Vol. 6 No. 1 February 2017Vol. 6 No. 1 February 2017Vol 6 No 1 February 201

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis, joint damage, and progressive disability. There are many treatment options for RA, including n o n - s t e r o i d a l a n t i - i n f l a m m a t o r y drugs (NSAIDs), g l u c o c o r t i c o i d s , d i sease -modi fy ing anti-rheumatic drugs (DMARDs) etc. Non-steroidal anti-inflammatory drugs are commonly prescribed for relief of pain in patients with RA, but these medications alone may not provide adequate pain relief. Combining analgesics may provide improved efficacy and tolerability, and this approach has been recommended by the American Medical Directors Association, which supports the addition of tramadol to acetaminophen (APAP) or an NSAID, alone or in combination, for the management of chronic pain. A 1-week, multicenter, double-blind, placebo-controlled trial was conducted in Korea using tramadol 37.5-mg /APAP 325-mg combination as an add-on therapy for RA pain management. The aim of the study was to evaluate the efficacy and tolerability of tramadol 37.5-mg/APAP 325-mg combination compared with placebo, as add-on therapy in patients with RA pain that was inadequately controlled by NSAIDs or DMARDs. From 5 centers of Korea 277 patients who were suffering from RA, were enrolled in the study. The enrolled subjects were suffering from RA (diagnosed according to American College of Rheumatology criteria) for at least 6 months before the study who had been taking a stable daily dose of an NSAID (including COX-2-selective inhibitors) or DMARD for at least 30 days before the study. Of the 277 subjects randomized to treatment, 267 (n=201 in tramadol/APAP group, n= 66 in placebo group) were included in the intent-to-treat population. Among 267 patients, 227 (85.0%) were women and 40 (15.0%) were men; the mean age of subjects was 52 years. But the study was ended with 223

patients (n= 160 in tramadol/APAR group and n=63 in placebo group). The primary efficacy variable was the mean daily pain relief score over 1 week, measured on a 6-point scale (4 = complete; 3 = a lot; 2 = some; 1 = a little; 0 = none; -1 = worse). Secondary outcomes were included the mean daily pain intensity score, measured on a

100-mm visual analog scale (VAS) (from 0 mm = no pain to 100 mm = extreme pain); pain intensity and pain relief at day 7; subjects' and investigators' mean overall assessments of study drug, measured on a Likert scale (from 2 = very good to -2 = very poor). Mean daily pain relief scores at the end of 1 week were significantly higher in the tramadol/APAP group than in the placebo group (1.04 [0.89] vs 0.78 [0.80], respectively; P = 0.037). Mean daily pain intensity at the end of 1 week was significantly lower in the tramadol/APAP group than in the placebo group (47.23 [19.96] mm vs 53.81 [16.59] mm; P = 0.018). Tramadol/APAP received significantly higher ratings on both the subjects' (P =0.006) and investigators' (P = 0.005) overall assessments of study drug: 54.4% of both subjects and investigators assessed tramadol/APAP as "good" or "very good," compared with corresponding ratings of 41.3% and 40.0% in the placebo group. Two hundred seventy-two subjects (n=205 in tramadol/APAP, n=67 in placebo) were evaluable for tolerability. Only one serious adverse event occurred in 1 subject receiving tramadol/APAP.In this study, tramadol/APAP combination was used as an add-on therapy in subjects with symptomatic RA. It was associated with a significant improvement in pain relief and a significant reduction in pain intensity compared with placebo. So, use of tramadol/APAP may be considered as an add-on therapy, when analgesics are needed in addition to conventional NSAIDs and DMARDs in subjects with RA.

Added on Tramadol/Acetaminophen Combination with Regular

RA Therapy Significantly Relief Pain in RA Patients

ARTICLES INSIDE

Published byBeximco Pharmaceuticals Ltd.19 Dhanmondi R/A Road No. 7 Dhaka- 1205, BangladeshPhone: +880-2-58611001-7Fax: +880-2-58614601E-mail: info@bpl.netWebsite: www.beximcopharma.com

Optical Control of a Neuroreceptor can Alleviates

Chronic Pain

High Cholesterol Level Leads

to Osteoarthritis

New Guidelines for Low Back Pain

Treatment

Page 02

Page 03

Page 04

Bexinfo pain is decorated with some recent pain related news. We collected these news from some reliable sources. We hope our this small endeavor will help you in your daily practice.

