Neuro-protective effect of pre-treatment with Sorghum bicolor and vitamin C on tramadol induced brain oxidative stress and anxiety-like behaviour in male albino rats.

The study focused on the neuroprotective role of Sorghum bicolor and vitamin C in the amelioration of oxidative stress and anxiety-like behavoiur induced by tramadol in male albino rats. The study design involved 7 groups and a control group with 5 male albino rats in each group. Tramadol (40 mg/kg) treatment was administered for 21 days. Tramadol 40mg/kg was administered in all groups. Pretreatment with varying doses of Sorghum bicolor and Vitamin C was done in three of the groups. Behavioral assessment of anxiety and locomotors actions of the groups were compared using Elevated Plus Maze (EPM) and Open Field Test (OFT). In conclusion, Sorghum bicolor and Vitamin C tramadol ameliorated oxidative stress and anxiety-like behaviour induced by tramadol. Pretreatment with Sorghum bicolor or vitamin C (100mg) can also reduced anxiogenic responses in male albino rats that are induced by chronic tramadol use.

Chiropractic spinal manipulation and likelihood of tramadol prescription in adults with radicular low back pain: a retrospective cohort study using US data.

OBJECTIVES: Patients receiving chiropractic spinal manipulation (CSM) for low back pain (LBP) are less likely to receive any opioid prescription for subsequent pain management. However, the likelihood of specifically being prescribed tramadol, a less potent opioid, has not been explored. We hypothesised that adults receiving CSM for newly diagnosed radicular LBP would be less likely to receive a tramadol prescription over 1-year follow-up, compared with those receiving usual medical care. DESIGN: Retrospective cohort study. SETTING: US medical records-based dataset including >115 million patients attending academic health centres (TriNetX, Inc), queried 9 November 2023. PARTICIPANTS: Opioid-naive adults aged 18-50 with a new diagnosis of radicular LBP were included. Patients with serious pathology and tramadol use contraindications were excluded. Variables associated with tramadol prescription were controlled via propensity matching. INTERVENTIONS: Patients were divided into two cohorts dependent on treatment received on the index date of radicular LBP diagnosis (CSM or usual medical care). PRIMARY AND SECONDARY OUTCOME MEASURES: Risk ratio (RR) for tramadol prescription (primary); markers of usual medical care utilisation (secondary). RESULTS: After propensity matching, there were 1171 patients per cohort (mean age 35 years). Tramadol prescription was significantly lower in the CSM cohort compared with the usual medical care cohort, with an RR (95% CI) of 0.32 (0.18 to 0.57; p<0.0001). A cumulative incidence graph demonstrated that the reduced incidence of tramadol prescription in the CSM cohort relative to the usual medical care cohort was maintained throughout 1-year follow-up. Utilisation of NSAIDs, physical therapy evaluation and lumbar imaging was similar between cohorts. CONCLUSIONS: This study found that US adults initially receiving CSM for radicular LBP had a reduced likelihood of receiving a tramadol prescription over 1-year follow-up. These findings should be corroborated by a prospective study to minimise residual confounding.

Tramadol-paracetamol for postoperative pain after spine surgery - A randomized, double-blind, placebo-controlled study.

