Are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Safe?

Non-steroidal anti-inflammatory drugs, or NSAIDs, are a class of drugs widely used throughout the world to relieve pain and treat inflammatory conditions such as osteoarthritis, back pain and rheumatoid arthritis. In 2001, NSAIDs accounted for 70 million prescriptions and 30 billion over-the-counter doses sold in the US. The reason for their popularity stems mainly from the perception that NSAIDs are safer than steroids, which are potent anti-inflammatories with potentially dangerous side effects ...

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But are NSAIDs really safer?

My Experience with NSAIDs

My first encounter with NSAID was in 2004 when I went for a surgery to remove my ingrown toenails. For those who are not familiar with this procedure, the removal of ingrown nails is a simple operation which only involves local anesthesia and patient is usually discharged on the same day. However, for my case, it turned out to be anything but simple.

The problem wasn’t with the surgery itself; it went smoothly and was completed in less than half an hour. It was the painkiller I was given that almost killed me. You can probably guess what sort of drug I was given then. Yup, it was a NSAID called Ketoprofen. After reaching home on the day of the surgery, I took the painkiller as instructed. Within ten to fifteen minutes, I realized my nose started to turn runny and my eyes watery. Very soon, my eyes were both swollen and I found my breathing labored. I was gasping for air and breathing as hard as I could. I knew something wasn’t right and decided to rush back to the same hospital which I came back from a few hours ago. It was then that I found out that I was allergic to NSAIDs. But, this whole thing may well be a blessing in disguise. Since I can’t use NSAIDs, I’d have less chances of developing stomach ulcer, gastrointestinal bleeding or NSAID-induced heart attack, which are some of the serious adverse effects associated with the use of NSAIDs.

According to Wikipedia, gastrointestinal complications caused by the use of NSAIDs are estimated to result in more than 100,000 hospitalizations and some 16,500 deaths per year in the US, representing 43% of drug-related emergency visits.

Why do NSAIDs have these serious side effects? Let us trace from the very beginning.

Aspirin: The First NSAID

A discussion about NSAIDs wouldn’t be complete without mentioning aspirin, the first NSAID concocted by men. First discovered in 1853 by French chemist Charles Gergardt, aspirin has been a popular over-the-counter NSAID commonly used as a pain reliever and anti-inflammatory drug for fever, headache, migraine and acute pain.

In the 1960s, scientists found that aspirin, or acetylsalicylic acid, also has an anti-clotting effect on blood. This new discovery ushered in a whole new lease of life for aspirin. Up to today, it is still used by doctors to cut the risk of heart attack, stroke and recurrent blockage of arteries for patients with a history of cardiovascular disease.

Aspirin Side Effects

But the benefits of aspirin don’t come without a price. Reported side effects of aspirin include:

Gastrointestinal bleeding. The risk of gastrointestinal bleeding is significantly increased by long-term use of aspirin. Combining aspirin with other NSAIDs has also been shown to further increase this risk and is, therefore, not recommended.

Prolonged bleeding. The property that gives aspirin its anticoagulant benefit also increases the risk of bleeding, including micro-bleeding in the brain, and slows the healing of wounds.

Hives. For people with salicylate intolerance, aspirin can trigger an allergy-like reaction which includes hives, swelling, and headache.

Ringing in the ears. Large doses of aspirin may cause tinnitus and even hearing loss.

Reye’s syndrome. Aspirin should not be used to treat flu, fever or chicken pox for children under the age of twelve as it may cause this rare but severe illness.

Due to the risks involved, long-term use of aspirin to prevent heart attack or stroke in healthy individuals is not recommended, even at low dosage. If you intend to use aspirin for this purpose, consult a qualified physician first to weigh the benefits against the possible dangers of prolonged aspirin use.

New Generation of NSAIDs

In 1971, Sir John Vane found how aspirin actually works, and took home a Nobel Prize in Physiology or Medicine for this discovery. The English pharmacologist postulated that aspirin acts by suppressing the production of prostaglandins, the messengers responsible for the inflammatory response.

Since prostaglandins are produced by the enzyme cyclooxygenase (COX), Vane suggested that by deactivating COX, inflammation and pain can be reduced. This scientific breakthrough subsequently lead to new types of NSAIDs that target COX specifically. Due to their chemical make-up, this new generation of NSAIDs does not possess the same anticoagulant effect as aspirin (and may even increase the risk of cardiovascular disease as we will see later). Despite the lack of long-term controlled clinical trials, the new NSAIDs were released and they quickly became a runaway success in the market.