Vol. 6 No. 1 February 2017

Pain serves as a valuable warning signal, but when it becomes chronic, it should be considered as a real disease. This disease is nevertheless associated with modifications to the nervous system. Around 20% of the European population has experienced episodes of chronic pain, treatments are only effective in fewer than half of them. Recently an international team including research scientists from France has identified a pain center in brain which is associated with chronic pain. This research news was published on 20 December 2016, in the journal Molecular Psychiatry. In this research scientists wanted to understand how the brain modulates physical pain and the affective and cognitive disorders that accompany it like anxiety, loss of positive emotions, hypersensitivity to pain etc. The researcher worked on mice which were conscious and free to move around, but suffering from chronic inflammatory pain. During the study period, they focused on the amygdala, a brain region involved in managing pain and

emotions, and on the type-4 glutamate receptor (mGlu4). This receptor is the principal transmitter of pain signals in the nervous system of mammals. This neuroreceptor detects the presence of glutamate and, depending on need, modulates its release at the synaptic level. In order to study these receptors, scientists generally use a ligand that can activate or inhibit them. The team innovated by creating a specific, photocontrolled ligand, optogluram, whose action on mGlu4 is directed by light. The use of optical fibers then enabled them to achieve very precise control of the activation of this neuroreceptor in a particular region of the brain. By activating optogluram with light, they were able to rapidly and reversibly

inhibit their painful symptoms, thus demonstrating that the brains of these mice preserved their ability to counteract these effects. By identifying a modulator that can act on chronic pain, this work raises hopes for the development of new therapies for treating chronic pain.focused on the amygdala, a brain region involved in managing pain and therapies for treating chronic pain.

Vol. 6 No. 1 February 2017Vol 6 No 1 February 201

Pain serves as a valuable warning signal, but when it becomes chronic it should be considered as a

emotions, and on the type-4 glutamate receptor (mGlu4) This receptor is the principal transmitter

Bacterial Cause of Gum Disease May Drive Rheumatoid Arthritis

Optical Control of a Neuroreceptor can Alleviates Chronic Pain

The bacteria that cause chronic gum infections may also trigger the autoimmune inflammation in rheumatoid arthritis (RA), according to a new research of Johns Hopkins School of Medicine. In this study investigators have identified the common denominator Aggregatibacter actinomycetemcomitans, which causes gum infection as well as RA. This study was published in the journal Science Translational Medicine. Medical investigators have observed a clinical association between periodontal disease and RA since the early 1900s, and over time, researchers have suspected that both diseases may be triggered by a common factor. In this recent study, the researcher team found that, infection with A. actinomycetemcomitans causes overproduction of citrullinated proteins, suspected of activating the immune system and driving the cascade of events leading to RA. Andrade, senior study investigator, explains that citrullination happens naturally in everyone as a way to regulate the function of proteins. But in people with RA, this process becomes overactive, resulting in the abnormal accumulation of citrullinated proteins. A. actinomycetemcomitans causes hypercitrullination in neutrophils. "Neutrophils are the most abundant inflammatory cells found in the joints and the gums of patients with RA and periodontal disease,” researcher said. Neutrophils are highly enriched with the peptidylarginine deiminase (PAD) enzymes required for citrullination. The A. actinomycetemcomitans initiates hypercitrullination through the bacterial secretion of a toxin, leukotoxin A (LtxA), as a selfdefense strategy to kill host immune cells. The toxin creates holes on the surface of neutrophils, allowing a flux of high amounts of calcium

into the cell where concentrations are normally kept low. In neutrophil the PAD enzymes are activated with calcium, the abrupt exposure to high amounts of calcium overactivates these enzymes, generating hypercitrullination. As a part of the study, the team developed a test using the bacterium and LtxA to detect antibodies against A. actinomycetemcomitans in blood. Using 196 samples from a large study of patients with RA, the researchers found that almost half of the patients (92 out of 196) had evidence of infection by A. actinomycetemcomitans. These data were similar to patients with periodontal disease with approximately 60 percent

positivity, but quite different in healthy controls, who only had 11 percent of people positive for A. actinomycetemcomitans. More strikingly, exposure to A. actinomycetemcomitans was a major determinant in the production of antibodies to citrullinated proteins in patients with genetic susceptibility to RA. Maximilian Konig, first author of the study, said "This research may be the closest we've come to uncovering the root cause of RA." The researcher said that, “this findings have important implications for prevention and treatment of RA”. But Andrade cautions that the study only looked at patients at a single point in time with established RA, and that to prove cause and effect of A. actinomycetemcomitans and RA, more research will be needed to track the potential role of the bacteria in the onset and evolution of the disease, which can span decades. He said, "If we know more about the evolution of both combined, perhaps we could prevent rather than just intervene."