OBJECTIVES: Multimodal pain management is one component in enhanced recovery after surgery protocol. Here we evaluate the efficacy of tramadol-paracetamol in acute postoperative pain and pain outcome at 12 months after spine surgery in randomized, double-blind, placebo-controlled trial. METHODS: We randomized 120 patients undergoing spine surgery to receive, for add-on pain management, two tramadol-paracetamol 37.5 mg/325 mg (n = 61) or placebo tablets (n = 59) twice a day for 5 postoperative days. In the hospital, multimodal pain management consisted of dexketoprofen and oxycodone. After discharge, patients were prescribed ibuprofen 200 mg, maximum 1,200 mg/day. Pain, analgesic use, and satisfaction with pain medication were followed up with the Brief Pain Inventory questionnaire before surgery and at 1 and 52 weeks after surgery. The primary outcome was patients' satisfaction with pain medication 1 week after surgery. RESULTS: At 1 week after surgery, patients' satisfaction with pain medication was similarly high in the two groups, 75% [interquartile range, 30%] in the placebo group and 70% [40%] in the tramadol-paracetamol group (p = 0.949) on a scale: 0% = not satisfied, 100% = totally satisfied. At 1 week, ibuprofen dose was lower in the placebo group 200 mg [1,000] compared to the tramadol-paracetamol group, 800 mg [1,600] (p = 0.016). There was no difference in the need for rescue oxycodone. Patients in the tramadol-paracetamol group had more adverse events associated with analgesics during the first postoperative week (relative risk = 1.8, 95% confidence interval, 1.2-2.6). CONCLUSION: Add-on pain treatment with tramadol-paracetamol did not enhance patients' satisfaction with early pain management after back surgery.

First derivative synchronous spectrofluorimetric method for the simultaneous determination of tramadol and celecoxib in their dosage forms and human plasma.

One of the most common features of many different clinical conditions is pain; hence, there is a crucial need for eliminating or reducing it to a tolerable level to retrieve physical, psychological and social functioning. A first derivative synchronous spectrofluorimetry technique is proposed for the simultaneous determination of celecoxib and tramadol HCl, a recent coformulation authorized for treating acute pain in adults. The method includes using synchronous spectrofluorimetry at ∆λ = 80 nm where tramadol HCl was determined using first derivative technique at λ = 230.2 nm, while celecoxib was determined at λ = 288.24 nm. The proposed method was successfully applied to their co-formulated dosage forms in addition to spiked human plasma and validated in agreement with the guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). The linear ranges were found to be 0.50-5.0 and 0.15-0.50, the limits of detection to be 0.088 and 0.011 and the limits of quantification to be 0.266 and 0.032 µg/ml for celecoxib and tramadol, respectively. Statistical analysis revealed no significant difference when compared with previously reported methods as evidenced by the values of the variance ratio F-test and Student t-test. The proposed method was successfully applied to commercial dosage forms and spiked human samples. Moreover, the greenness of the proposed method was investigated based on the analytical eco-scale approach, with the results showing an excellent green scale with a score of 95.

Analgesic and Psychotropic Effects of a New Bradykinin Antagonist.

A bradykinin B1 receptors antagonist PAV-0056, an 1,4-benzodiazepin-2-one derivative, intragastrically administrated to mice at doses of 0.1 and 1 mg/kg causes analgesia in the "formalin test" not inferior to that of diclofenac sodium (10 mg/kg) and tramadol (20 mg/kg). PAV-0056 at doses of 0.1 and 10 mg/kg has no anxiolytic and central muscle relaxant effects in mice and does not damage the gastric mucosa in rats. Based on the results of the conditioned place preference test, PAV-0056 also does not induce addiction in mice.

Comparative safety of tramadol and other opioids following total hip and knee arthroplasty.

