REKOVER study protocol: a pRospective patient treatment rEgistry of tramadol and dexKetoprofen trometamol oral fixed-dose combination (SKUDEXA) in mOderate to seVere acutE pain in Real-world setting in Asia.

INTRODUCTION: Satisfactory management of acute pain remains a major medical challenge despite the availability of multiple therapeutic options including the fixed-dose combination (FDC) drugs. Tramadol and dexketoprofen trometamol (TRAM/DKP) 75/25 mg FDC was launched in 2018 in Asia and is widely used in the management of moderate to severe acute pain. There are limited data on its effectiveness and safety in Asian patients, and therefore, a need to better understand its usage patterns in clinical practice. We aim to understand the usage pattern of TRAM/DKP FDC, its effectiveness and tolerability in patients with moderate to severe acute pain in Asia. METHODS AND ANALYSIS: REKOVER is a phase-IV, multicountry, multicentre, prospective, real-world observational study. A total of 750 postsurgical and non-surgical patients (male and female, aged 18-80 years) will be recruited from 13 tertiary-care hospitals (15 sites) in Singapore, Thailand, the Philippines and Malaysia. All patients prescribed with TRAM/DKP FDC and willing to participate in the study will be enrolled. The recruitment duration for each site will be 6 months. The severity of pain will be collected using Numeric Pain Rating Scale through the treatment period from day 1 to day 5, while satisfaction with the treatment will be evaluated using Patient Global Evaluation Scale at the end of treatment. Any adverse event reported during the study duration will be recorded for safety analysis (up to day 6). The study data will be entered into the ClaimIt portal and mobile application (app) (ObvioHealth, USA). All the inpatient data will be entered into the portal by the study site and for outpatient it will be done by patients through an app. ETHICS AND DISSEMINATION: The study has been approved by the local ethics committee from each study sites in Singapore, Thailand, the Philippines and Malaysia. Findings will be disseminated through local and global conference presentations, publications in peer-reviewed scientific journals and continuing medical education.

Classification of elderly pain severity from automated video clip facial action unit analysis: A study from a Thai data repository.

Data from 255 Thais with chronic pain were collected at Chiang Mai Medical School Hospital. After the patients self-rated their level of pain, a smartphone camera was used to capture faces for 10 s at a one-meter distance. For those unable to self-rate, a video recording was taken immediately after the move that causes the pain. The trained assistant rated each video clip for the pain assessment in advanced dementia (PAINAD). The pain was classified into three levels: mild, moderate, and severe. OpenFace© was used to convert the video clips into 18 facial action units (FAUs). Five classification models were used, including logistic regression, multilayer perception, naïve Bayes, decision tree, k-nearest neighbors (KNN), and support vector machine (SVM). Out of the models that only used FAU described in the literature (FAU 4, 6, 7, 9, 10, 25, 26, 27, and 45), multilayer perception is the most accurate, at 50%. The SVM model using FAU 1, 2, 4, 7, 9, 10, 12, 20, 25, and 45, and gender had the best accuracy of 58% among the machine learning selection features. Our open-source experiment for automatically analyzing video clips for FAUs is not robust for classifying pain in the elderly. The consensus method to transform facial recognition algorithm values comparable to the human ratings, and international good practice for reciprocal sharing of data may improve the accuracy and feasibility of the machine learning's facial pain rater.

Ischemic preconditioning upregulates Mitofusin2 and preserves muscle strength in tourniquet-induced ischemia/reperfusion.

