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Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

I would be surprised if you do not keep a supply of aspirin in your home and probably also ibuprofen. These and other nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely consumed medications today. They can be miraculously effective at relieving pain, lowering fever, and reducing swelling associated with inflammation. Over-the-counter (OTC) forms are so familiar that most people consider them totally benign and take them frequently or even regularly with little awareness of their risks.

Salicylic acid, the precursor of aspirin, is a constituent of willow bark, a folk remedy used for centuries in diverse parts of the world. Hippocrates prescribed willow bark tea for headache 2,400 years ago. Aspirin was synthesized in 1897. Today, it is one of the most widely used medications in the world, with an estimated 40,000 tons of it consumed each year. In the 1960s, the first non-aspirin NSAID was introduced: indomethacin (Indocin), a prescription medication still used today. Currently, there are at least twenty prescription-only formulations, as well as a multitude of brand-name and generic versions of OTC NSAIDs; aspirin, ibuprofen (Advil, Motrin), and naproxen (Aleve) are familiar examples.

But these widely used drugs are not benign, as the following story of a patient illustrates.

Angela, a sixty-six-year-old woman, made a New Year’s resolution to lose some extra pounds and get in better shape. Her weight had increased over the past ten years due to a more sedentary lifestyle after she was diagnosed with osteoarthritis of her knees and lower back. She had been taking anti-inflammatories (600 to 800 milligrams of ibuprofen) to control her pain. In the past month, Angela started to attend Zumba (dance fitness) classes twice a week. Initially, her aches and pains worsened, so she doubled her dose of ibuprofen most days. For the past week, Angela has experienced unusual fatigue and trouble catching her breath when she climbs the stairs in her house. Today, she pushed herself to go to her Zumba class and developed chest pain when she started moving. Her instructor called 911, and she was brought by ambulance to the emergency room, where she was found to be profoundly anemic from bleeding gastric ulcers, requiring admission to the hospital, cardiac monitoring, and transfusion.

Angela’s serious adverse gastrointestinal effect from taking an OTC anti-inflammatory medication is—unfortunately—not uncommon. Through her hospital experience, she realized she needed to find alternative methods to address her pain, including dietary change and other lifestyle modifications, as well as more gentle physical activity before going back to high-impact exercise. She found a health provider to help her select appropriate integrative treatments to decrease pain and improve her general well-being.

HOW NONSTEROIDAL ANTI-INFLAMMATORIES WORK

Like Angela, a great many adults in the United States take anti-inflammatory medications prescribed by health professionals or purchased over the counter. The class of medications called NSAIDs includes a large number of pain-and fever-reducing drugs. Notable anti-inflammatory medications not in this class are prednisone and acetaminophen (Tylenol). Prednisone is a steroid (see chapter 7); acetaminophen is an OTC drug that reduces pain and fever by a different mechanism than that of NSAIDs. NSAIDs come in many forms: long-acting, short-acting, injectable; in liquids and tablets; and as creams, gels, and patches for topical application. They are often included in cold and flu remedies.

NSAIDs fall into two categories, selective and non-selective, based on how they work. All NSAIDs act at the level of cells by inhibiting an enzyme called COX (cyclooxygenase). There are two forms of the enzyme: COX-1 is produced constantly in the tissues, whereas COX-2 is elicited mainly by inflammation. Both are involved in making prostaglandins, regulatory compounds found in every tissue that modulate our response to injury. It is prostaglandins that directly cause pain, fever, and more inflammation. Blocking their synthesis decreases those responses. Most NSAIDs, including aspirin and ibuprofen, are non-selective in that they block both forms of the COX enzyme. Unfortunately, their suppression of COX-1 also increases the risk of gastrointestinal ulceration and bleeding, the main adverse effects of these medications. Selective COX-2 inhibitors were developed to reduce those problems. Celecoxib (Celebrex), a prescription NSAID, is now the only selective NSAID still available. Two other selective NSAIDs were removed from the market in 2004 and 2005 due to increased risk of heart attack and stroke.

Topical NSAIDs have some effect on pain and inflammation, though less than oral forms. When applied to the skin, some of the drug is absorbed into the tissue at the site of application. Patches and gels can cause local irritation, but because little of the drug is absorbed into the bloodstream, overall they are a less risky option, with far fewer adverse effects than oral forms. OTC Aspercreme contains a milder relative of aspirin, trolamine salicylate, which has a minimal effect on pain; some preparations combine it with lidocaine, a topical anesthetic.

The cost of NSAIDs varies widely—from $4 a month for a generic OTC product to $1,500 a month for a brand-name prescription drug. There are few differences among the non-selective NSAIDs, whether OTC or by prescription. Except for Aspercreme, topical NSAIDs are still available only by prescription and range in price from $196 to $498 per tube.

