The Dangers of NSAIDs: The Black Box Warning
NSAID, or nonsteroidal anti-inflammatory drugs, are the most widely used class of drugs in the United States today. There are more than 30 different types of NSAIDs, with more than 80 million prescriptions written and more than 30 billion OTC (over-the-counter) products purchased every single year in the United States alone.
This means that almost one-third of all Americans take a prescription NSAID. When we include OTC NSAID use, it is equivalent to every man, woman, and child in the United States taking a NSAID daily for over three months. Even for pennies on the dollar, the NSAID market is incredibly lucrative.
Most of us have taken NSAIDs, but maybe we don’t know what class of drug we were or are taking. Let me give you a few examples of common NSAIDs:
- Ibuprofen (Motrin, Advil, Caldolor)
- Naproxen and naproxen sodium (Aleve, Naprosyn, Midol, Pamprin, Anaprox)
- Aspirin (Bayer, Anacin, Bufferin, St. Joseph)
- Diclofenac (Voltaren, Voltarol, Cataflam)
- Celocoxib (Celebrex)
As the class name suggests, nonsteroidal anti-inflammatory drugs (NSAIDs) reduce inflammation but are not related to steroids, which also reduce inflammation. NSAIDs work by reducing the production of prostaglandins, chemicals that promote inflammation, pain, and fever. Prostaglandins also protect the lining of the stomach and intestines from the damaging effects of acids (including stomach acid) and promote blood clotting by activating blood platelets. Prostaglandins also affect kidney function.
The enzymes that produce prostaglandins are called cyclooxygenase (COX). There are two types of COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining.
NSAIDs block COX enzymes and reduce the production of prostaglandins, which is how they reduce inflammation, pain, and fever. Since they reduce the prostaglandins that protect the stomach and promote blood clotting along with pain and inflammation, NSAIDs can cause ulcers in the stomach and intestines without warning and increase the risk of internal bleeding. In fact, the new cardiology guidelines are showing that NSAIDS such as aspirin should not be used for primary prevention of cardiovascular events since the harm is now outweighing the good. 
Unfortunately, even with such data, medical practitioners downplay the dangers of NSAIDs, as do the pharmaceutical companies that make these popular OTC drugs. Over the last twenty years or so, dozens of published clinical research studies have demonstrated the dangers of NSAID use.  Most of this research, however, was completed and published in Europe and the rest of the world, and, thus, the results did not get the attention of the medical establishment in the United States. This is largely due to grievances expressed by pharmaceutical companies and lobbyist groups who influence the regulatory systems that are supposed to protect us. Sadly, our scientific journals aren’t much better; they are almost all funded by their advertisers — pharmaceutical companies.
What exactly are the dangers of NSAIDs that these pharmaceutical companies want to downplay? If you regularly use NSAIDs to treat your arthritis, for example, you are in for quite an unpleasant surprise.
The downplayed international research reveals that NSAIDs have been shown to do the following: 
- Accelerate the progression of osteoarthritis
- Decrease joint-space width
- Increase joint forces/loads
- Increase risk of joint replacement
- Inhibit proteoglycan synthesis (the proteins in connective tissue)
- Inhibit synthesis of cellular matrix components (molecules that provide structural and biochemical support to the surrounding cells)
- Inhibit chondrocyte proliferation (the cells that form cartilage)
- Inhibit collagen synthesis (the structural protein found in connective tissue)
- Inhibit glycosaminoglycan synthesis (molecules that form substances that act as a lubricant and shock absorber)
The scientific literature makes it abundantly clear that NSAIDs — from in vitroThis means "outside the body" – or in the laboratory. and in vivoThis means "in the body." studies, in both animals and humans — have a significant negative effect on cartilage matrix, which causes an acceleration of the deterioration of articular cartilage in osteoarthritic joints. The preponderance of evidence shows that NSAIDs have no beneficial effect on articular cartilage and accelerate the very disease for which they are most used and prescribed.