Background: Tourniquet-induced ischemia and reperfusion (I/R) has been related to postoperative muscle atrophy through mechanisms involving protein synthesis/breakdown, cellular metabolism, mitochondrial dysfunction, and apoptosis. Ischemic preconditioning (IPC) could protect skeletal muscle against I/R injury. This study aims to determine the underlying mechanisms of IPC and its effect on muscle strength after total knee arthroplasty (TKA). Methods: Twenty-four TKA patients were randomized to receive either sham IPC or IPC (3 cycles of 5-min ischemia followed by 5-min reperfusion). Vastus medialis muscle biopsies were collected at 30 â€‹min after tourniquet (TQ) inflation and the onset of reperfusion. Western blot analysis was performed in muscle protein for 4-HNE, SOD2, TNF-ɑ, IL-6, p-Drp1ser616, Drp1, Mfn1, Mfn2, Opa1, PGC-1ɑ, ETC complex I-V, cytochrome c, cleaved caspase-3, and caspase-3. Clinical outcomes including isokinetic muscle strength and quality of life were evaluated pre- and postoperatively. Results: IPC significantly increased Mfn2 (2.0 â€‹± â€‹0.2 vs 1.2 â€‹± â€‹0.1, p â€‹= â€‹0.001) and Opa1 (2.9 â€‹± â€‹0.3 vs 1.9 â€‹± â€‹0.2, p â€‹= â€‹0.005) proteins expression at the onset of reperfusion, compared to the ischemic phase. There were no differences in 4-HNE, SOD2, TNF-ɑ, IL-6, p-Drp1ser616/Drp1, Mfn1, PGC-1ɑ, ETC complex I-V, cytochrome c, and cleaved caspase-3/caspase-3 expression between the ischemic and reperfusion periods, or between the groups. Clinically, postoperative peak torque for knee extension significantly reduced in the sham IPC group (-16.6 [-29.5, -3.6] N.m, p â€‹= â€‹0.020), while that in the IPC group was preserved (-4.7 [-25.3, 16.0] N.m, p â€‹= â€‹0.617). Conclusion: In TKA with TQ application, IPC preserved postoperative quadriceps strength and prevented TQ-induced I/R injury partly by enhancing mitochondrial fusion proteins in the skeletal muscle. The translational potential of this article: Mitochondrial fusion is a potential underlying mechanism of IPC in preventing skeletal muscle I/R injury. IPC applied before TQ-induced I/R preserved postoperative quadriceps muscle strength after TKA.

CoenzymeQ10 and Ischemic Preconditioning Potentially Prevent Tourniquet-Induced Ischemia/Reperfusion in Knee Arthroplasty, but Combined Pretreatment Possibly Neutralizes Their Beneficial Effects.

Tourniquet (TQ) use during total knee arthroplasty (TKA) induces ischemia/reperfusion (I/R) injury, resulting in mitochondrial dysfunction. This study aims to determine the effects of coenzyme Q10 (CoQ10) and ischemic preconditioning (IPC), either alone or in combination, on I/R-induced mitochondrial respiration alteration in peripheral blood mononuclear cells (PBMCs) and pain following TKA. Forty-four patients were allocated into four groups: control, CoQ10, IPC, and CoQ10 + IPC. CoQ10 dose was 300 mg/day for 28 days. IPC protocol was three cycles of 5/5-min I/R time. Mitochondrial oxygen consumption rates (OCRs) of PBMCs were measured seven times, at baseline and during ischemic/reperfusion phases, with XFe 96 extracellular flux analyzer. Postoperative pain was assessed for 48 h. CoQ10 improved baseline mitochondrial uncoupling state; however, changes in OCRs during the early phase of I/R were not significantly different from the placebo. Compared to ischemic data, IPC transiently increased basal OCR and ATP production at 2 h after reperfusion. Clinically, CoQ10 significantly decreased pain scores and morphine requirements at 24 h. CoQ10 + IPC abolished analgesic effect of CoQ10 and mitochondrial protection of IPC. In TKA with TQ, IPC enhanced mitochondrial function by a transient increase in basal and ATP-linked respiration, and CoQ10 provides postoperative analgesic effect. Surprisingly, CoQ10 + IPC interferes with beneficial effects of each intervention.

Possible roles of mitochondrial dysfunction in neuropathy.

OBJECTIVES: The present review aims to present and discuss the consistent and inconsistent evidence regarding the associations between mitochondrial dysfunction and several neuropathic models, including trauma-induced, chemotherapy-induced, diabetes-induced and HIV-associated sensory neuropathy. METHODS: The searching strategy and inclusion criteria for this review are all research articles in the PubMed database published before July 2019. We used the search terms 'mitochondria' and 'neuropathy' for the present review and non-English articles were excluded. RESULTS: Damage to mitochondria via trauma, chemotherapy drugs, hyperglycaemia and HIV infection has been widely discussed to play an important role in the pathogenesis of neuropathy. Several mechanisms of mitochondrial damages have been proposed. CONCLUSION: The damage of mitochondria results in cellular apoptosis, which appears to be one of the key factors in the pathogenesis of neuropathy. Novel therapeutic strategies targeting mitochondria could be a potential therapeutic target in neuropathy.

