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01-13-2011, 04:40 PM   #1
David in Seattle
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NSAID, acetaminophen/paracetamol news/cautions

British Medical Journal, 2011;342:c7086.

All Nonsteroidal Anti-Inflammatory Drugs Have Cardiovascular Risks

New data showing nonsteroidal anti-inflammatory drugs (NSAIDs) have cardiovascular risks are putting the well-known pain relievers back in the headlines. Investigators evaluating available evidence report they have found little to suggest that any of the investigated options are safe.

Regulatory agencies have already pointed to cardiovascular signals with NSAIDs, but these concerns are based mainly on observational evidence. This new study provides a comprehensive analysis of all randomized controlled trials of the drugs.

During an interview, senior investigator Peter Jüni, MD, from the University of Bern in Switzerland, said his team expected to see an increased risk but was surprised by the magnitude of the signal. "We never thought we'd see 2- and 4-fold increased risks," he said. "The doses were admittedly high," he pointed out, "however, this is clearly clinically relevant."

Several earlier meta-analyses were unable to resolve the debate over risk because they failed to include all randomized evidence in 1 study. This new network meta-analysis, published online January 11 in BMJ, includes all available evidence.

The team led by Sven Trelle, MD, also at the University of Bern, included 31 trials and 116,429 patients taking naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, lumiracoxib, rofecoxib, or placebo.

risk.jpg

Investigators saw an increase in myocardial infarctions, stroke, and cardiovascular death in patients taking all of these NSAIDs. Not surprisingly, rofecoxib was associated with the highest risk for myocardial infarction, with a rate ratio of 2.12. The drug's manufacturer, Merck, voluntarily withdrew the product marketed as Vioxx in 2004 because of concerns over cardiotoxicity.

Lumiracoxib had the next highest rate of myocardial infarction in the current study. Ibuprofen was associated with the highest risk for stroke with a rate ratio of 3.36 followed by diclofenac at 2.86. Etoricoxib was linked to the highest rate of cardiovascular death at 4.07 followed by diclofenac at 3.98.

Dr. Jüni recommends that physicians take special care in evaluating patients prone to cardiovascular events. Those who require treatment should take the lowest possible dose for the shortest period.

Dr. Jüni says he would like to see black box warnings added to drug packaging for the products still available on the market.

Of all the NSAIDs, naproxen seemed least harmful in this study. The finding is in agreement with recommendations made by regulatory agencies when rofecoxib was first removed from the market and physicians were evaluating alternatives.

"I think we should reserve our final judgment on naproxen until after we've completed the overall safety study," Dr. Jüni said. His team is currently studying the gastrointestinal safety of the drug and weighing the benefits and risks from that perspective.

"With naproxen, we tend to need a proton pump inhibitor to protect the stomach," Dr. Jüni added. "This is far from ideal."

No Clear Link Between Specificity and Risk

In an interesting twist, investigators found no clear relation between specificity of cyclooxygenase-2 inhibitors and risk for cardiovascular events. This finding contrasts with previous claims that increased selectivity for cyclooxygenase-2 inhibitors is associated with cardiovascular risk.

Several mechanisms have been proposed, but the hypothesis of an imbalance between prostacyclin and thromboxane A2 leading to an increased risk for thrombotic events is the most well known.

The researchers suggest the lack of a clear association between specificity of cyclooxygenase-2 inhibitors and cardiovascular risk implies that other mechanisms should be considered. "Multiple effects most probably contribute to the increased risk of cardiovascular events, including differential effects on prostacyclin and thromboxane A2 synthesis, endothelial function, nitric oxide production, blood pressure, volume retention, and other renal effects," they note.

Millions of Patients Taking NSAIDs

In an accompanying editorial, Wayne Ray, PhD, from Vanderbilt in Nashville, Tennessee, pointed out that millions of patients with chronic musculoskeletal symptoms are long-term NSAID users.

In the United States, an estimated 5% of all visits to a physician are related to prescriptions of anti-inflammatories, and they are among the most commonly used medications.

"Given that both mechanistic and clinical data suggest that individual NSAIDs may have different cardiovascular risk profiles," Dr. Ray noted, "a natural question is, 'Which NSAID is safest for patients with high cardiovascular risk?'"

He points out the ongoing PRECISION trial, otherwise known as the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen, will eventually provide more information on the relative cardiovascular safety of these options. "Until these results become available, naproxen seems to be the best choice with regard to cardiovascular safety."

Dr. Ray says the controversy and confusion about the cardiovascular safety of these products provides an important lesson. "Drugs for symptomatic relief must be evaluated with regard to the target symptoms as well as less frequent yet serious adverse effects. NSAIDs are not an ideal treatment with respect to efficacy or safety. Perhaps it is time for a larger more systematic evaluation of a broader range of alternatives."
01-13-2011, 04:42 PM   #2
David in Seattle
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FDA Limits Acetaminophen in Prescription Analgesics

The US Food and Drug Administration (FDA) today announced that it is asking drug makers to limit the amount of acetaminophen in prescription combination pain relievers to no more than 325 mg per tablet or capsule to reduce overdoses and the severe liver injury that can follow.

The decision, to be phased in over 3 years, affects dozens of prescription analgesics that contain both acetaminophen and another ingredient, typically opioids such as codeine, oxycodone, and hydrocodone. Some of these combination products now have as much as 750 mg of acetaminophen per dose.