BACKGROUND: Tramadol is increasingly used to treat acute postoperative pain among older adults following total hip and knee arthroplasty (THA/TKA). However, tramadol has a complex pharmacology and may be no safer than full opioid agonists. We compared the safety of tramadol, oxycodone, and hydrocodone among opioid-naïve older adults following elective THA/TKA. METHODS: This retrospective cohort included Medicare Fee-for-Service beneficiaries ≥ 65 years with elective THA/TKA between January 1, 2010 and September 30, 2015, 12 months of continuous Parts A and B enrollment, 6 months of continuous Part D enrollment, and no opioid use in the 6 months prior to THA/TKA. Participants initiated single-opioid therapy with tramadol, oxycodone, or hydrocodone within 7 days of discharge from THA/TKA hospitalization, regardless of concurrently administered nonopioid analgesics. Outcomes of interest included all-cause hospitalizations or emergency department visits (serious adverse events (SAEs)) and a composite of 10 surgical- and opioid-related SAEs within 90-days of THA/TKA. The intention-to-treat (ITT) and per-protocol (PP) hazard ratios (HRs) for tramadol versus other opioids were estimated using inverse-probability-of-treatment-weighted pooled logistic regression models. RESULTS: The study population included 2,697 tramadol, 11,407 oxycodone, and 14,665 hydrocodone initiators. Compared to oxycodone, tramadol increased the rate of all-cause SAEs in ITT analyses only (ITT HR 1.19, 95%CLs, 1.02, 1.41; PP HR 1.05, 95%CLs, 0.86, 1.29). Rates of composite SAEs were not significant across comparisons. Compared to hydrocodone, tramadol increased the rate of all-cause SAEs in the ITT and PP analyses (ITT HR 1.40, 95%CLs, 1.10, 1.76; PP HR 1.34, 95%CLs, 1.03, 1.75), but rates of composite SAEs were not significant across comparisons. CONCLUSIONS: Postoperative tramadol was associated with increased rates of all-cause SAEs, but not composite SAEs, compared to oxycodone and hydrocodone. Tramadol does not appear to have a superior safety profile and should not be preferentially prescribed to opioid-naïve older adults following THA/TKA.

Simultaneous determination of methadone and tramadol in serum samples by ultrasonic-assisted micro solid phase extraction and gas chromatography-mass spectrometry.

Ultrasonic-assisted dispersive micro solid phase extraction (UA-DMSPE) is proposed as a fast and easy technique for the extraction and preconcentration of methadone and tramadol from serum samples. Different sorbents including carbon nanotubes, oxidized carbon nanotubes, and TiO2 nanoparticles were compared to extract methadone and tramadol. The best performance was obtained using oxidized carbon nanotubes due to the strong affinity between the drugs and carbon nanotube adsorbents. Final analysis of drugs performed by using gas chromatography-mass spectrometric detection. Different parameters affecting the extraction efficiency, such as the sample volume, amount of adsorbent, desorption solvent type and volume, centrifugation time, and speed were investigated and optimized. The striking features of this technique are correlated to its speed and the small volumes of sample (about 1 mL), desorption solvent (about 50 µL), and adsorbent (about 0.001 g) for analysis of drugs, and finally, milder centrifugation conditions relative to the previously reported adsorbent. The optimal parameters were achieved as follows: pH value was set at 9, the sample volume was adjusted to 1200 µL, the amount of adsorbent used was 1 mg, the extraction time was set at 5 min, and the volume of the desorption solvent was adjusted to 50 µL. The limits of detections (0.5 and 0.8 ng mL-1) and quantifications (1.5 and 2.5 ng mL-1) were obtained for methadone and tramadol, respectively. The developed method also showed good repeatability, relative standard deviation (RSD) of 9.49 % and 7.47 % (n = 5), for the spiked aqueous solution at the concentration level of 10, 50, and 100 ng mL-1 for analytes, and linearity, R ≥ 0.9809. The results showed that UA-DMSPE is a quick, relatively inexpensive, and environmentally friendly alternative technique for the extraction of opiate drugs from serum samples.

Assessing the Trends of Tramadol Utilization in the Medicare Part D Population in Rhode Island.

OBJECTIVE: To assess the trends in tramadol dispensing among Medicare Part D patients in Rhode Island. METHODS: An analysis was conducted of the Medicare Part D Provider Utilization and Payment Data Public Use File for the years 2013-2021. Chi squared tests were conducted to assess statistical significance of annual changes in proportions. RESULTS: Following tramadol becoming a controlled substance in 2014, the number of dispensed tramadol prescriptions and patients with a tramadol prescription decreased every subsequent year through 2021 (prescriptions: 42,157 to 33,026; patients: 12,654 to 9,653). The percentage of opioid prescriptions that were tramadol increased from 16.32% in 2013 to 21.19% in 2020. CONCLUSION: Tramadol utilization has been decreasing among the Medicare Part D population in Rhode Island while the percentage of opioid dispensings that were tramadol have been increasing. Future studies are needed to assess whether patients utilizing tramadol are at a higher risk for adverse outcomes.