Mitochondrial Fusion Promoter Alleviates Brain Damage in Rats with Cardiac Ischemia/Reperfusion Injury.

BACKGROUND: Cardiac ischemia/reperfusion (I/R) injury induces brain damage through increased blood-brain barrier (BBB) breakdown, microglial hyperactivity, pro-inflammatory cytokines, amyloid-ß deposition, loss of dendritic spines, brain mitochondrial dysfunction, and imbalanced mitochondrial dynamics. Previous studies demonstrated that mitochondrial fusion promoter reduced cardiac damage from cardiac I/R injury; however, following cardiac I/R injury, the roles of mitochondrial dynamics on the brain have not been investigated. OBJECTIVE: To investigate the effects of pharmacological modulation using mitochondrial fusion promoter (M1) in the brain of rats following cardiac I/R injury. METHODS: Twenty-four male Wistar rats were separated into two groups; 1) sham-operation (n = 8) and 2) cardiac I/R injury (n = 16). Rats in the cardiac I/R injury group were randomly received either normal saline solution as a vehicle or a mitochondrial fusion promoter (M1, 2 mg/kg) intravenously. Both treatments were given to the rats 15 minutes before cardiac I/R injury. At the end of the reperfusion protocol, the brain was rapidly removed to investigate brain mitochondrial function, mitochondrial dynamics proteins, microglial activity, and Alzheimer's disease (AD) related proteins. RESULTS: Cardiac I/R injury induced brain mitochondrial dynamics imbalance as indicated by reduced mitochondrial fusion proteins expression without alteration in mitochondrial fission, brain mitochondrial dysfunction, BBB breakdown, increased macrophage infiltration, apoptosis, and AD-related proteins. Pretreatment with M1 effectively increased the expression of mitofusin 2, a mitochondrial outer membrane fusion protein, reduced brain mitochondrial dysfunction, BBB breakdown, macrophage infiltration, apoptosis, and AD-related proteins in rats following cardiac I/R injury. CONCLUSION: This mitochondrial fusion promoter significantly protected rats with cardiac I/R injury against brain damage.

Coenzyme Q10 supplementation alleviates pain in pregabalin-treated fibromyalgia patients via reducing brain activity and mitochondrial dysfunction.

Although coenzyme Q10 (CoQ10) supplementation has shown to reduce pain levels in chronic pain, the effects of CoQ10 supplementation on pain, anxiety, brain activity, mitochondrial oxidative stress, antioxidants, and inflammation in pregabalin-treated fibromyalgia (FM) patients have not clearly elucidated. We hypothesised that CoQ10 supplementation reduced pain better than pregabalin alone via reducing brain activity, mitochondrial oxidative stress, inflammation, and increasing antioxidant levels in pregabalin-treated FM patients. A double-blind randomised placebo-controlled trial was conducted. Eleven FM patients were enrolled with 2 weeks wash-out then randomly allocated to 2 treatment groups; pregabalin with CoQ10 or pregabalin with placebo for 40 d. Then, patients in CoQ10 group were switched to placebo, and patients in placebo group were switched to CoQ10 for another 40 d. Pain pressure threshold (PPT), FM questionnaire, anxiety, and pain score were examined. Peripheral blood mononuclear cells (PBMCs) were isolated to investigate mitochondrial oxidative stress and inflammation at day 0, 40, and 80. The level of antioxidants and brain positron emission tomography (PET) scan were also determined at these time points. Pregabalin alone reduced pain and anxiety via decreasing brain activity compared with their baseline. However, it did not affect mitochondrial oxidative stress and inflammation. Supplementation with CoQ10 effectively reduced greater pain, anxiety and brain activity, mitochondrial oxidative stress, and inflammation. CoQ10 also increased a reduced glutathione levels and superoxide dismutase (SOD) levels in FM patients. These findings provide new evidence that CoQ10 supplementation provides further benefit for relieving pain sensation in pregabalin-treated FM patients, possibly via improving mitochondrial function, reducing inflammation, and decreasing brain activity.