Unfortunately, this new class of NSAIDs also come with side effects that sometimes lead to death. Some of the obvious adverse reactions include gastritis, gastric ulcers and stomach bleeding. Ironically, NSAIDs, which are supposed to be anti-inflammatory, have become one of the leading causes of gastric inflammation.

Birth of Selective NSAIDs

In early 1990s, scientists found that the enzyme COX doesn’t exist as a single substance. It actually comes in at least two different forms, COX-1 and COX-2, and each plays a different function. It was believed that COX-2 was responsible for inflammation, while COX-1 has a protective effect on the stomach lining. Aspirin and the new generation of NSAIDs created to date inhibit both COX-1 and COX-2 as they are non-selective. And the suppression of COX-1 by these NSAIDs is popularly thought to the the cause of gastrointestinal side effects.

The discovery of COX-2 opened up fresh opportunities for pharmaceutical companies. They believed that by blocking only COX-2, they’ll be able to create a perfect anti-inflammatory drug that works without the annoying and potentially life-threatening side effects of non-selective NSAIDs. As a result, a new type of NSAIDs known as COX-2 inhibitors, or selective NSAIDs, is born.

This new group of drugs, which includes Celebrex, Bextra and Vioxx, quickly surpassed the sales of non-selective NSAIDs in the late 1990s and early 2000s as they were thought to be safer. They were prescribed for a wide range of inflammatory conditions such as arthritis, back pain, osteoarthritis, acute pain, menstrual symptoms and rheumatoid arthritis. In 2003 alone, the sales of Celebrex, Bextra and Vioxx were estimated to be in the region of US$9 billion in the US.

Downfall of Bextra & Vioxx

But, the golden geese didn’t last for long. In September 2004, Merck & Co. withdrew Vioxx (chemical name: Rofecoxib) from the market voluntarily because of concerns about increased risk of heart attack and stroke. According to the Journal of American Medical Association, Vioxx increases the risk of heart attack even at low doses. Believed to be the greatest drug safety catastrophe in the world, Vioxx has purportedly caused as many as 139,000 heart attacks and 55,000 deaths before it was recalled from the market.

Following the withdrawal of Vioxx, the safety of other selective NSAIDs was called into question. In 2005, the US Food and Drug Administration (FDA) announced a series of important changes to the marketing of NSAIDs. These changes include:

Pfizer was asked to withdraw Bextra (chemical name: Valdecoxib) voluntarily from the market. According to the FDA website, the request is based on:

The lack of adequate data on the cardiovascular safety of long-term use of Bextra, along with the increased risk of adverse cardiovascular events in short-term coronary artery bypass surgery trials that FDA believes may be relevant to chronic use.

Reports of serious and potentially life-threatening skin reactions, including deaths, in patients using Bextra. The risk of these reactions in individual patients is unpredictable, occurring in patients with and without a prior history of sulfa allergy, and after both short- and long-term use.

Lack of any demonstrated advantages for Bextra compared with other NSAIDs.

Note: Pfizer only removed Bextra from the US market. The product may still be available in other countries.

Celebrex (chemical name: Celecoxib) is allowed to stay in the market as the FDA concluded that its ‘benefits outweigh the potential risks in properly selected and informed patients’. But, Pfizer was asked to include a boxed warning in the Celebrex label to warn patients about cardiovascular and gastrointestinal bleeding risk.

Manufacturers of prescription and over-the-counter NSAIDs (excluding aspirin) are also requested to include the same boxed warning, as well as information to assist consumers in the safe use of the drugs.

Prescription and over-the-counter NSAIDs affected by the changes include:

COX-2 Selective NSAIDs

Chemical Name

Brand Name

Celecoxib

Celebrex

Rofecoxib

Vioxx (withdrawn in 2004)

Valdecoxib

Bextra (withdrawn in 2005)

Non-Selective NSAIDs

Chemical Name

Brand Name

Diclofenac

Cataflam, Voltaren, Arthrotec (combination with misoprostol)

Diflunisal

Dolobid

Etodolac

Lodine, Lodine XL

Fenoprofen

Nalfon, Nalfon 200

Flurbiprofen

Ansaid

Ibuprofen**

Motrin, Motrin IB, Motrin Migraine Pain, Advil, Advil Migraine Liqui-gels, Ibu-Tab 200, Medipren, Cap-Profen, Tab-Profen, Profen, Ibuprohm, Children’s Elixsure *, Vicoprofen (combination with hydrocodone), Combunox (combination with oxycodone)