The INTELLIGENT pain killer

For comprehensive pain management

Vol. 6 No. 1 February 2017

Recently researchers from the Massachusetts General Hospital (MGH), have identified the initial steps of joint inflammation in inflammatory arthritis by using an imaging procedure. This amazing news was published in the Science Immunology, January 2017 issue. Andrew Luster senior author of the study said, "Inflammatory arthritis is caused when immune cells are recruited from the blood into the joint in a highly regulated process controlled by chemoattractants and adhesion receptors. But when the disease has become symptomatic, it is difficult to determine the initial steps that set off the recruitment of immune cells into the joint and the specific roles of the different chemoattractants. Our study was designed to more fully understand this process." Inflammatory arthritis includes a number of autoimmune diseases of the joints, including rheumatoid Arthritis (RA) and lupus. These are caused by a type of inflammation called type III hypersensitivity. This type III hypersensitivity reaction results when a localized accumulation of immune complexes (ICs) -- antibodies bound to their antigens-- are deposited in tissue and sets off an inflammatory response involving the infiltration and activation of immune cells, initially the neutrophil. Immune complexes also promotes the recruitment of neutrophils. To understand the mechanism that triggers and sets off the attraction of neutrophils, the researcher

team at MGH have used an imaging technology to follow processes in a living animal. This imaging technology is called multiphoton intravital microscopy. By this technology the researchers were able to follow in real time the development of IC-induced inflammatory arthritis in mice. The researcher team also found that a specific receptor called complement C5a receptor (C5aR) was the key protein triggering neutrophil adhesion to the endothelial cells in the joint, setting off inflammation. Once neutrophils reach the joint space, they initiate a signaling cascade that leads to the release of chemokines (interleukin-1) by cells lining the joint, which in turn amplifies the infiltration of the immune cells and their

movement into the joint space. Regarding the use of this imaging technology author said, "The control of immune cell entry into the joint represents a major point at which new therapies could be developed to reduce the symptoms of inflammatory arthritis. Imaging of the joint could help evaluate the mechanism of a drug’s therapeutic effect, and if a process turns out to be mediated by more than one chemoattractant, understanding the mechanism would allow the rational design of combination therapies to completely shut down critical steps in the process.”

mechanism that triggers and sets off the attraction of neutrophils, the researcher

Vol. 6 No. 1 February 2017Vol 6 No 1 February 201

Recently researchers from theMassachusetts General Hospital (MGH)

team at MGH have used an imaging technology to follow processes in a living

Imaging can Identify Protein That Triggers Inflammatory Arthritis

According to a new study of Queensland University of Brisbane Australia, high cholesterol might harm more than our cardiovascular systems. This study suggests that high cholesterol levels trigger mitochondrial oxidative stress on cartilage cells, causing them to die, and ultimately leading to the development of osteoarthritis. The study was published in the online issue of The Federation of American Societies for Experimental Biology (FASEB) Journal. Researcher tested the potential therapeutic role of mitochondria targeting antioxidants in high cholesterol induced osteoarthritis and provided proof of concept for the use of mitochondrial targeting antioxidants to treat osteoarthritis. To make this discovery Indira Prasadam, researcher of the study, and her colleagues used two different animal models to mimic human hypercholesterolemia. The first was a mouse model that had an altered gene called ApoE-/- , that made the animals hypercholesteremic. The other model was a rat model. Both models were fed a high cholesterol diet or control normal diet, after which they underwent a surgery that mimics knee injuries in people and was designed to bring on

osteoarthritis. Both the mice and the rats that were subjected to surgery and fed with high cholesterol diets showed more severe osteoarthritis development than seen in the normal diet group. However, when both the mice and the rats were exposed to the cholesterol lowering drug atorvastatin and mitochondrion targeted antioxidants, the development of osteoarthritis was markedly decreased in relation to the untreated groups. Thoru Pederson, editor-in-chief of The FASEB Journal said, "Just when we thought all the angles on osteoarthritis had been uncovered, a new lead like this comes along. The focus of hypercholesterolemia, whether familial or sporadic, has, of course, always been on arterial disease, but here we

have a fascinating new discovery." This research suggests that, mitochondria targeting antioxidants could be a viable treatment strategy for osteoarthritis before cartilage reaches a stage of complete degradation. Prasadam concluded, "Our team has already begun working alongside dietitians to try to educate the public about healthy eating and how to keep cholesterol levels at a manageable level that won't damage joints."

