Tramadol Linked to Increased Hip Fracture Risk in Adults Aged ≥50

In continuation of my update on Tramadol

For older adults, initiation of tramadol is associated with an increased risk for hip fracture compared with initiation of codeine, ibuprofen, and other commonly used nonsteroidal anti-inflammatory drugs, according to a study published online Feb. 5 in the Journal of Bone and Mineral Research.

Jie Wei, Ph.D., from Central South University in Changsha, China, and colleagues examined the association between tramadol and the risk for hip fracture among individuals aged 50 years or older without a history of hip fracture, cancer, or opioid use disorder. Five sequential propensity score-matched cohort studies were assembled, including participants initiating tramadol (146,956 participants) or one of the following: codeine (146,956 participants), naproxen (115,109 participants), ibuprofen (107,438 participants), celecoxib (43,130 participants), or etoricoxib (27,689 participants).

The researchers identified 518 hip fractures in the tramadol cohort and 401 in the codeine cohort (3.7 versus 2.9/1,000 person-years) during one-year follow-up (hazard ratio, 1.28 for tramadol versus codeine). Hip fracture risk was higher in the tramadol cohort compared with the naproxen (2.9 versus 1.7/1,000 person-years; hazard ratio, 1.69), ibuprofen (3.4 versus 2.0/1,000 person-years; hazard ratio, 1.65), celecoxib (3.4 versus 1.8/1,000 person-years; hazard ratio, 1.85), and etoricoxib (2.9 versus 1.5/1,000 person-years; hazard ratio, 1.96) cohorts.

"Considering the significant impact of hip fracture on morbidity, mortality, and health care cost, our results point to the need to consider tramadol's associated risk of fracture in clinical practice and treatment guidelines," the authors write.

https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.3933

https://en.wikipedia.org/wiki/Tramadol












Tramadol Linked to Increased Hip Fracture Risk in Adults Aged ≥50 

Inhalable ibuprofen holds potential to treat cystic fibrosis

In continuation of my update on Ibuprofen 

Ibuprofen: You can buy it at any drug store, and it will help with that stabbing headache or sprained ankle. One of the ways it does so is by reducing inflammation, and it is this property that may also help patients with cystic fibrosis.

Research has found that ibuprofen, when taken at high doses, helps slow the progression of lung function decline in people with cystic fibrosis, a disease caused by having two 'bad' copies of a gene that codes for a protein important in fluid secretion. Improved lung function is important, given that most people diagnosed die by their early 50s, usually due to chronic lung infections caused by their inability to move particles, including bacteria, up and out of the lungs. The downside is that ibuprofen doses that high, when taken routinely, can result in gastrointestinal (GI) bleeding and—when combined with the antibiotics that these patients often have to take for their recurring lung infections—acute kidney injury.

But what if you could get the drug just to the area that needs it: the lungs? You could harness ibuprofen's benefits without the negative side effects.

Carolyn Cannon, MD, PhD, an associate professor at the Texas A&M Health Science Center College of Medicine, is working on a way to do just that.

"We feel that nanoparticle ibuprofen delivered by aerosol to the lungs would be a fantastic therapeutic," Cannon said. And because it is essentially a repurposed drug—only the delivery method is different—the development and regulatory approval process should be relatively easy, in comparison to the requirements for a novel therapeutic.

"The researchers who performed the original ibuprofen study thought it was working solely by inhibiting the migration of a type of white blood cell, called the neutrophil, to the lung. It goes hand-in-hand with acute inflammation," Cannon said. "However, although this may be one mechanism of action, at the high doses that were being given to the cystic fibrosis patients, the drug also has antimicrobial properties."

The inhaled ibuprofen would work in conjunction with the antibiotics the patient is already being given for the underlying infection. "We determined that not only does ibuprofen act as an antimicrobial itself, it is also synergistic with the antibiotics we already give to these patients," Cannon said.

"Together, they kill the pathogens much better than either one does alone and we could get the same great effects of the high concentrations of ibuprofen without the side effects."

Cannon and her team are pursuing international patent protection on this technology and, in the next year or so, hope to begin discussions with the Food and Drug Administration (FDA) about working towards receiving Investigational New Drug (IND) status to allow for future clinical trials.