Indomethacin

Indocin, Indocin SR, Indo-Lemmon, Indomethegan

Ketoprofen**

Oruvail, Orudis, Actron

Ketorolac

Toradol

Mefenamic Acid

Ponstel

Meloxicam

Mobic

Nabumetone

Relafen

Naproxen**

Aleve, Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole)

Oxaprozin

Daypro

Piroxicam

Feldene

Salsalate

Disalcid

Sulindac

Clinoril

Tolmetin

Tolectin, Tolectin DS, Tolectin 600

Source: US Food & Drug Administration (as of 26 November 2009)

* There are many OTC combination with ibuprofen: Advil Cold And Sinus, Advil Cold, Advil Allergy Sinus, Children’s Advil Allergy Sinus, Ibuprohm Cold and Sinus, Sine-Aid IB, Children’s Motrin Cold.

** There are over-the-counter versions of these prescription medications.

NSAID Side Effects You Should Know

The Vioxx debacle puts the spotlight on the potential adverse effects of NSAIDs, including those that may have been overlooked in the past. For instance, it’s now believed that NSAIDs as a class may pose an increased risk of cardiovascular events. Here’s a list of potential side effects of NSAIDs that you should be aware of:

Potential Side Effects of NSAIDs

Increased cardiovascular risks. Based on trials of up to three years in duration, a few selective and non-selective NSAIDs have been found to increase the risk of heart attack and stroke. Other NSAIDs may also possess a similar risk.

Hypertension. NSAIDs can cause hypertension or worsen existing hypertension, either of which heightens the chances of getting a heart attack or stroke.

Congestive heart failure and edema. Fluid retention, edema (swelling caused by the accumulation of fluid) and unexplained weight gain have been observed in some patients taking NSAIDs.

Gastrointestinal effects. NSAIDs can cause gastrointestinal discomfort, such as nausea, vomiting and abdominal pain, and sometimes even serious gastrointestinal complications including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine. These adverse reactions can occur with or without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.

Effects on kidneys. Long-term use of NSAIDs can cause renal papillary necrosis and other injury to the kidneys. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion.

Life-threatening allergic reactions. Serious allergic reactions may occur in patients without known prior exposure to NSAIDs. NSAIDs should not be given to patients who are allergic to aspirin.

Skin reactions. NSAIDs can cause serious skin reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome and toxic epidermal necrolysis, which can be fatal. These serious events may occur without warning.

Pregnancy. In late pregnancy, NSAIDs should be avoided because it may cause premature closure of the ductus arteriosus.

What Can We Learn?

The story about NSAIDs unfolds like a Hollywood epic. Except that in this case, the lives of millions of people are at stake. What lessons can we learn from all these events that have happened? Here are my two-cent worth:

Respect your body. Our body is a highly complex set-up with many interconnected pathways which we do not understand. By trying to suppress certain enzyme with NSAIDs, we could be messing up biological functions elsewhere and creating problems in other parts of our body.

Don’t mistaken a relief as a cure. NSAIDs can only relieve symptoms, not eliminate the causes of disease. Address the root cause of your ailment instead of always relying on drugs to make yourself feel better.

Seek safer, natural alternatives. Look out for natural anti-inflammatory treatment with fewer side effects, such as omega-3 fatty acids and anti-inflammatory herbs, and include more foods that reduce inflammation.

Keep it low and short. If you can’t avoid the use of NSAIDs, always use the lowest effective dose for the shortest duration to address your health problem. NSAIDs should never be used long-term. Monitor your condition closely while under NSAID medication.

Know the risks. Before using NSAIDs, make sure you’re well aware of the risks involved and the precautions to take. Certain groups of people are more prone to developing NSAID-associated side effects than others. For example, aside from those allergic to NSAIDs, those who have kidney or liver disease, heart disease, stomach ulcers, gastrointestinal bleeding, or pregnant should avoid NSAIDs.

Don’t trust your government blindly. You can’t depend on your government to ensure the safety of the drugs you use. Read the well-written article Should We Trust the FDA? by Vin Miller to find out why the FDA is not as trustworthy as you thought. Even if you do not live in the US, you should also be concerned about the actions taken by the FDA because many countries take the cue from the US when it comes to approving drugs, foods, supplements, cosmetics and other medical products.

What is your experience with NSAIDs? Do share with us in the comments.

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