COMMON USES OF NSAIDS

Common conditions treated with anti-inflammatory medications include back and neck pain, joint pain associated with various types of arthritis (such as rheumatoid arthritis, osteoarthritis, gout, and psoriatic arthritis), chronic muscle and body aches and pains, musculoskeletal injuries (fractures, tears, or strains), menstrual cramps, headaches, and fever, among others. Daily low-dose aspirin is used to aid in the prevention of stroke, heart attack, and some forms of cancer (esophageal and colorectal, for example)—most appropriately in people with preexisting disease or significant risk factors. The risks and benefits of a low-dose aspirin regimen for prevention should be discussed with a health professional; they vary, depending on age, bleeding risk, current medications, and other health conditions.

NSAIDs can be particularly problematic when used daily for chronic pain because of the side effects described above. In low to moderate doses for short periods of time (days to weeks), they can greatly reduce pain and inflammation without significant risk, as long as blood pressure is well controlled, and there is no kidney disease, heart disease, intestinal ulceration, or known gastrointestinal inflammation. When used daily for more than a few weeks, the likelihood of serious adverse effects increases.

Inflammation is the body’s normal response to injury and leads to swelling, pain, and sometimes heat and redness. This response is beneficial: it lets us know that we have been injured and that we need to protect the affected body part. Furthermore, the inflammatory response promotes healing by bringing more blood, nutrients, and immune activity to an injured site. NSAIDs can decrease the inflammatory response after trauma to bones, joints, muscles, or tendons, rapidly reducing pain and swelling. When left untreated, serious injuries can develop into chronic pain syndromes due to compensations by other body parts to protect the injured part and to changes in the brain. Other types of inflammation and pain syndromes that occur in the body can result from daily “wear and tear,” inactivity or over-activity, stress, and chronic illness. Because NSAIDs do not treat the root causes of chronic pain syndromes but simply suppress symptoms, they may, over time, intensify or prolong the problem by allowing people to continue the activities that have caused it. (See chapter 12 for more information on medications for chronic pain.)

Recent research has shown chronic inflammation to be associated with depression, and trials of NSAID therapy as a novel treatment for severe depression suggest that it works better than antidepressant drugs in some patients.

THE PROBLEMS WITH NSAIDS

Despite being highly effective at reducing acute and chronic pain, fever, and inflammation, all NSAIDs come with significant risks. The side effects and adverse reactions caused by them impact the stomach, intestines, heart, lungs, blood vessels, and blood cells. Individuals vary in susceptibility to these, based on their health status and disease risks.

The most significant and common adverse effects of NSAIDs occur in the gastrointestinal (GI) tract. Many users will experience stomach pain, flatulence, or some type of stomach irritation with only one dose. The real potential for harm comes with daily use, generally for more than two weeks. When NSAIDs get into the bloodstream and block the COX-1 enzyme, synthesis of prostaglandins decreases. Among other functions, these hormone-like substances protect the stomach lining from acid and other irritants. Over time, deficiency of prostaglandins increases the possibility of gastric bleeding, ulceration, and perforation, any of which can occur in the absence of warning symptoms. Thousands of people die each year from episodes of NSAID-related GI bleeding; many of them had no awareness of the harm the drugs were causing. The decrease in prostaglandins can also damage the small and large intestines, especially in the setting of ulcerative colitis and Crohn’s disease. (The selective COX-2 medication celecoxib has a lesser impact on the GI tract, though it is not entirely without risk.)

NSAIDs also affect our blood cells, particularly platelets. Platelets protect the walls of blood vessels by binding to them to patch holes and keep blood from leaking out of arteries and veins. Aspirin acts in a unique way: it blocks platelets from clumping together to form clots for the entire life of the platelet, which is eight to twelve days. Ibuprofen and other NSAIDs exert this effect for a much shorter time. In the case of a heart attack, platelet blocking is desirable; in other instances—such as an upcoming surgery, intestinal bleeding, or a low platelet count to begin with—it is potentially dangerous.

All these risks need to be considered when deciding whether or not to take aspirin or other NSAIDs.

Aspirin is routinely given to patients who are having a heart attack, and low daily doses of it have been shown to help prevent both heart attacks and strokes. Regular use of NSAIDs other than aspirin can increase blood pressure, worsen heart failure, and increase the risk of death from heart disease. Much research has looked at this. Naproxen (Aleve) appears to increase heart attack risk least and diclofenac (Voltaren) most. The COX-2 inhibitor celecoxib, despite having lower gastrointestinal risk, is the worst of all NSAIDs when it comes to heart disease. Anyone at high risk for heart disease and stroke should avoid it.

NSAIDs also impact the kidneys, which need prostaglandins produced by the COX-2 enzyme to maintain the blood flow that keeps them healthy and functioning. Because all the NSAIDs block this enzyme and decrease renal blood flow, those with kidney disease should not take them. Even in the absence of kidney disease, those who take diuretics (“water pills”) for heart failure or hypertension should be careful, because the combined effects of diuretics and NSAIDs can cause kidney problems.

Drug Interactions

The major category of drugs that can interact with NSAIDs is blood thinners. When taken with any blood thinner, especially warfarin (Coumadin), NSAIDs will increase the risk of GI bleeding. Alcohol intake on its own increases this risk; together with regular use of NSAIDs, alcohol multiplies it. Long-term use of corticosteroids, such as prednisone, can cause stomach ulcers; combined with NSAIDs, the risk is amplified.