High Cholesterol Level Leading to Osteoarthritis

Vol. 6 No. 1 February 2017

Only one session of 20 minutes moderate exercise can stimulate the immune system and producing an anti-inflammatory cellular response, according to a new study of University of California San Diego. It's well known that regular physical activity has health benefits, including weight control, strengthening the heart, bones and muscles and reducing the risk of certain diseases. Recently, researchers have found how just one session of moderate exercise can also povide anti-inflammatory effect. This finding has encouraging implications for chronic diseases like arthritis, fibromyalgia and for more pervasive conditions, such as obesity. This study was published in January 2017 online issue of Brain, Behavior and Immunity journal. Senior author Suzi Hong said, "Each time we exercise, we are truly doing something good for our body on many levels, including at the immune cell level. The anti-inflammatory benefits of exercise have been known to researchers, but finding out how that process happens is the key to safely maximizing those benefits." The brain and sympathetic nervous system that serves to accelerate heart rate and raise blood pressure, among other things are activated during exercise to enable the body to carry out work. Hormones, such as epinephrine and norepinephrine, are released into the blood stream and trigger adrenergic receptors, which immune cells possess. This activation process during exercise produces immunological responses, which include the production of many cytokines, or proteins, one of which is TNF- a key regulator of local and systemic inflammation that also helps boost immune responses. "Our study

found one session of about 20 minutes of moderate treadmill exercise resulted in a five percent decrease in the number of stimulated immune cells producing TNF. Knowing what sets regulatory mechanisms of inflammatory proteins in motion may contribute to developing new therapies for the overwhelming number of individuals with chronic inflammatory conditions, including nearly 25 million Americans who suffer from autoimmune diseases" Hong added. The 47 study participants walked on a treadmill at an intensity level that was adjusted based on their fitness level. Author also said "Our study shows a workout session doesn't actually have to be intense to have anti-inflammatory effects. Twenty minutes to

half-an-hour of moderate exercise, including fast walking, appears to be sufficient. Feeling like a workout needs to be at a peak exertion level for a long duration can intimidate those who suffer from chronic inflammatory diseases and could greatly benefit from physical activity." Inflammation is a vital part of the body's immune response. It is the body's attempt to heal itself after an injury; defend itself against foreign invaders, such as viruses and bacteria; and repair damaged tissue. However, chronic inflammation can lead to serious health issues associated with diabetes, celiac disease, obesity and other conditions. Hong concluded, "Patients with chronic inflammatory diseases should always consult with their physician regarding the appropriate treatment plan, but knowing that exercise can act as an anti-inflammatory is an exciting step forward in possibilities."

Vol. 6 No. 1 February 2017Vol 6 No 1 February 201

Only one session of 20 minutes moderate exercise can stimulate the immune system and

found one session of about 20 minutes of moderate treadmill exercise resulted in a five

Only 20 Minutes Moderate Exercise Helps to Suppress Inflammation in The Body

Low back pain (LBP) is one of the most common reasons for all physician visits in the United States (US). Approximately one quarter of US adults reported having LBP lasting at least one day in the past three months. This LBP is categorized as acute (lasting less than four weeks), subacute (lasting four to 12 weeks, and chronic (lasting more than 12 weeks). The American College of Physicians (ACP) have published their clinical practice guideline for treating nonradicular low back pain in the journal Annals of Internal Medicine, on 14 February 2017. Nonradicular low back pain refers to pain that does not irradiate from, and is not caused by, damage to the spinal nerve root. The guideline of ACP have provided clinical recommendations on noninvasive treatment of low back pain.

Recommendation 1: Given that most patients with acute or subacute low back pain improve over time regardless of treatment, clinicians and patients should select nonpharmacologic treatment with superficial heat (moderate-quality evidence), massage, acupuncture, or spinal manipulation (low-quality evidence). If pharmacologic treatment is desired, clinicians and patients should select nonsteroidal anti-inflammatory drugs or skeletal muscle relaxants

(moderate-quality evidence). (Grade: strong recommendation)

Recommendation 2: For patients with chronic low back pain, clinicians and patients should initially select nonpharmacologic treatment with exercise, multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction (moderate-quality evidence), tai chi, yoga, motor control exercise, progressive relaxation, electromyography biofeedback, low-level laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation (low-quality evidence). (Grade: strong recommendation)

Recommendation 3: In patients with chronic low back pain who have had an inadequate response to nonpharmacologic therapy, clinicians and patients should consider pharmacologic treatment with nonsteroidal anti-inflammatory drugs as first-line therapy, or tramadol or duloxetine as second-line therapy. Clinicians should only consider opioids as an option in patients who have failed the aforementioned treatments and only if the potential benefits outweigh the risks for individual patients and after a discussion of known risks and realistic benefits with patients. (Grade: weak recommendation, moderate-quality evidence)

systemic inflammation that also helps boost immune responses. "Our study forward in possibilities."

Low back pain (LBP) is one of the most common reasons for all physician visits in the United States

(moderate-quality evidence). (Grade: strong recommendation)

New Guidelines for Low Back Pain Treatment