This is why those of you who have taken NSAIDs for years or decades still have joint pain. Although NSAIDs temporarily help with pain, they actually degenerate your joints; therefore, arthritis sufferers keep taking NSAIDs because the pain persists.
The immediate pain relief offered by NSAIDs leads most people to not question why they have taken something for so long and, most crucially, why their problem hasn’t been resolved. So many patients of mine will tell me that they started using a NSAID like ibuprofen to treat their arthritis pain. They clearly remember only taking one or two pills a day and then, over time, needing to take more and more to the point that they may take one to two pills every few hours plus another NSAID like naproxen sodium (i.e., Aleve). Some of these people have been taking NSAIDs for more than 20 years, without a doctor once warning them about the damage this long-term use is causing in their joints.
The inappropriate use of NSAIDs and the deceptive marketing pushing their overuse in the United States began in the early 1980s. If you remember the NSAID commercials from back then, they generally showed a person who was over sixty-five taking an Advil or Motrin for joint pain caused by playing golf or lifting their grandchildren. Over time, the people in the commercials became younger and younger. Now when you see a NSAID commercial, many of the people shown are under the age of 21. Some are even teens — riding bikes, holding backpacks, etc. The change was so gradual that no one seems to have noticed or asked, “Why are young teens taking Advil?”
Aleve is well known for advertising the fact that you need to take just two Aleve, versus many ibuprofen pills, for “all day long, all day strong” relief. The problem is that although the pain relief from Aleve may last longer than that from ibuprofen (Advil, Motrin, etc.), it still causes the same side effects. Even more concerning to me is that most MDs, health-care providers, pharmacists, and patients do not know that NSAIDs — both prescription (e.g., Celebrex) and OTC (e.g., Advil, Motrin, Aleve, Midol, and Pamprin) — all carry what is called a “boxed warning” or “black-box warning.”
What are the side effects of NSAIDs?
I will get to the black-box warning in just a moment. First, there are a few other important things you should know about NSAIDs.
Every drug on the market today has a monograph; this is a set of important information about the drug that the drug company provides to the FDA. The monograph shows pictures of how it is supplied and tells the proper dosages, indications, and conditions the product is used for, drug interactions, adverse reactions, safety monitoring, and manufacturing/pricing. Every drug, whether prescribed or OTC, has what are called “common reactions.” These are side effects that commonly occur when the product is taken.
The common reactions for NSAIDs, in general, follow:
- Abdominal pain
- Elevated ALT, AST (liver enzymes)
- Fluid retention
- Ecchymosis (bruising)
- Dyspnea (shortness of breath)
- Photosensitivity (sensitivity to light)
This list of common reactions means that someone who takes a NSAID will often experience one or more of these side effects. None of these common reactions are immediately life-threatening, but they can become problematic, as they can cause the person experiencing them to go to the doctor for more medications to treat the side effects. For example, if a NSAID causes heartburn, a doctor might prescribe a proton-pump inhibitor (acid blocker) such as Prilosec or Nexium, creating the beginning of a “drug cocktail” situation.
Most worrying to me as a physician is that NSAIDs commonly cause mild elevations in serum aminotransferase levels (AST liver enzymes); this occurs in up to 18 percent of patients taking NSAIDs over a prolonged period.  Many physicians downplay this elevation because it is considered mild. Most of us were taught that the liver enzymes (AST, ALT, and Alk Phos) had to be severely elevated to cause problems. But most MDs were not trained to understand what liver-enzyme testing actually measures.
From a functional standpoint, liver enzymes only elevate when about 60 percent of the liver is having some difficulty performing its normal metabolic breakdown of all foods, medicines, supplements, and so on, after digestion. Thus a mild elevation is not dangerous but will cause someone to be temporarily unable to break down toxinsA poison made by certain bacteria, plants, or animals, including insects.. This mild elevation causes some medications (and supplements) to metabolize either more quickly or more slowly than expected.
This, in turn, causes medications, like those for blood pressure or blood sugar, to have a stronger or weaker effect. If the patient (and often the physician) does not know about this side effect of mild liver enzymeA protein that speeds up chemical reactions in the body. elevation, the resulting change in blood pressure or blood-sugar numbers may cause the doctor to make unnecessary changes to the dosage of the relevant medications.