The pharmaceutical antidepressants known as selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil), decrease platelet clumping in a different way from NSAIDs. When NSAIDs and SSRIs are taken together, the risk of bleeding increases. Herbal remedies and supplements that affect platelets and should be avoided by those on NSAIDs include danshen (Salvia miltiorrhiza), dong quai (Angelica sinensis), evening primrose oil, and willow bark.

INTEGRATIVE MEDICINE APPROACHES TO TREATING ACUTE INJURY, CHRONIC INFLAMMATION, AND PAIN

Rest, ice, compression, and elevation of an acutely injured limb or body part as soon as possible will decrease swelling and pain and speed recovery. Topical application of tincture of arnica (Arnica montana), as long as the skin is not broken, is also helpful and can reduce bruising.

Lifestyle Change

Lifestyle change is the most useful approach when trying to manage chronic pain syndromes associated with inflammation. Improved diet and exercise can lead to weight loss, and weight loss often reduces chronic pain by decreasing the workload on joints, especially in the knees, hips, and back. In women with hormone-related migraine, exercise helps by lowering estrogen levels.

The single most effective strategy is adopting an anti-inflammatory diet. Over the course of weeks to months, it can decrease inflammation, promote weight loss, and alleviate chronic pain. The anti-inflammatory diet focuses on a diversity of fresh vegetables and fruits, whole grains (as opposed to products made with flour), healthy fats (extra-virgin olive oil in particular, which contains a unique anti-inflammatory compound called oleocanthal), seeds and nuts, oily fish, whole soy foods, healthy herbs and spices (especially turmeric and ginger), tea (white, green, or oolong), and occasional healthy sweets such as dark chocolate or dried fruits. Many of these foods have been shown to decrease chronic inflammatory markers in the body. Notably missing from the anti-inflammatory diet pyramid are many of the foods commonly consumed in the standard American diet (referred to as the SAD diet in some health circles), especially processed and manufactured foods, which are major sources of pro-inflammatory fats and carbohydrates (sugar and flour). Except for fish, eggs, and high-quality dairy products, animal foods are minimized.

Exercise is one of the best-studied treatments for pain. This can include physical therapy following injury (after the swelling has reduced and a professional has cleared the patient for exercise), as well as routine exercise and stretching programs to improve function. Activities like yoga, Pilates, and tai chi can help large-joint pain; walking or swimming can improve sciatic pain and lower back pain; and weight training can strengthen muscles that surround problematic joints, decreasing pain by reducing the burden on the joints themselves. It is important to start exercise slowly and build up steadily. Exercise is also one of the best treatments for insomnia, and it is well established that improved sleep can result in decreased chronic pain.

Smoking is associated with increased chronic pain, including lower back pain, and quitting smoking is likely to result in improvement.

Nutritional Supplements and Botanicals

Several herbal remedies and dietary supplements have been shown to decrease inflammation and treat pain. Arnica can be applied topically, as mentioned above, to the site of an injury to reduce pain and swelling. It has also been shown to decrease pain and swelling after surgery. Additionally, arnica has been shown to decrease pain associated with mild to moderate osteoarthritis. Capsaicin cream is another useful topical product that can decrease pain, particularly nerve pain, as from peripheral neuropathy or an outbreak of shingles. Capsaicin is the compound that gives hot peppers their heat; it can initially cause a mild to moderate burning sensation. The greatest effects are felt after several weeks of use.

Fish oil supplements have consistently been found to decrease chronic inflammation and pain, including arthritis pain, neuropathy, and menstrual cramping. Turmeric is the most powerful natural anti-inflammatory; both the whole spice and its main active component—curcumin—have been shown to decrease inflammatory markers and improve chronic pain associated with inflammation. In fact, curcumin supplementation has been found to be as effective as ibuprofen for osteoarthritis of the knee, without any of the troubling side effects of that drug. Extracts of a familiar relative of turmeric—ginger—have been shown to modestly improve pain associated with osteoarthritis of the knee.

Other Therapies

Manual therapies such as massage, chiropractic, and osteopathic manipulation can be effective for chronic pain management. Most research using these modalities has focused on lower back pain. Acupuncture can also work as an alternative to chronic NSAID use for a number of painful conditions, including menstrual cramps, chronic lower back pain, joint pain, dental pain, and migraine or tension headache.

Mind-body approaches, such as hypnosis, guided imagery, and guided meditation, can provide relief by teaching patients to change their perception of painful sensations.

Clearly, there are a number of possibilities to help manage pain before reaching for an anti-inflammatory medication.

BOTTOM LINE

Widespread use and easy availability of nonsteroidal anti-inflammatory drugs promote the mistaken belief that these drugs are perfectly safe. Many people take them regularly and thoughtlessly. In fact, they are powerful medications with significant potential for harm when used long term. For chronic pain syndromes, they should never be the sole treatment. Integrative medicine offers many ways to manage chronic pain, so that NSAIDs are required intermittently or not at all.