Persistent Severe Hiccups After Dexamethasone Intravenous Administration.

BACKGROUND Hiccups induced by steroids administration is not common. Although it is not life-threatening and is always recognized as a transient and minor complication, it can be severely uncomfortable and significantly diminished patient quality of life. In this case report, persistent hiccups were observed in 2 middle-aged Thai men receiving low-dose intravenous dexamethasone. This case report highlights the awareness of severe dexamethasone-induced hiccups. CASE REPORT A 49-year-old man and a 38-year-old man were admitted to our hospital and received IV dexamethasone. The hiccups started after each patient received a single dose of dexamethasone. The frequency and severity of their hiccups increased over time during dexamethasone treatment. Hiccups still continued to occur despite the discontinuation of dexamethasone and lasted for 72 h after drug termination. CONCLUSIONS Dexamethasone can cause persistent hiccups. Although hiccups are not life-threatening, it should not be neglected since it can be severely uncomfortable and significantly diminish patient quality of life. Termination of dexamethasone can gradually relieve hiccups. Dexamethasone should be used cautiously and clinicians must be aware of this undesirable effect.

The Possible Pathophysiological Outcomes and Mechanisms of Tourniquet-Induced Ischemia-Reperfusion Injury during Total Knee Arthroplasty.

Ischemia and reperfusion (I/R) injury induced by tourniquet (TQ) application leads to the release of both oxygen free radicals and inflammatory cytokines. The skeletal muscle I/R may contribute to local skeletal muscle and remote organ damage affecting outcomes after total knee arthroplasty (TKA). The aim of the study is to summarize the current findings associated with I/R injury following TKA using a thigh TQ, which include cellular alterations and protective therapeutic interventions. The PubMed database was searched using the keywords "ischemia reperfusion injury," "oxidative stress," "tourniquet," and "knee arthroplasty." The search was limited to research articles published in the English language. Twenty-eight clinical studies were included in this qualitative review. Skeletal muscle I/R reduces protein synthesis, increases protein degradation, and upregulates genes in cell stress pathways. The I/R of the lower extremity elevates local and systemic oxidative stress as well as inflammatory reactions and impairs renal function. Propofol reduces oxidative injury in this I/R model. Ischemic preconditioning (IPC) and vitamin C may prevent oxygen free radical production. However, a high dose of N-acetylcysteine possibly induces kidney injury. In summary, TQ-related I/R during TKA leads to muscle protein metabolism alteration, endothelial dysfunction, oxidative stress, inflammatory response, and renal function disturbance. Propofol, IPC, and vitamin C show protective effects on oxidative and inflammatory markers. However, a relationship between biochemical parameters and postoperative clinical outcomes has not been validated.

Role of microglia under cardiac and cerebral ischemia/reperfusion (I/R) injury.

Both cerebral and cardiac ischemia causes loss of cerebral blood flow, which may lead to neuronal cell damage, neurocognitive impairment, learning and memory difficulties, neurological deficits, and brain death. Although reperfusion is required immediately to restore the blood supply to the brain, it could lead to several detrimental effects on the brain. Several studies demonstrate that microglia activity increases following cerebral and cardiac ischemic/reperfusion (I/R) injury. However, the effects of microglial activation in the brain following I/R remains unclear. Some reports demonstrated that microglia were involved in neurodegeneration and oxidative stress generation, whilst others showed that microglia did not respond to I/R injury. Moreover, microglia are activated in a time-dependent manner, and in a specific brain region following I/R. Recently, several therapeutic approaches including pharmacological interventions and electroacupuncture showed the beneficial effects, while some interventions such as hyperthermia and hyperoxic resuscitation, demonstrated the deteriorated effects on the microglial activity after I/R. Therefore, the present review summarized and discussed those studies regarding the effects of global and focal cerebral as well as cardiac I/R injury on microglia activation, and the therapeutic interventions.

Effect of coenzyme Q10 on mitochondrial respiratory proteins in trigeminal neuralgia.