"We have several nanoparticle formulations, one of which, developed by our collaborator, Dr. Hugh Smyth at the University of Texas in Austin, is almost pure ibuprofen," Cannon said. "We are excited about this formulation, but we still have to prove that it achieves our goal of high lung concentrations of the drug and low systemic concentrations."

To test this, this summer Cannon and Smyth and their teams plan to deliver the ibuprofen nanoparticles to the lungs of animal models and measure the drug concentrations in the lungs and serum at different time points. "This type of experiment addresses the pharmacokinetics of the drug and aims to investigate our hypothesis that we can achieve high local concentrations in the lung while maintaining low systemic concentrations," Cannon said. She and her collaborators will also investigate the capacity of the ibuprofen nanoparticles to improve pneumonia survival rates in animal models.

"The staff in the Office of Technology Translation at the Health Science Center have been wonderful through the whole process," Cannon said. "They have served as advocates for our projects with the Texas A&M Technology Commercialization (TTC) team, which has helped actualize our vision to move our inventions from the lab into use by patients."

Combination of COX-2-selective NSAID with PPI can reduce risk of stomach, intestinal ulcers

Non-steroidal anti-inflammatory drugs (NSAIDs)—including ibuprofen, diclofenac, naproxen and others—are commonly used pain medications that are generally safe but may increase the risk of developing stomach and intestinal ulcers.

After researchers analyzed a large number of clinical trials that compared different ways of reducing these risks of NSAIDs, they found that the best strategy with the lowest overall risk was to combine a certain type of NSAID, known as a COX-2-selective NSAID, with a proton pump inhibitor (PPI). PPIs are most often used to treat heartburn and gastro-oesophageal reflux disease.

"The combination of a COX-2-selective NSAID with a PPI will be expensive and is not recommended for all patients who need to be on a NSAID; however, it is the safest and most effective treatment strategy for those at high risk of ulcer bleeding from NSAID treatment," said Prof. Jin Ling Tang, co-author of the Alimentary Pharmacology and Therapeutics study.

Scientists Spot How Cox-2 Painkillers Raise Heart Risks

In continuation of my update on COX-II inhibitors....

New research has uncovered how some cox-2 painkillers increase the risk for both heart attacks and stroke. The once popular cox-2 drugs, Vioxx and Bextra, were pulled off the market in 2004 and 2005, respectively, after research showed that both raised the chances of cardiovascular trouble. Meanwhile, Celebrex, a painkiller in the same drug class that remains on the market, carries a "black box" warning alerting patients to potential heart risks.

Now, a team of scientists from the University of Pennsylvania in Philadelphia say that, although cox-2 inhibitors are very good at inhibiting the workings of the cox-2 enzyme -- and thereby easing pain -- they also throw off the cardiovascular system's delicate balance by inhibiting an enzyme that relaxes blood vessels and guards against clotting.

"It's really about a rock and a hard place," said Dr. Christopher Cannon, a cardiologist at Brigham and Women's Hospital in Boston. "There's a balance in the bloodstream of clotting and vasoconstriction, as well as protection against clotting and vasodilation, which means that there's a constant balance of clotting and preventing clotting, and constricting arteries and dilating arteries."

"But with cox-2 inhibitors, they have found that you knock the protective side of that balance off," Cannon said. "And then you're left only with the constrictive part, which means the drugs up the risk for clotting and arterial constriction."

"This problem is bigger than just Vioxx, which no longer exists," he added. "It applies to every single NSAID (non-steroidal anti-inflammatory drug), because with all NSAIDs -- including Celebrex and ibuprofen, which zillions of people take -- the same issue exists. You block out the good stuff and leave the bad stuff unchecked. The one exception is Naproxen, which has an anti-platelet effect that seems to work against stroke and heart attack risk."

"Sometimes you have to take a cox-2 because you have really bad daily pain," said Cannon. "But this is a dose-dependent problem, with the more cox-2 you take the greater the cardiovascular risk. So you have to limit the dose and take the least amount you can get away with, so you can try to control crippling pain but also try not to poison your blood vessels and predispose yourself to clotting and high blood pressure."

Ref : http://stm.sciencemag.org/content/4/132/132ra54.abstract?sid=25c1e6c3-e6ee-449c-ae09-b83f14efc9f2

FDA's approval of Injectable ibuprofen

We did know about the oral form of ibuprofen, now FDA has approved the injectable form of ibuprofen. Injectable ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) are promising pain management options said Dr. Bob Rappaport, Director, Division of Anesthesia, Analgesia and Rheumatology Drug Products in the FDA’s Center for Drug Evaluation and Research. But until now (as for as my knowldge goes, diclofenac sodium is being used), there were only oral forms of most NSAIDs. An injectable ibuprofen product can provide patients with relief from pain and fever when they cannot take oral product.