Doctors are accustomed to warning their patients about consuming alcohol, for example, while on certain medications; they advise that a glass of wine or beer may feel either stronger or weaker than usual when taken in tandem with many other medications, but they seldom mention NSAIDs. More importantly, mildly elevated liver enzymes can affect medications used for prevention, such as oral contraceptive pills. So, if you are taking birth-control pills and if your liver enzymes are ever elevated, it is recommended to use a second form of birth control until those enzymes return back to normal.
One does not have to take NSAIDs for long periods of time to experience one or more of the common side effects. One double-blind trial found that six out of 32 healthy volunteers (or 19 percent) developed a gastric ulcer that was visible on endoscopic examination after only one week’s treatment with naproxen (at a commonly prescribed dose of 500 mg twice daily—the same amount as five nonprescription Aleve).  Even worse, NSAID use can cause erosions and ulcerations in the small intestine (which is not visualized on normal endoscopy) causing chronic iron-deficiency anemia and protein loss due to increasing gut permeability. 
Mild side effects from NSAID use are altogether too common. But these mild side effects are not the main problem with NSAIDs. The main problem with NSAIDs is what are called “serious reactions.”
Serious reactions (side effects) of NSAIDs
Serious reactions are those types of adverse reactions that can be life-threatening or cause severe damage to one’s health. The serious reactions for NSAIDs, in general, follow:
- GI bleeding
- GI perforation/ulcer
- MI (myocardial infarction: heart attack)
- Congestive heart failure
- Renal papillary necrosis
- Anaphylaxis/anaphylactoid reaction
- Exfoliative dermatitis
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis (Lyell’s syndrome)
- Thrombocytopenia (reduction of platelets in the blood)
- Agranulocytosis (dangerously low white-blood-cell count)
- Aplastic anemia
- Anemia, hemolytic
These are side effects that you definitely do not want. But these aren’t even the biggest problems with NSAIDs. The biggest problem with NSAIDs is that they carry black-box warnings.
The Black-Box Warning — your worst nightmare
After reading about all the mild and serious NSAID side effects, you’re probably wondering how it could possibly get any worse.
A black-box warning (see figure below) is a warning that manufacturers have to place on the insert and inside information about a drug once serious reactions serious enough to put users into a black box become common. Yes, a black-box warning is the FDA’s attempt to let you know that you can end up in a coffin or casket if you are unlucky enough to suffer one of a medication’s serious reactions.
Now, not every serious reaction becomes a black-box reaction, but the serious reactions that happen frequently enough to require a black-box warning are far more likely to put you in a black box (see figure below).
Again, this all means that tens of millions of people today are at risk of heart attacks, strokes, and GI bleeds from America’s love affair with NSAIDs. And we are unlikely to fall out of love with NSAIDs anytime soon. As long as most people in the United States follow some variation of the pro-inflammatory standard American diet, the average person will want to take NSAIDs, putting him or her at an even greater risk of heart attacks and strokes. Even more frightening is the fact that the risk is still there, even if someone doesn’t have elevated cholesterol/lipids (heart disease) if that person has heart-disease risk factors such as obesity, high blood pressure, and diabetes.
Consider for a moment how common the risk of stroke and heart attack is in America today. Americans suffer approximately 735,000 heart attacks per year; that amounts to almost two people having a heart attack per minute.  It is nearly impossible to find someone in the United States who is not at risk of taking one too many NSAIDs and winding up in the black box. In fact, recently the FDA issued a new safety announcement to strengthen the black-box warning. New data from the FDA has shown that NSAIDs increase heart attack and strokes up to 50 percent. 
Now with the new, updated black-box warning soon to take effect, the FDA will require the drug manufacturers to remove the word “may” and now state that the medication will “cause an increased risk” of serious heart attacks and strokes. The black-box warning will also include the following language: “The risk of heart attack or stroke can occur as early as the first weeks of using a NSAID.