Trigeminal neuralgia (TN) is the neuropathic pain. Mitochondrial dysfunction, increased oxidative stress, and inflammation demonstrated in chronic pain. Carbamazepine (CBZ) is the first-line drug for TN, however, it is still insufficient. Coenzyme Q10 (CoQ10) has been used as the additional supplement for pain therapy. Nonetheless, mitochondrial respiratory proteins, oxidative stress, and inflammation in TN, and the add-on effects of CoQ10 on those defects have never been investigated. CBZ-treated TN-patients, naïve TN-patients, and control subjects were included. CBZ-treated TN-patients were randomised into two subgroups, received either CoQ10 or placebo for 2 months. Pain levels were evaluated, and peripheral blood mononuclear cells were isolated to determine the oxidative stress, mitochondrial oxidative phosphorylation (OXPHOS), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and cytokines including TNF-α, IL-1ß and IL-18 mRNA expression. Pain scales, oxidative stress, and OXPHOS levels were greater in naïve TN-patients than control, whereas the cytokine profiles were unchanged. Although pain scales were lower in CBZ-treated TN-patients than in naïve TN-patients, oxidative stress, OXPHOS, and cytokine expression profiles were not different. PGC-1α levels found to be increased in CBZ-treated TN patients when compared with the naïve group. CoQ10 supplement in CBZ-treated TN patients reduced pain scale and oxidative stress and increased antioxidants levels when compared with placebo group. However, OXPHOS, PGC-1α, and cytokines were not different between groups. These findings suggest that increased oxidative stress could be potentially involved in the pathogenesis of TN. CoQ10 supplements can reduce oxidative stress, leading to more effective pain reduction in TN patients being treated with CBZ.

Alterations of brain activity in fibromyalgia patients.

Fibromyalgia is a chronic pain syndrome, characterized by widespread musculoskeletal pain with diffuse tenderness at multiple tender points. Despite intense investigations, the pathophysiology of fibromyalgia remains elusive. Evidence shows that it could be due to changes in either the peripheral or central nervous system (CNS). For the CNS changes, alterations in the high brain area of fibromyalgia patients have been investigated but the definite mechanisms are still unclear. Magnetic Resonance Imaging (MRI) and Functional Magnetic Resonance (fMRI) have been used to gather evidence regarding the changes of brain morphologies and activities in fibromyalgia patients. Nevertheless, due to few studies, limited knowledge for alterations in brain activities in fibromyalgia is currently available. In this review, the changes in brain activity in various brain areas obtained from reports in fibromyalgia patients are comprehensively summarized. Changes of the grey matter in multiple regions such as the superior temporal gyrus, posterior thalamus, amygdala, basal ganglia, cerebellum, cingulate cortex, SII, caudate and putamen from the MRI as well as the increase of brain activities in the cerebellum, prefrontal cortex, anterior cingulate cortex, thalamus, somatosensory cortex, insula in fMRI studies are presented and discussed. Moreover, evidence from pharmacological interventions offering benefits for fibromyalgia patients by reducing brain activity is presented. Because of limited knowledge regarding the roles of brain activity alterations in fibromyalgia, this summarized review will encourage more future studies to elucidate the underlying mechanisms involved in the brains of these patients.

Comparison of efficacy and effectiveness between ULTRACET and tramadol/acetaminophen in acute postoperative pain after upper extremity surgery.

OBJECTIVE: To compare the efficacy and effectiveness between ULTRACE, a new analgesic combination of tramadol/ acetaminophen, and tramadol/acetaminophen for acute postoperative pain after upper extremity surgery. STUDY DESIGN: A double blind randomized controlled trial. MATERIAL AND METHOD: One hundred and eighty patients who underwent upper extremity surgery under brachial plexus block were randomized to receive either ULTRACE (n = 87) or tramadol and acetaminophen (n = 93) immediately after surgery in the postanesthetic care unit (PACU). Total morphine requirement, pain score (VRS) and drug adverse effects were compared between those two groups using independent single t-test, Mann-Whitney U-test, Chi-square test and Fisher-exact test respectively. RESULTS: Total morphine requirement was significantly lower in subjects who used ULTRACE when compared with the tramadol and acetaminophen group (0.51 and 0.69 mg in the first 6 hours after the operation, 0.0 and 0.13 mg in hours 6-12 after the operation). Moreover there were fewer side effects in this ULTRACE group too. CONCLUSION: ULTRACET has more efficacy and fewer side effects when compared with tramadol and acetaminophen in acute postoperative pain surgery.