Concomitant use of pre-emptive analgesia with local and general anesthesia in rat uterine pain surgical model.

Preemptive analgesia is used for postoperative pain management, providing pain relief with few adverse effects. In this study, the effect of a preemptive regime on rat behavior and c-fos expression in the spinal cord of the uterine surgical pain model was evaluated. It was a lab-based experimental study in which 60 female Sprague-Dawley rats; eight to 10 weeks old, weighing 150-300 gm were used. The rats were divided into two main groups: (i) superficial pain group (SG) (with skin incision only), (ii) deep pain group (with skin and uterine incisions). Each group was further divided into three subgroups based on the type of preemptive analgesia administered i.e., "tramadol, buprenorphine, and saline subgroups." Pain behavior was evaluated using the "Rat Grimace Scale" (RGS) at 2, 4, 6, 9 and 24 h post-surgery. Additionally, c-fos immunohistochemistry was performed on sections from spinal dorsal horn (T12-L2), and its expression was evaluated using optical density and mean cell count 2 hours postoperatively. Significant reduction in the RGS was noted in both the superficial and deep pain groups within the tramadol and buprenorphine subgroups when compared to the saline subgroup (p ≤ .05). There was a significant decrease in c-fos expression both in terms of number of c-fos positive cells and the optical density across the superficial laminae and lamina X of the spinal dorsal horn in both SD and DG (p ≤ .05). In contrast, the saline group exhibited c-fos expression primarily in laminae I-II and III-IV for both superficial and deep pain groups and lamina X in the deep pain group only (p ≤ .05). Hence, a preemptive regimen results in significant suppression of both superficial and deep components of pain transmission. These findings provide compelling evidence of the analgesic efficacy of preemptive treatment in alleviating pain response associated with uterine surgery.

A novel comparison of erector spinae plane block and paravertebral block in laparoscopic cholecystectomy.

OBJECTIVE: Erector spinae plane block is an updated method than paravertebral block, possessing a lower risk of complications. This study aimed to compare erector spinae plane and paravertebral blocks to safely reach the most efficacious analgesia procedure in laparoscopic cholecystectomy cases. METHODS: The study included 90 cases, aged 18-70 years, classified as American Society of Anesthesiologists I-II, who underwent an laparoscopic cholecystectomy procedure. They were randomly separated into three groups, namely, Control, erector spinae plane, and paravertebral block. No block procedure was applied to Control, and a patient-controlled analgesia device was prepared containing tramadol at a 10 mg bolus dose and a 10-min locked period. The pain scores were recorded with a visual analog scale for 24 h postoperatively. RESULTS: The visual analog scale values at 1, 5, 10, 20, and 60 min at rest and 60 min coughing were found to be significantly higher in Control than in paravertebral block. A significant difference was revealed between Control vs. paravertebral block and paravertebral block vs. erector spinae plane in terms of total tramadol consumption (p=0.006). Total tramadol consumption in the first postoperative 24 h was significantly reduced in the paravertebral block compared with the Control and erector spinae plane groups. CONCLUSION: Sonography-guided-paravertebral block provides sufficient postoperative analgesia in laparoscopic cholecystectomy surgery. Erector spinae plane seems to attenuate total tramadol consumption.

Evaluation of histological and ultrastructural changes provoked by prenatal tramadol on postnatal cortical cerebellar neuronal development in rats: possible implication of Ki67, GFAP and MicroRNA-7/P53 signalling trajectories.