In a clinical trial of 319 women who had undergone an elective abdominal hysterectomy, patients were less likely to request morphine for pain on an as-needed basis when administered Caldolor.

Caldolor should be used with caution in patients with congestive heart failure, kidney impairment, at risk of blood clots and those who have a prior history of ulcers or gastrointestinal bleeding. When used in such patients, attention to using the lowest effective dose for the shortest time period is important to reduce the risk of serious adverse events. The drug has also been associated with high blood pressure, serious skin reactions, and serious allergic reactions. Though the side effects like nausea, flatulence, vomiting, and headache are being noticed during clinical trials. Its a good move becoz., the dose by IP route will be less and definitely reduce the risk of the ulcerogenecity (a common problem due to NSAIDs).

Ref : http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm165971.htm

Explanation for the side effect of COX-2 inhibitors !....

When I read this article, went back to my research days (1993-1998). We did prepare some triazoles, oxadiazoles, thiadiazoles and their derivatives. The parent triazoles and oxadiazoles were tested for thier antiinflammatory activity by Carrageenan induced rat paw edema, Cotton pellet induced granuloma tissue formation methods and the results were encouraging and were even better tolerated than the standards (Diclofenac and Ibuprofen). We had many research papers that time claiming that, the selective inhibitors of COX-2 and 5-LO are the best NSAIDs. After few years there were three COX-2 inhibitors in the market (namely-Vioxx (rofecoxib), Bextra (valdecoxib) and Celebrex (celecoxib) and we were happy that atleast the ulcerogenecity of NSAIDS has been taken care of. But the days were countable and the first two drugs were withdrawn from the market, because of the cardiovascular toxicity and only celecoxib is available in the market. Now thanx to Dr. Andrew J. Dannenberg (Director of the Weill Cornell Cancer Center) and group, who have come up with a novel explanation for the cardiovascular toxicity of the COX-2 inhibitors. I would say one more "serendipity" to the drug discovery, because the trial was originally designed to identify biomarkers in urine which could indicate the presence of incipient, smoking-related lung disease. The researchers had hypothesized that early-stage lung injury could "turn on" the COX-2 gene, increasing levels of the major prostaglandin metabolite PGE-M in the urine. In addition to determining PGE-M levels, the investigators also looked at levels of the biomarker leukotriene E4 (LTE4), formed by the 5-lipoxygenase (5-LO) pathway. Both biomarkers, representing these two different pathways, are synthesized from arachidonic acid. The 5-LO pathway has also been implicated in inflammation, cancer and cardiovascular problems. The authors found that Celebrex treatment led to increases in urinary LTE4 levels, primarily among individuals who had started out with high PGE-M levels, which indicated that Celebrex 'shunted' or redirected arachidonic acid into the 5-LO pathway from the COX pathway. When one went down, the other went up." This is important because other studies have suggested an important role for the 5-LO pathway in atherosclerosis, heart attacks and stroke. And it is this increased shunting of arachidonic acid into the 5-LO pathway that may help explain why COX-2 inhibitors contribute to cardiovascular problems, the researchers say. Though further studies are essential to substantiate the claims, is a good beginning and hope with selective inhibitors of both COX-2 (cyclooxygenase) and 5-LO (lipoxygenase) are the need of today's world (I did mention in the beginning about that..)...

Ref: http://news.med.cornell.edu/wcmc/wcmc_2009/04_29_09.shtml

Oral Etoricoxib as post surgery drug?

Developed as an alternative to conventional non-steroidal anti-inflammatory drugs (NSAIDs), which can cause intestinal bleeding, "coxibs" are licensed for chronic and acute pain.

Single dose oral etoricoxib produces high levels of good quality pain relief after surgery, says lead researcher Andrew Moore, of the Pain Research and Nuffield Department of Anaesthetics at the University of Oxford.Moore adds that the long lasting action of etoricoxib makes it qualitatively different from other coxibs and ibuprofen. A longer time before remedication is likely to benefit patients by providing long-lasting pain relief. More...