The risk may increase with longer use of the NSAID. In general, patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use.” More disturbingly, “patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack.” Finally, there is also an “increased risk of heart failure with NSAID use.” 
In addition to heart attacks and strokes, the average NSAID user is at high risk for life-threatening GI bleeding. Again, the warning states, “bleeding ulcer, stomach or intestine perforation, which can be fatal at any time, can occur without warning symptoms.” Can you believe this? How many people already have GI problems and are taking antacids and acid blockers such as Zantac, Pepcid, Prilosec, and Nexium? If they add NSAIDs to the mix (and they almost certainly are), they are putting themselves at an even greater risk of a fatal GI bleed.
In addition, think about all the people who get ulcers just from high amounts of stress. What about everyone who drinks alcohol in excess (occasionally or regularly) or who smokes? What about everyone who takes any number of other medications that cause stomach irritation? What about those people with food allergies who deal with constant stomach or intestinal issues? Or people with IBS, ulcerative colitis, or Crohn’s disease? Or people having chemotherapy?
People are being set up for serious health consequences from something that is marketed as being very benign. NSAIDs are in everyone’s medicine cabinets, office drawers, lockers, purses, and backpacks, and millions take them on a daily basis. This false sense of security means that you might never see a black-box side effect until — at best — you wake up in the hospital, or at worst, you never wake up again.
If this all seems sensationalistic because you’ve been taking NSAIDs for years and have never experienced anything but pain relief, please believe me; black-box events are terrifyingly under-reported. You might be wondering, in that case, “If these drugs don’t help my joint pain in the long run and are putting me at an elevated risk of a heart attack, stroke, or fatal GI bleed, why are NSAIDs still on the market?”
The answer is that the companies that make these drugs have no incentive to take them off the market. Once a drug gets a black-box warning, this information is simply listed (or alluded to) on every insert, printout from the pharmacy, and web page (usually buried deep down), and it is included in small print on the bottom of the screen during every prescription-NSAID television commercial (e.g., Celebrex). The black-box warning has been provided to you whether you realize it or not, and therefore, drug companies are free of legal liability.
For example, on every Celebrex commercial, you will see and hear the black-box warning in full. Yet most people don’t notice it, as they are misguided by the wonderful images of people walking, hiking, and being pain-free, accompanied by upbeat music in the background. Pay attention next time you see a NSAID commercial; listen closely to the black-box warnings and hear all about the side effects you are legally agreeing to experience.
The Black-Box Warning — the unknown, unconsented agreement
Once the black-box warning has been placed upon a product, you, by opening the product bottle and swallowing the pills, or even by picking up the prescription at the pharmacy, have given consent to the “terms and conditions herein.” Yes — whether you knew it or not — by opening the bottle or package you have accepted that these black-box warnings of serious and fatal side effects can occur.
An analogy to this is the “terms and conditions” form you agree to when you’re updating software for your smartphone or your computer. You see a pop-up that asks, “Do you want to upgrade?” Of course, you do — so you click the box that says, “I agree to the Terms and Conditions.” Most of us, and I’m guilty of this myself, agree on a daily basis to “terms and conditions” we haven’t read.
Have you ever read a T&C agreement? These agreements free software, computer, and phone companies from any liability if your data is lost or stolen, if your information is sold to third-party vendors, if your personal information is collected, and if you encounter any number of other invasion-of-privacy-type situations. What choice do we have, really? In order for us to upgrade our software, we must agree to the “terms and conditions,” or we will be left behind.
As bad as an invasion of privacy is, no one has had a heart attack, stroke, or GI bleed after upgrading his or her software (at least not as a direct result). However, hundreds of thousands of people each year have heart attacks, strokes, or GI bleeds after agreeing to black-box warnings on drugs, never knowing that they were at risk. To my mind, these blanket, fine-print black-box warnings are un-American and grossly unethical.
How can there be no legal liability upon a manufacturer if you have a stroke from taking their product? Why are products with such severe side effects sold over-the-counter? You cannot call “1-800-BAD DRUG” if you end up having any of the serious side effects because you have accepted that those risks can occur just by opening the bottle or package.