Tramadol is a novel centrally acting analgesic. Despite, its implementation during pregnancy may impair neuronal survival and synaptic development in neonatal cerebella. The current investigation assessed the histological and ultrastructural alterations in postnatal cortical cerebellar neuronal development induced by prenatal tramadol. 30 offsprings were divided to control group I: fifteen pups born to mothers given saline from D10 till D21 of gestation. Tramadol-treated group II: fifteen pups born to mothers received tramadol HCL (50 mg/kg/day) from D10 till D21 of gestation. Pups were categorized into three subgroups (a, b, and c) and offered for sacrifice on the seventh, fourteenth and twenty-first post-natal days. Light microscopic examination revealed the overcrowding and signs of red degeneration affecting purkinje cell layer. Neurodegenerative signs of both purkinje and granule cell neurons were also confirmed by TEM in form of chromatin condensation, dilated Golgi channels, disrupted endoplasmic reticulum, marked infolding of the nuclear envelope and decrease in granule cell precursors. In addition, the astrocytic processes and terminal nerve axons appeared with different degrees of demyelination and decreased number of oligodendrocytes and degenerated mitochondria. Furthermore, group II exhibited an increase in P53 immune expression. The area percentage of apoptotic cells detected by TUNEL assay was significantly increased. Besides to the significant decrease of Ki67 immunoreactivity in the stem neuronal cell progenitors. Quantitative PCR results showed a significant decline in micro RNA7 gene expression in tramadol treated groups resulting in affection of multiple target genes in P53 signaling pathways, improper cortical size and defect in neuronal development.

Modified thoracoabdominal nerves block through perichondrial approach for laparoscopic cholecystectomy.

OBJECTIVE: A new block, namely, modified thoracoabdominal nerves block through perichondrial approach, is administered below the costal cartilage. We sought to compare the analgesic efficacy of the modified thoracoabdominal nerves block through perichondrial approach block with local anesthetic infiltration at the port sites in an adult population who underwent laparoscopic cholecystectomy. METHODS: Patients who will undergo laparoscopic cholecystectomy were randomized to receive bilateral ultrasound-guided modified thoracoabdominal nerves block through perichondrial approach blocks or local anesthetic infiltration at the port insertion sites. The primary outcome was the total amount of tramadol used in the first 12 h postoperatively. The secondary outcomes were total IV tramadol consumption for the first postoperative 24 h and visual analog scale scores. RESULTS: The modified thoracoabdominal nerves block through perichondrial approach group had significantly less tramadol use in the first 12 h postoperatively (p<0.001). The modified thoracoabdominal nerves block through perichondrial approach group's visual analog scale scores at rest (static) and with movement (dynamic) were significantly lower compared with the port infiltration group (p<0.05). CONCLUSION: Patients who received modified thoracoabdominal nerves block through perichondrial approach block had significantly less analgesic consumption and better pain scores than those who received port-site injections after laparoscopic cholecystectomy.

Efficacy of Serratus Posterior Superior Intercostal Plane Block on Postoperative Pain and Total Analgesic Consumption in Patients Undergoing Reduction Mammoplasty Surgery: An Evidence Based Report.

Serratus posterior superior intercostal plane block (SPSIPB) is a novel technique that provides analgesia in shoulder, hemithorax and in the back of the neck. In this study, the efficacy of this block on postoperative pain and quality of recovery is reported in ten consecutive patients who had undergone reduction mammoplasty. Blocks were performed bilaterally with 30 ml 0.25 % bupivacaine for each side, at the end of surgery. Cumulative tramadol consumption and numerical rating scale (NRS) scores during rest (static) and coughing (dynamic) were assessed within the first postoperative 24 hours. Mean total tramadol consumption was 39 ±9.94 mg. NRS scores above 4 were observed in 5 patients in the dynamic NRS assessment at the postoperative 1st hour, while static and dynamic NRS scores were ≤4 at other durations. SPSIPB may play a part in postoperative multimodal analgesia following mammoplasty in the future and may reduce total analgesic consumption. Key Words: Serratus posterior superior intercostal plane block, Reduction mammoplasty, Breast surgery, Postoperative analgesia.

Green innovation in analytical chemistry: A sustainable densitometric HPTLC approach for the distinctive separation and quantification of structurally related abused drugs - tramadol, tapentadol, and venlafaxine - in seized pharmaceutical dosage forms.

