n = 6, P = 0.180). Western Ontario and McMaster Universities Arthritis (WOMAC) score decreased significantly in groups A and C. The PGIC was positive in the majority (>50%) in groups A, B, and C, whereas negative in 83.3% in group D (control). CONCLUSION: CMO is effective in alleviating knee pain in persons with mild degree arthritis of the knee joint, at an effective dose of 62.4%.

An exploratory study on the effectiveness of "Calmare therapy" in patients with cancer-related neuropathic pain: A pilot study.

PURPOSE: Calmare therapy (CT) has been suggested as a novel treatment for managing chronic pain. Recently, it was reported to show a positive therapeutic outcome for managing neuropathic pain condition. We performed an exploratory prospective study on the effectiveness of CT in patients with various types of cancer-related neuropathic pain (CNP). METHOD: We performed an open-labeled, single-arm, exploratory study on the effectiveness of CT in patients with various types of cancer-related neuropathic pain (CNP). The primary endpoint was a comparison of the 11-point Numerical Rating Scale (NRS) pain score at one month with the baseline score in each patient. Brief Pain Inventory (BPI) and consumption of opioid were also evaluated during follow-up period. RESULTS: CT significantly decreased NRS pain score at one month from baseline (p < 0.001) in 20 patients with chemotherapy-induced peripheral neuropathy (n = 6), metastatic bone pain (n = 7), and post-surgical neuropathic pain (n = 7). It also improved overall BPI scores, decreased consumption of rescue opioid (p = 0.050), and was found satisfactory by a half of patients (n = 10, 50.0%). CONCLUSIONS: Our preliminary results suggest that CT may be considered for cancer patients with various types of CNP. Large studies are necessary to confirm our findings and ascertain which additional CNP show positive response to CT.

Predictive factors associated with success and failure for Calmare (Scrambler) therapy: a multicenter analysis.

OBJECTIVE: Calmare (Scrambler) therapy is a novel therapeutic modality that purports to provide pain relief by "scrambling" afferent pain signals and replacing them with "non-pain" information through conventional lines of neural transmission. The goal of this study is to identify which factors are associated with treatment outcome for Calmare therapy. METHODS: Data were garnered from 3 medical centers on 147 patients with various pain conditions who underwent a minimum of either 3 Calmare therapies on consecutive days or 5 therapies overall. A successful outcome was predefined as ≥50% pain relief on a 0 to 10 numerical rating scale that persisted for longer than 1 month after the last treatment. Variables evaluated for their association with outcome included age, sex, study site, baseline pain score, etiology, type of pain, diagnosis, treatment compliance, coexisting psychopathology, opioid use, antidepressant use, and membrane stabilizer use. RESULTS: Overall, the success rate was 38.1%. Variables found to be associated with a positive outcome in multivariate logistic regression included the presence of neuropathic (OR=24.78; 95% CI, 2.47-248.97; P=0.006) or mixed (OR=10.52; 95% CI, 1.09-101.28; P=0.042) pain, and treatment at either Walter Reed (OR=6.87; 95% CI, 1.60-29.51; P=0.010) or Seoul National University (OR=12.29; 95% CI, 1.73-87.43; P=0.012). Factors that correlated with treatment failure were disease (OR=0.04; 95% CI, 0.002-0.59; P=0.020) or traumatic/surgical etiologies (OR=0.05; 95% CI, 0.005-0.56; P=0.015) and antidepressant use (OR=0.47; 95% CI, 0.18-1.02; P=0.056). CONCLUSIONS: A neuropathic or mixed neuropathic-nociceptive pain condition was associated with a positive treatment outcome. Investigators should consider these findings when developing selection criteria in clinical trials designed to determine the efficacy of Calmare therapy.

An alternative distal approach for the lumbar medial branch radiofrequency denervation: a prospective randomized comparative study.

BACKGROUND: An alternative technique involving a "distal approach" can be used for lumbar medial branch radiofrequency denervation (LMBRFD). We described and assessed this technique by comparing it with a conventional tunnel vision approach in a prospective randomized trial. METHODS: Eighty-two patients underwent LMBRFD by a distal (n = 41) or a tunnel vision approach (n = 41). The primary end point was a comparison of the mean difference in the change of 11-point numeric rating scale (NRS) scores of low back pain from entry to the scores at 1 month (NRS at baseline--NRS at 1 month) and at 6 months (NRS at baseline--NRS at 6 months) between the distal approach group and the tunnel vision approach group. The secondary end points were a change of NRS and the Oswestry disability index over time. RESULTS: Thirty-four patients in each group had complete time courses. There were no statistically significant differences in the change of NRS scores between the groups at 1 month (corrected P = 0.19; 97.5% 2-sided confidence interval [CI], -1.37 to 0.37) and 6 months (corrected P = 0.53; 97.5% CI, -1.36 to 0.77). Patients in both groups showed a statistically significant reduction in NRS and Oswestry disability index scores from baseline to that of the scores at 1 and 6 months (all P < 0.0001, Bonferroni corrected). The procedure-related pain score was significantly lower in the distal approach group (P = 0.001; 99% CI, -2.00 to -0.23). CONCLUSIONS: Patients who underwent LMBRFD by the tunnel vision or distal approaches showed significant pain relief at the 6-month follow-up. Less periprocedural pain was reported in the distal approach group. We consider that the distal approach provides an improved option for LMBRFD.