So why do almost every retail outlet and pharmacy in the country still sell these products? The answer is what it always is: money and greed. Almost two-thirds of the US population takes a NSAID at least once a week, and fully one-third takes a NSAID on a daily basis. Remember, there are seventy million NSAID prescriptions filled in the United States every year; minimum estimates show that over thirty billion OTC NSAID medicines are purchased every year as well. 
In 2013 Americans bought more than 275 million boxes of over-the-counter NSAIDs, racking up $1.7 billion in sales, according to retail tracker IRI.  Visit any pharmacy today and you will see dozens of companies selling NSAIDs, from brand names to generics. Since NSAIDs are incredibly popular, and there is no legal liability associated with their use, lots of companies sell their own versions. NSAID sales benefit pharmacies, too, as pharmacies themselves make money selling them to you.
If you’re unlucky enough to get a common or serious side effect from taking the NSAID, doctors, emergency rooms, hospitals, medical and surgical equipment companies, and insurance companies make money trying to save your life. There is plenty of money to be made by everyone involved. But if true health care were the goal of these pharmaceutical companies, pharmacies, and conventional health care, they would have warned you not to take NSAIDs in the first place.
Most of the patients I see for an initial integrative medicine consultation tell me that they take ibuprofen on a daily basis. Almost everyone in the United States has a bottle of NSAIDs in his or her locker at school, at the gym, in a desk drawer, purse, briefcase, medicine cabinet, or even glove compartment in the car. People go to warehouse stores and purchase huge bottles of 2,000 pills or “twin packs” of 4,000 tablets. I even have soccer moms and dads who give every kid who leaves their minivan one ibuprofen before the game and one after the game. Many active adults and children are taking four to eight ibuprofen tablets daily; that’s two tablets every few hours.
Before my integrative medical training, I too took a NSAID if I had a headache or back pain. Like most people, I thought, “Those side effects won’t affect me,” or “Side effects only happen to those people who take too many pills.” I thought, “I only take them rarely,” or “It hasn’t bothered me so far.” And I was well aware of the black-box warnings. I think we all (including doctors) inherently believe that we are exceptions to the rule, as no one wants to think something terrible could happen out of the blue. It’s in our nature to think we will beat the odds, or that such terrifying side effects happen only to other people.
I haven’t taken a NSAID in 14 years. I stopped taking them once even conservative medical journals started publishing statistics about the shocking number of deaths that occur from taking NSAIDs. I was not expecting data that was so overwhelming and compelling, and I am eternally grateful that one journal, in particular, was confident enough to publish researchers’ findings. I immediately made a lifestyle change that has protected me from this common, unnecessary risk, which most Americans are exposed to every day. It also led me to develop Bosmeric-SR.
So, how compelling is the data? Is it really so bad that it compelled me to formulate a replacement product? You bet it is. After learning what I did, you may (and should) change how you think about NSAIDs.
Here is the data that will make you think twice about taking another NSAID — ever:
Conservative estimates published in The American Journal of Medicine, The New England Journal of Medicine, Journal of the American Medical Association, Therapeutics and Clinical Risk Management, and The Journal of Rheumatology all have stated that the average number of people hospitalized for complications from NSAID use as properly prescribed is more than 100,000 per year — with about 20,000 deaths every year (see figure below). 
This means that when health-care providers prescribe a NSAID such as Advil, Motrin, Aleve, or Celebrex and the patients take it appropriately, 100,000 of these people end up in the hospital from complications each year. Each hospital admission is estimated to cost between $15,000 and $20,000.  (The study was conducted to assess the origins of uncontrolled health-care costs.) And that’s if the patient is fortunate enough not to end up as one of the 20,000 who never leave the hospital alive.
What affects me deeply as a doctor is the fact that these are conservative estimates and do not include inappropriate use (taking more than recommended or prescribed dosages) or OTC administrations. That’s right — the 100,000 hospitalizations and 20,000 deaths annually do not include the 30 billion OTC NSAIDs that are purchased at pharmacies, grocery stores, or big-box stores.