The new dose restriction does not apply to numerous over-the-counter (OTC) pain relievers and cold, sinus, and cough medicines that contain acetaminophen. Normally, the maximum level allowed for these products is 500 mg, although a few extended-action pain relievers that are taken less frequently can go up to 650 mg.

The FDA also is requiring manufacturers to update the labels of all prescription products containing acetaminophen with a boxed warning on the risk of severe liver injury if too much of the ingredient is taken or consumed with alcohol.

Agency officials stress that patients prescribed analgesics with acetaminophen at doses above 325 mg can safely continue to take them under a physician’s supervision. The key to safety, they say, is not exceeding the maximum daily dose of 4000 mg, whether it comes in the form of prescription medications, OTC medications, or both.

"When taken as directed, acetaminophen is a very safe product, and our goal is to make it safer," said Sandra Kweder, MD, deputy director of the Office of New Drugs in the FDA’s Center for Drug Evaluation and Research, at a press conference today.

Accidental overdoses are all too common because patients may be taking a cough medicine containing the ingredient, for example, as well as a prescription analgesic for back pain without knowing the latter also includes acetaminophen. That mistake can easily happen, said Dr. Kweder, because labels for prescription analgesics do not make it crystal clear that acetaminophen is an ingredient. They often use an abbreviation for the medication — APAP — that consumers may not understand.

Overdoses from prescription combination analgesics account for nearly half of all cases of acetaminophen-related liver failure, which often leads to liver transplantation or death, according to the FDA.

More information about today’s announcement is available on the FDA Web site http://www.fda.gov/Drugs/DrugSafety/ucm239821.htm.

To report adverse events related to products containing acetaminophen, contact MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.
01-13-2011, 06:08 PM   #3
Astra
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Hi David
hope you're doing ok?
Thanks for the reports, very important, and it's amazing how many people overdose with the paracetamol, not realising that it's in all flu and cold remedies too!
Here in the UK, supermarkets won't sell more than 32 paracetamol at any one time, but my pharmacist was quite happy to give me 100! Mental.
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01-13-2011, 06:50 PM   #4
David in Seattle
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Hi David
hope you're doing ok?
Thanks for the reports, very important, and it's amazing how many people overdose with the paracetamol, not realising that it's in all flu and cold remedies too!
Here in the UK, supermarkets won't sell more than 32 paracetamol at any one time, but my pharmacist was quite happy to give me 100! Mental.
Joan - I'm not too bad. Got a new GI, at my request, he's prescribed a 2 week regimen of Rifaximin. He was hesitant, until I buried him in study data (you know, like I do everyone HERE ) I even got him to go up from the 1100 mg/day he wanted to prescribe to 1650. In for a penny, in for a pound, right? Can't wait to try it, only problem is the 2 week course is about $1,000. I'm hoping my insurance company (what is you Brits call such people? Oh yes, WANKERS!!! ) pays for it!

In terms of an OTC analgesic, most of us can only take paracetamol/Tylenol/Acetaminophen, but it really can be quite hard on the liver. Especially important not to take it with alcohol.

I've always thought that the limited pain relief man has available speaks volumes to the really low level of current medical effectiveness. What's more a part of sickness than pain? And yet, the most effective pain relievers we have are opioids, drugs with many negatives, and which mankind has been using for over 6,000 years.
01-13-2011, 07:27 PM   #5
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In terms of an OTC analgesic, most of us can only take paracetamol/Tylenol/Acetaminophen, but it really can be quite hard on the liver. Especially important not to take it with alcohol.

I've always thought that the limited pain relief man has available speaks volumes to the really low level of current medical effectiveness. What's more a part of sickness than pain? And yet, the most effective pain relievers we have are opioids, drugs with many negatives, and which mankind has been using for over 6,000 years.
Well said, David! And more great info as usual; I also inundate my doctors with data,too.

As far as pain meds, I can't take Vicodin or Tramadol because of the nausea and vomiting. The only other thing that works is Morphine at the hospital or
Dilaudid, which is kinda like shooting an ant with a canon unless I'm having an emergency.

Then I have acquaintences who hit me up for leftover pain drugs-no way,are they crazy?? I guess some people hear crohnic disease and think-cool,maybe she'll have pain drugs, maybe she'll share!

Best wishes on the Rifaximin-I took a short course two years ago and it induced remission for 6 months...Hope you get even better results David!
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01-13-2011, 07:50 PM   #6
katiesue1506
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You know I was reading another article someone else had posted up here and it stated that there is a very valid reason as to why many of our GI docs won't prescribe pain medications to us regularly. The reasoning was because in studies of side effects with particular medications, those who were using pain meds AND the Crohn's meds had a higher risk of getting the rare and scary side effects. Maybe due to the strain the pain meds put on your body? I dunno-- that was purely a guess on my part. But it did make me go "hmm... interesting" because none of my docs have prescribed me pain meds and my firs doc refused to because he wanted to get control of my CD and not just mask pain.

At any rate, I pretty much refuse to take any pain meds. I also wait to take Tylenol until I'm super uncomfortable because of the high dose of Imuran I'm on. If I HAVE to take something with acetaminophen in it I usually skip my Imuran dose for the day I really worry about my liver function and try to baby it.
01-15-2011, 03:12 PM   #7
Rebecca85
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Astra- http://cebmh.warne.ox.ac.uk/csr/resparacet.html

I assume pharmacies can sell more because you have to make a special trip,and do probably have a need for them, not like you just pick up 100 with your weekly shop. (although now with supermarket pharmacies you can!)
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