An innovative ecofriendly high-performance thin layer chromatographic (HPTLC) method with spectrophotometric detection for simultaneous determination of Tramadol (TMD), Tapentadol (TAP), and Venlafaxine (VEN) in seized dosage forms was presented. Our method was conducted to achieve separation following the optimal conditions: pre-coated silica gel plates using a green mobile phase (heptane: acetone: ammonia, 7:3:0.5 v/v), with absorbance scanning at 272 nm. The validation of the method was done following International Conference on Harmonization (ICH) guidelines, demonstrates linearity, accuracy, precision, selectivity, robustness, and system suitability. Separation was achieved with a detection limit of 0.34, 0.16, and 0.084 (ug/band) for TMD, TAP, and VEN, respectively, the method successfully analyzes seized samples. Trueness is confirmed through a high degree of similarity between HPTLC and gas chromatography results. The study's ecofriendly approach, simplicity, and selectivity position it as a promising method for efficient, on-site monitoring of seized samples.

PHARMACOKINETICS OF TRAMADOL AND O-DESMETHYLTRAMADOL IN GIANT TORTOISES (CHELONOIDIS VANDENBURGHI, CHELONOIDIS VICINA).

The objective of this study was to determine the pharmacokinetics of two orally administered doses of tramadol (1 mg/kg and 5 mg/kg) and its metabolite, O-desmethyltramadol (M1) in giant tortoises (Chelonoidis vandenburghi, Chelonoidis vicina). Eleven giant tortoises (C. vandenburghi, C. vicina) received two randomly assigned, oral doses of tramadol (either 1 mg/kg or 5 mg/kg), with a washout period of 3 wk between each dose. The half-life (t½) of orally administered tramadol at 1 mg/kg and 5 mg/kg was 11.9 ± 4.6 h and 13.2 ± 6.1 h, respectively. After oral administration of tramadol at 1 mg/kg and 5 mg/kg, the maximum concentration (Cmax) was 125 ± 69 ng/ml and 518 ± 411 ng/ml, respectively. There were not enough data points to determine pharmacokinetic (PK) parameters for the M1 metabolite from either dose. Tramadol administered orally to giant tortoises at both doses provided measurable plasma concentrations of tramadol for approximately 48 h with occasional transient sedation. Oral tramadol at 5 mg/kg, on average, achieves concentrations of >100 ng/ml, the reported human therapeutic threshold, for 24 h. Based on the low levels of M1 seen in this study, M1 may not be a major metabolite in this taxon.

The effect of an ultrasound-guided sacral erector spinae plane block on the postoperative pain of lumbar discectomy: a randomized controlled trial.

BACKGROUND: Pain management is essential after discectomy, the surgical treatment for lumbar disc herniation. This study evaluated the effect of sacral erector spinae plane block (SESPB) versus standard analgesic methods on postoperative analgesia and opioid consumption in lumbar discectomy operations. METHODS: Over 18 years of age, ASA 1-3 group, 54 patients undergoing elective lumbar discectomy were included in the prospective, randomized, controlled, double-blind, study. They were randomly divided into groups, SESPB and non-block (control). Both groups completed surgery under general anesthesia. At the end of the surgery, group SESPB received a bilateral 20 cc block with 0.25% bupivacaine at the level of the second sacral vertebra. Both groups received tramadol via a patient-controlled analgesia (PCA) device. The primary outcome was total opioid consumption in the first 24 hours after surgery. Pain assessment by Visual Analog Scale (VAS), rescue analgesic requirements, time to first rescue analgesic requirement and adverse effects were recorded 24 hours postoperatively. RESULTS: Total tramadol consumption was 168.8±143 mg (P<0.04) higher in the control group. The first six-hour VAS scores and the number of rescue analgesic users were lower in the SESPB group (P<0.01). The first rescue analgesic use time was 440±140.3 minutes in SESPB group and 47.5±116.1 minutes in control group (P<0.01). Nausea-vomiting was more frequent in the control group (P<0.01) and patient satisfaction was higher in the SESPB group (P<0.01). CONCLUSIONS: In lumbar discectomy surgery, ultrasound-guided SESPB provided adequate analgesia by reducing opioid consumption and pain scores without complications.

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.