To put these numbers in perspective, Sept 11, 2001, was a tragic day in our nation’s history. More than 3,500 people died in the terrorist attacks that day. That means the annual number of deaths related to prescribed NSAIDS is almost seven times that of the fatalities on 9/11. In other words, it’s like 14 World Trade Centers falling year after year, senselessly killing innocent Americans. And, again, that doesn’t include the deaths from OTC use or intentional overdoses. Let’s have a look at those numbers.
The most recent data from 1984 to 2009 show that approximately 300,000 people have died from GI complications due to NSAIDs, with almost 1.7 million hospitalizations, at a cost of $38.8 billion  To put these total statistics into perspective, the number of people killed from NSAID GI bleeding is greater than the number of Americans who died during the Revolutionary War, the War of 1812, the Mexican-American War, the Spanish-American War, World War I, the Korean War, the Vietnam War, the first Persian Gulf War, and the conflicts in Iraq and Afghanistan — combined (287,371 versus 300,000).  The total number of people hospitalized from 1984 to 2009 due to NSAID bleeding (1.7 million people) is higher than the American casualties from all American wars combined (1.4 million people).  
Even worse, now the number-one cause of death in the United States is adverse drug reactions and medical errors (see above figure). Yes, you read that correctly. More people die from the drugs that we are using to treat them (or more precisely to manage their disease) than the diseases themselves.
These adverse drug reactions and medical errors kill more people yearly than heart disease (number two), cancer (number three), and stroke (number four). You don’t hear about this data because the cause of death is not a disease. Most people know that heart disease is the number-one cause of death (from a disease). But don’t be misled by worrying only about heart disease, cancer, and stroke. Your bigger risk comes from some of the approaches and treatments of our current medical system, which in my opinion has aspects and behaviors like those of a disease.
This is a hard truth to swallow, but millions of Americans swallow it every day without thinking about it.
In addition to the side effects listed in the black-box warnings, NSAIDs also do the following: 
- Increase cardiovascular problems, like heart attacks, by 40 percent to 60 percent;
- Increase the risk of heart failure by 60 percent;
- Increase the risk of miscarriage by 80 percent;
- Increase the risk of hearing loss up to 20 percent;
- Increase the risk allergic reactions in people with asthma by 10 percent to 30 percent.
Remember the NSAID called Vioxx (rofecoxib)? In 2004, it was pulled off the market because more than 60,000 people were killed from cardiac events; in addition, at least 88,000, and possibly as many as 139,000 Americans, experienced a nonfatal heart attack as a result of taking Vioxx. In 2005, another similar drug, Bextra (valdecoxib), was pulled off the market. In 2007, Prexige (lumiracoxib) was also removed. Can you see a pattern here? Maybe NSAIDs cause more harm than reported?
Celebrex (celecoxib) was spared from this regulatory carnage because it put a black-box warning on its label while these other drugs were being taken off the market. With this warning on the label, however, it was freed from liability in the United States (even though it has been pulled off the market in other countries). The makers of Celebrex got a very lucrative green light, and today many other drug companies continue to sell NSAID drugs like Celebrex because you the consumer are the only one to blame legally if something goes wrong when you’re taking them.
While it is clearly easy for me to write about the many dangers of NSAIDs, there is an alternative. It’s the result of years of research conducted by some of the most venerable physicians in the world, and it is a far better option to help with pain and inflammation. You’re about to learn all about it in my article on the synergistic combination of specific potencies, purities, and delivery system of four key ingredients including curcumin, boswellia, ginger and black pepper in the patented, clinically tested safe and effective natural anti-inflammatory called Bosmeric-SR. (see The Vital Role of Boswellia (Frankincense) for Cancer).
For more detailed information on 10 steps to optimum health using diet and lifestyle changes and the use of natural anti-inflammatories, please read An Inflammation Nation.
Modified by permission from An Inflammation Nation by Sunil Pai © 2015.
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